Pathophysiology doi: 10.3390/pathophysiology31010013
Authors: Travis Nemkov Francesca Cendali Monika Dzieciatkowska Daniel Stephenson Kirk C. Hansen Catherine M. Jankowski Angelo D’Alessandro Ryan J. Marker
To molecularly characterize the impact of exercise on mitigating neoadjuvant treatment (NAT)-induced physical decline in pancreatic ductal adenocarcinoma (PDAC) patients, a multi-omics approach was employed for the analysis of plasma samples before and after a personalized exercise intervention. Consisting of personalized aerobic and resistance exercises, this intervention was associated with significant molecular changes that correlated with improvements in lean mass, appendicular skeletal muscle index (ASMI), and performance in the 400-m walk test (MWT) and sit-to-stand test. These alterations indicated exercise-induced modulation of inflammation and mitochondrial function markers. This case study provides proof-of-principal application for multiomics-based assessments of supervised exercise, thereby supporting this intervention as a feasible and beneficial intervention for PDAC patients to potentially enhance treatment response and patient quality of life. The molecular changes observed here underscore the importance of physical activity in cancer treatment protocols, advocating for the development of accessible multiomics-guided exercise programs for cancer patients.
]]>Pathophysiology doi: 10.3390/pathophysiology31010012
Authors: Chet Brazile Ruping Fan Beau Benoit Thomas Arnold Nadejda Korneeva
Opioid abuse in the United States has been increasing at an alarming rate over the past 20 years. Sex differences are documented for the rates of opioid-related overdoses, abuse patterns, and drug-induced physiological effects. In our previous study, we demonstrated that chronic oxycodone administration in young female rats is associated with neurodegeneration in the brain. Males and females are susceptible to neurodegenerative diseases via differing mechanisms. To investigate whether opioid exposure affects males and females differently, we treated young mice with chronic morphine. We observed that females had stronger antinociceptive responses to acute morphine and showed a delayed development of tolerance. Males had a higher basal Bax level in the brain that correlated with a higher number of apoptotic cells. Morphine increased Bax levels in both males and females without affecting the numbers of apoptotic cells. Morphine increased activated caspase 3 in axons and increased the MBP level in plasma only in females, suggesting a demyelination process. Our data suggest that males are protected from demyelination by having a higher basal BDNF level. Altogether, our results suggest that males and females have different molecular signaling underlying their patterns in the development of morphine tolerance and drug-induced neuronal degeneration.
]]>Pathophysiology doi: 10.3390/pathophysiology31010011
Authors: Anatolii Kubyshkin Sergey Bolevich Leonid Churilov Vladimir Jakovljevic Evgeniia Kovalenko Aleksandr Korovin
This article provides a summary of the 9th International Congress of the International Society for Pathophysiology (ISP 2023) which took place in Belgrade, Serbia, from 4 to 6 July 2023. It describes the main trends and the most promising areas of research in current pathophysiology, including investigations of new pathogenic pathways, and the identification of cellular and molecular mechanisms, target molecules, genetic mechanisms, and new therapeutic strategies. The present article also highlights the research conducted by leading scientific teams and national pathophysiological societies from various countries that adds to our understanding of the pathogenesis of diseases and pathological processes.
]]>Pathophysiology doi: 10.3390/pathophysiology31010010
Authors: Anna Yu. Ryabinina Anna A. Bryk Mikhail L. Blagonravov Vyacheslav A. Goryachev Andrey A. Mozhaev Vera S. Ovechkina
Changes in lighting accompany modern urbanization trends and can lead to various pathologies based on circadian disturbances. In this study, we assessed the changes in the circadian rhythm of core body temperature (Tcore) and locomotor activity of Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) following exposure to different lighting conditions: extended light phase of the day (16 h–8 h, 20 h–4 h, 24 h–0 h), light pollution, monochromatic light, and bright light therapy. The telemetry data was collected after experimental lighting conditions during periods with standard lighting (12 h of light and 12 h of darkness) and was processed using linear and cosinor analysis. The daily rhythms of rats’ parameters persisted in accordance with the standard lighting regime. Tcore changes were observed in both groups compared to the initial period: in WKY, a decrease in Tcore during the darkness and an increase during the light; in SHR, the opposite trend, with Tcore increased during the darkness and decreased during the light phase of the day. A relationship between Tcore and activity was observed with weak correlation. WKY exhibited more pronounced signs of adaptive variation and desynchronization compared to SHR, which could be associated with a wider range of functional capabilities of the organism without cardiovascular pathology.
]]>Pathophysiology doi: 10.3390/pathophysiology31010009
Authors: Olanrewaju Oladosu Emma Chin Christian Barksdale Rhonda R. Powell Terri Bruce Alexis Stamatikos
Atherosclerosis is caused by cholesterol accumulation within arteries. The intima is where atherosclerotic plaque accumulates and where lipid-laden foam cells reside. Intimal foam cells comprise of both monocyte-derived macrophages and macrophage-like cells (MLC) of vascular smooth muscle cell (VSMC) origin. Foam cells can remove cholesterol via apoAI-mediated cholesterol efflux and this process is regulated by the transporter ABCA1. The microRNA miR-33a-5p is thought to be atherogenic via silencing ABCA1 which promotes cholesterol retention and data has shown inhibiting miR-33a-5p in macrophages may be atheroprotective via enhancing apoAI-mediated cholesterol efflux. However, it is not entirely elucidated whether precisely inhibiting miR-33a-5p in MLC also increases ABCA1-dependent cholesterol efflux. Therefore, the purpose of this work is to test the hypothesis that inhibition of miR-33a-5p in cultured MLC enhances apoAI-mediated cholesterol efflux. In our study, we utilized the VSMC line MOVAS cells in our experiments, and cholesterol-loaded MOVAS cells to convert this cell line into MLC. Inhibition of miR-33a-5p was accomplished by transducing cells with a lentivirus that expresses an antagomiR directed at miR-33a-5p. Expression of miR-33a-5p was analyzed by qRT-PCR, ABCA1 protein expression was assessed via immunoblotting, and apoAI-mediated cholesterol efflux was measured using cholesterol efflux assays. In our results, we demonstrated that lentiviral vector-mediated knockdown of miR-33a-5p resulted in decreasing expression of this microRNA in cultured MLC. Moreover, reduction of miR-33a-5p in cultured MLC resulted in de-repression of ABCA1 expression, which caused ABCA1 protein upregulation in cultured MLC. Additionally, this increase in ABCA1 protein expression resulted in enhancing ABCA1-dependent cholesterol efflux through increasing apoAI-mediated cholesterol efflux in cultured MLC. From these findings, we conclude that inhibiting miR-33a-5p in MLC may protect against atherosclerosis by promoting ABCA1-dependent cholesterol efflux.
]]>Pathophysiology doi: 10.3390/pathophysiology31010008
Authors: Shoya Fukatsu Hinami Sashi Remina Shirai Norio Takagi Hiroaki Oizumi Masahiro Yamamoto Katsuya Ohbuchi Yuki Miyamoto Junji Yamauchi
Abnormal nucleotide insertions of C9orf72, which forms a complex with Smith–Magenis syndrome chromosomal region candidate gene 8 (SMCR8) protein and WD repeat-containing protein 41 (WDR41) protein, are associated with an autosomal-dominant neurodegenerative frontotemporal dementia and/or amyotrophic lateral sclerosis type 1 (FTDALS1). The differentially expressed in normal and neoplastic cells (DENN) domain-containing C9orf72 and its complex with SMCR8 and WDR41 function as a guanine-nucleotide exchange factor for Rab GTP/GDP-binding proteins (Rab GEF, also called Rab activator). Among Rab proteins serving as major effectors, there exists Rab11a. However, it remains to be established which Rab protein is related to promoting or sustaining neuronal morphogenesis or homeostasis. In this study, we describe that the knockdown of Rab11a decreases the expression levels of neuronal differentiation marker proteins, as well as the elongation of neurite-like processes, using N1E-115 cells, a well-utilized neuronal differentiation model. Similar results were obtained in primary cortical neurons. In contrast, the knockdown of Rab11b, a Rab11a homolog, did not significantly affect their cell morphological changes. It is of note that treatment with hesperetin, a citrus flavonoid (also known as Vitamin P), recovered the neuronal morphological phenotypes induced by Rab11a knockdown. Also, the knockdown of Rab11a or Rab11b led to a decrease in glial marker expression levels and in morphological changes in FBD-102b cells, which serve as the oligodendroglial differentiation model. Rab11a is specifically involved in the regulation of neuronal morphological differentiation. The knockdown effect mimicking the loss of function of C9orf72 is reversed by treatment with hesperetin. These findings may reveal a clue for identifying one of the potential molecular and cellular phenotypes underlying FTDALS1.
]]>Pathophysiology doi: 10.3390/pathophysiology31010007
Authors: Ivan A. Alvarez Minsup Lee Randa S. Eshaq Wendy Leskova Norman R. Harris
Our purpose in this study was to identify the role played by oxidative stress in the changes to proteoglycans that occur under hyperglycemic conditions, using primary rat retinal microvascular endothelial cells (RRMEC) and cultured ophthalmic arteries. The cells and blood vessels obtained from rats were cultured in normal glucose (5.6 mM) and high glucose (25 mM) with or without N-acetylcysteine (NAC), an antioxidant. Intracellular oxidative stress was determined by measuring dihydroethidium (DHE) fluorescence and malondialdehyde (MDA)-modified protein levels. mRNA and protein levels were evaluated using quantitative real-time polymerase chain reaction and immunoblot, respectively. High glucose increased levels of glypican-1 mRNA and protein. The level of syndecan-1 mRNA also was increased, but its protein level was decreased, by high glucose. Evaluation of DHE and MDA showed that high glucose increased oxidative stress. These changes caused by high glucose were significantly reversed by NAC treatment. Matrix metalloproteinase-9 (MMP-9) levels, which increased under high glucose conditions, were suppressed by NAC treatment. Oxidative stress caused by hyperglycemia may be responsible for significant changes to the ocular endothelial glycocalyx.
]]>Pathophysiology doi: 10.3390/pathophysiology31010006
Authors: Wendi Zhao Prabhath Kodancha Soumitra Das
Anorexia nervosa (AN) remains a challenging condition in psychiatric management and its pathogenesis is not yet fully understood. An imbalance in the gut microbiota composition may contribute to its pathophysiology. This review aims to explore the link between the human gut microbiota and AN (objective 1) or refeeding syndrome in AN (objective 2). The online databases MEDLINE and PsycINFO were searched for relevant studies. A total of 14 studies met the inclusion and exclusion criteria and only answered objective 1. A total of 476 AN patients, 554 healthy-weight (HC) controls, and 0 patients with other psychiatric disorders were included. Compared to HC, there were consistently reduced abundances of Faecalibacterium prausnitzii and Roseburia inulinivorans, and increased Methanobrevibacter smithii, in AN patients. Changes in alpha diversity were inconsistent, while beta diversity increased in four of six studies. Our model suggests that an imbalance in gut microbiota composition leads to reduced short-chain fatty acids, contributing to a proinflammatory state in AN, which is also common in other psychiatric comorbidities. Microbial changes may also contribute to the semistarvation state through endocrine changes and altered energy utilization.
]]>Pathophysiology doi: 10.3390/pathophysiology31010005
Authors: Emilio Jirillo Raffaele Palmirotta Marica Colella Luigi Santacroce
For a long time, urine has been considered sterile in physiological conditions, thanks to the particular structure of the urinary tract and the production of uromodulin or Tamm–Horsfall protein (THP) by it. More recently, thanks to the development and use of new technologies, i.e., next-generation sequencing and expanded urine culture, the identification of a microbial community in the urine, the so-called urobiota, became possible. Major phyla detected in the urine are represented by Firmicutes, Bacteroidetes, Proteobacteria, and Actinobacteria. Particularly, the female urobiota is largely represented by Lactobacillus spp., which are very active against urinary pathogenic Escherichia (E.) coli (UPEC) strains via the generation of lactic acid and hydrogen peroxide. Gut dysbiosis accounts for recurrent urinary tract infections (UTIs), so-called gut–bladder axis syndrome with the formation of intracellular bacterial communities in the course of acute cystitis. However, other chronic urinary tract infections are caused by bacterial strains of intestinal derivation. Monomicrobial and polymicrobial infections account for the outcome of acute and chronic UTIs, even including prostatitis and chronic pelvic pain. E. coli isolates have been shown to be more invasive and resistant to antibiotics. Probiotics, fecal microbial transplantation, phage therapy, antimicrobial peptides, and immune-mediated therapies, even including vaccines for the treatment of UTIs, will be described.
]]>Pathophysiology doi: 10.3390/pathophysiology31010004
Authors: Mijo Meter Josip Andelo Borovac
An electrical storm (ES) is defined as the presence of at least three episodes of sustained ventricular tachycardia or ventricular fibrillation within 24 h. This patient had a previously known arterial hypertension, type II diabetes mellitus, and chronic kidney disease and has presented to the Emergency Department (ED) with symptoms of retrosternal chest pain lasting for several hours prior. The initial 12-lead electrocardiogram revealed ST segment elevation in the anterior leads (V1–V6). Emergent coronary angiography revealed an acute occlusion of the proximal left anterior descending artery (pLAD) and percutaneous coronary intervention was performed with successful implantation of one drug-eluting stent in the pLAD. On day 8 of hospitalization, the patient developed a refractory ES for which he received 50 DC shocks and did not respond to multiple lines of antiarrhythmic medications. Due to a failure of medical therapy, we decided to implant a temporary pacemaker and initiate ventricular overdrive pacing (VOP) that was successful in terminating ES. Following electrical stabilization, the patient underwent a successful ICD implantation. This case demonstrates that VOP can contribute to hemodynamic and electrical stabilization of a patient that suffers from refractory ES and this treatment modality might serve as a temporary bridge to ICD implantation.
]]>Pathophysiology doi: 10.3390/pathophysiology31010003
Authors: Matthew Leonard Repp Ikeotunye Royal Chinyere
The use of catheter-based irreversible electroporation in clinical cardiac laboratories, termed pulsed-field ablation (PFA), is gaining international momentum among cardiac electrophysiology proceduralists for the non-thermal management of both atrial and ventricular tachyrhythmogenic substrates. One area of potential application for PFA is in the mitigation of ventricular tachycardia (VT) risk in the setting of ischemia-mediated myocardial fibrosis, as evidenced by recently published clinical case reports. The efficacy of tissue electroporation has been documented in other branches of science and medicine; however, ventricular PFA’s potential advantages and pitfalls are less understood. This comprehensive review will briefly summarize the pathophysiological mechanisms underlying VT and then summarize the pre-clinical and adult clinical data published to date on PFA’s effectiveness in treating monomorphic VT. These data will be contrasted with the effectiveness ascribed to thermal cardiac ablation modalities to treat VT, namely radiofrequency energy and liquid nitrogen-based cryoablation.
]]>Pathophysiology doi: 10.3390/pathophysiology31010002
Authors: Luigi Santacroce Skender Topi Ioannis Alexandros Charitos Roberto Lovero Paolo Luperto Raffaele Palmirotta Emilio Jirillo
Superantigens, i.e., staphylococcal enterotoxins and toxic shock syndrome toxin-1, interact with T cells in a different manner in comparison to conventional antigens. In fact, they activate a larger contingent of T lymphocytes, binding outside the peptide-binding groove of the major histocompatibility complex class II. Involvement of many T cells by superantigens leads to a massive release of pro-inflammatory cytokines, such as interleukin (IL)-1, IL-2, IL-6, tumor necrosis factor-alpha and interferon-gamma. Such a storm of mediators has been shown to account for tissue damage, multiorgan failure and shock. Besides conventional drugs and biotherapeutics, experiments with natural and biological products have been undertaken to attenuate the toxic effects exerted by superantigens. In this review, emphasis will be placed on polyphenols, probiotics, beta-glucans and antimicrobial peptides. In fact, these substances share a common functional denominator, since they skew the immune response toward an anti-inflammatory profile, thus mitigating the cytokine wave evoked by superantigens. However, clinical applications of these products are still scarce, and more trials are needed to validate their usefulness in humans.
]]>Pathophysiology doi: 10.3390/pathophysiology31010001
Authors: Varvara A. Ryabkova Artemiy V. Rubinskiy Valeriy N. Marchenko Vasiliy I. Trofimov Leonid P. Churilov
Background: There is a considerable overlap between the clinical presentation of post-COVID-19 condition (PCC) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Many of their common symptoms can be linked to dysregulation of the autonomic nervous system (dysautonomia). This study aimed to objectively assess autonomic function in a general group of patients with PCC and in a group of patients with ME/CFS whose disease was not related to COVID-19. We hypothesize that the similarity in the chronic symptoms of patients with PCC and ME/CFS extends to objective autonomic nervous system abnormalities. Methods: Synchronous recordings of an electrocardiogram and continuous dynamics of blood pressure in the digital artery using the Penaz method were obtained using the spiroarteriocardiorhythmography method in 34 patients diagnosed with ME/CFS, in whom the onset of the disease was not associated with COVID-19, 29 patients meeting the PCC definition and 32 healthy controls. Heart rate variability (HRV) and systolic and diastolic blood pressure variability (BPV) were assessed at rest and in tests with fixed respiratory rates. Indicators of baroreflex regulation (baroreflex effectiveness index and baroreflex sensitivity) were additionally determined at rest. Results: The total power and power of low-frequency and high-frequency of RR interval variability at rest as well as baroreflex sensitivity were significantly lower both in PCC and ME/CFS patients compared to healthy controls. Several diagnostic prediction models for ME/CFS were developed based on HRV parameters. During slow breathing, the HRV parameters returned to normal in PCC but not in ME/CFS patients. The correlation analysis revealed a close relationship of HRV, BPV parameters and baroreflex sensitivity with fatigue, but not with HADS depressive/anxiety symptoms in the ME/CFS and PCC patients. Conclusions: A similar pattern of HRV and baroreflex failure with signs of a pathological acceleration of age-dependent dysautonomia was identified in the ME/CFS and PCC patients. The clinical, diagnostic and therapeutic implications of these findings are discussed, in light of previously described relationships between inflammation, vascular pathology, atherosclerotic cardiovascular disease and autonomic dysfunction.
]]>Pathophysiology doi: 10.3390/pathophysiology30040046
Authors: Elena Zelikovna Golukhova Inessa Viktorovna Slivneva Olga Sergeevna Kozlova Bektur Shukurbekovich Berdibekov Ivan Ivanovich Skopin Vadim Yuryevich Merzlyakov Renat Kamilyevich Baichurin Igor Yuryevich Sigaev Milena Abrekovna Keren Mikhail Durmishkhanovich Alshibaya Damir Ildarovich Marapov Milena Artemovna Arzumanyan
In this meta-analysis, we examine the advantages of invasive strategies for patients diagnosed with chronic coronary heart disease (CHD) and preserved left ventricular (LV) function, as well as those with significant LV systolic dysfunction (LV ejection fraction (EF) < 45%). Material and methods: We conducted a systematic search to identify all randomized trials directly comparing invasive strategies with optimal medical therapy (OMT) in patients diagnosed with chronic CHD. Data from these trials were pooled using a random-effects meta-analysis. The primary outcome assessed was the all-cause mortality, while secondary endpoints included cardiovascular (CV) death, stroke, myocardial infarction (MI), and unplanned revascularization. This study was designed to assess the benefits of both invasive strategies and OMT in patients with preserved LV function and in those with LV systolic dysfunction. The statistical analysis of the data was conducted using the Review Manager (RevMan) software, version 5.4.1 (The Cochrane Collaboration, 2020). Results: Twelve randomized studies enrolling 13,912 patients were included in the final analysis. Among the patients with chronic CHD and preserved LV systolic function, revascularization did not demonstrate a reduction in all-cause mortality (8.52% vs. 8.45%, p = 0.45), CV death (3.41% vs. 3.62%, p = 0.08), or the incidence of MI (9.88% vs. 10.49%, p = 0.47). However, the need for unplanned myocardial revascularization was significantly lower in the group following the initial invasive approach compared to patients undergoing OMT (14.75% vs. 25.72%, p < 0.001). In contrast, the invasive strategy emerged as the preferred treatment modality for patients with ischemic LV systolic dysfunction. This approach demonstrated lower rates of all-cause mortality (40.61% vs. 46.52%, p = 0.004), CV death (28.75% vs. 35.82%, p = 0.0004), and MI (8.19% vs. 10.8%, p = 0.03). Conclusions: In individuals diagnosed with chronic CHD and preserved LV EF, the initial invasive approach did not demonstrate a clinical advantage over OMT. Conversely, in patients with ischemic LV systolic dysfunction, myocardial revascularization was found to reduce the risks of CV events and enhance the overall outcomes. These findings hold significant clinical relevance for optimizing treatment strategies in patients with chronic CHD, contingent upon myocardial contractility status.
]]>Pathophysiology doi: 10.3390/pathophysiology30040045
Authors: Thiago Guedes Pinto Milena de Barros Viana Patricia Ramos Cury Manoela Domingues Martins Jean Nunes dos Santos Daniel Araki Ribeiro
The aim of this systematic review was to answer the question of whether crack cocaine can induce cellular and molecular alterations and whether such alterations are somehow related to clinical lesions in the oral mucosa. The searches were undertaken in three electronic databases and conducted based on the PRISMA 2020 statement. Eleven studies published between 1994 and 2020 were analyzed. The quality of the included studies was assessed by two independent reviewers (TGP and DAR) through a confounder’s categorization methodology, in which final ratings were attributed (strong, moderate or weak) for each study. From 11 studies included, 7 evaluated the cellular/molecular impact of the addiction in a total of 492 individuals and compared to a control (non-exposure) group (n = 472). The main tests used for cellular alteration were MN and AgNORs. Cells from crack cocaine groups exhibited increased proliferation and MN counting. Only four studies evaluated the prevalence of oral lesions. All of them showed that individuals exposed to crack cocaine presented an increased number of oral lesions. Most studies showed good quality. In conclusion, our results demonstrate that crack use may induce changes at the cellular and molecular level and also exhibit an increased number of oral lesions. However, a correlation between such changes and oral mucosa lesions still needs further investigation and elucidation through other clinical studies in humans.
]]>Pathophysiology doi: 10.3390/pathophysiology30040044
Authors: Hannah R. Popper Brian E. Fliegel Dawn M. Elliott Alvin W. Su
The menisci increase the contact area of load bearing in the knee and thus disperse the mechanical stress via their circumferential tensile fibers. Traumatic meniscus injuries cause mechanical symptoms in the knee, and are more prevalent amongst younger, more active patients, compared to degenerative tears amongst the elderly population. Traumatic meniscus tears typically result from the load-and-shear mechanism in the knee joint. The treatment depends on the size, location, and pattern of the tear. For non-repairable tears, partial or total meniscal resection decreases its tensile stress and increases joint contact stress, thus potentiating the risk of arthritis. A longitudinal vertical tear pattern at the peripheral third red-red zone leads to higher healing potential after repair. The postoperative rehabilitation protocols after repair range from immediate weight-bearing with no range of motion restrictions to non-weight bearing and delayed mobilization for weeks. Pediatric and adolescent patients may require special considerations due to their activity levels, or distinct pathologies such as a discoid meniscus. Further biomechanical and biologic evidence is needed to guide surgical management, postoperative rehabilitation protocols, and future technology applications for traumatic meniscus injuries.
]]>Pathophysiology doi: 10.3390/pathophysiology30040043
Authors: Masatoshi Hayashi
The pathophysiology of myasthenia gravis (MG) has been largely elucidated over the past half century, and treatment methods have advanced. However, the number of cases of childhood-onset MG is smaller than that of adult MG, and the treatment of childhood-onset MG has continued to be based on research in the adult field. Research on pathophysiology and treatment methods that account for the unique growth and development of children is now desired. According to an epidemiological survey conducted by the Ministry of Health, Labour and Welfare of Japan, the number of patients with MG by age of onset in Japan is high in early childhood. In recent years, MG has been reported from many countries around the world, but the pattern of the number of patients by age of onset differs between East Asia and Western Europe, confirming that the Japanese pattern is common in East Asia. Furthermore, there are racial differences in autoimmune MG and congenital myasthenic syndromes according to immunogenetic background, and their pathophysiology and relationships are gradually becoming clear. In addition, treatment options are also recognized in different regions of the world. In this review article, I will present recent findings focusing on the differences in pathophysiology.
]]>Pathophysiology doi: 10.3390/pathophysiology30040042
Authors: Nana Gogiberidze Aleksandr Suvorov Elizaveta Sultygova Zhanna Sagirova Natalia Kuznetsova Daria Gognieva Petr Chomakhidze Victor Frolov Aleksandra Bykova Dinara Mesitskaya Alena Novikova Danila Kondakov Alexey Volovchenko Stefano Omboni Philippe Kopylov
It would be useful to develop a reliable method for the cuffless measurement of blood pressure (BP), as such a method could be made available anytime and anywhere for the effective screening and monitoring of arterial hypertension. The purpose of this study is to evaluate blood pressure measurements through a CardioQVARK device in clinical practice in different patient groups. Methods: This study involved 167 patients aged 31 to 88 years (mean 64.2 ± 7.8 years) with normal blood pressure, high blood pressure, and compensated high blood pressure. During each session, three routine blood pressure measurements with intervals of 30 s were taken using a sphygmomanometer with an appropriate cuff size, and the mean value was selected for comparison. The measurements were carried out by two observers trained at the same time with a reference sphygmomanometer using a Y-shaped connector. In the minute following the last cuff-based measurements, an electrocardiogram (ECG) with an I-lead and a photoplethysmocardiogram were recorded simultaneously for 3 min with the CardioQVARK device. We compared the systolic and diastolic BP obtained from a cuff-based mercury sphygmomanometer and smartphone-case-based BP device: the CardioQVARK monitor. A statistical analysis plan was developed using the IEEE Standard for Wearable Cuffless Blood Pressure Devices. Bland–Altman plots were used to estimate the precision of cuffless measurements. Results: The mean difference between the values defined by CardioQVARK and the cuff-based sphygmomanometer for systolic blood pressure (SBP) was 0.31 ± 3.61, while that for diastolic blood pressure (DBP) was 0.44 ± 3.76. The mean absolute difference (MAD) for SBP was 3.44 ± 2.5 mm Hg, and that for DBP was 3.21 ± 2.82 mm Hg. In the subgroups, the smallest error (less than 3 mm Hg) was observed in the prehypertension group, with a slightly larger error (up to 4 mm Hg) found among patients with a normal blood pressure and stage 1 hypertension. The largest error was found in the stage 2 hypertension group (4–5.5 mm Hg). The largest error was 4.2 mm Hg in the high blood pressure group. We, therefore, did not record an error in excess of 7 mmHg, the upper boundary considered acceptable in the IEEE recommendations. We also did not reach a mean error of 5 mmHg, the upper boundary considered acceptable according to the very recent ESH recommendations. At the same time, in all groups of patients, the systolic blood pressure was determined with an error of less than 5 mm Hg in more than 80% of patients. While this study shows that the CardioQVARK device meets the standards of IEEE, the Bland–Altman analysis indicates that the cuffless measurement of diastolic blood pressure has significant bias. The difference was very small and unlikely to be of clinical relevance for the individual patient, but it may well have epidemiological relevance on a population level. Therefore, the CardioQVARK device, while being worthwhile for monitoring patients over time, may not be suitable for screening purposes. Cuffless blood pressure measurement devices are emerging as a convenient and tolerable alternative to cuff-based devices. However, there are several limitations to cuffless blood pressure measurement devices that should be considered. For instance, this study showed a high proportion of measurements with a measurement error of <5 mmHg, while detecting a small, although statistically significant, bias in the measurement of diastolic blood pressure. This suggests that this device may not be suitable for screening purposes. However, its value for monitoring BP over time is confirmed. Furthermore, and most importantly, the easy measurement method and the device portability (integrated in a smartphone) may increase the self-awareness of hypertensive patients and, potentially, lead to an improved adherence to their treatment. Conclusion: The cuffless blood pressure technology developed in this study was tested in accordance with the IEEE protocol and showed great precision in patient groups with different blood pressure ranges. This approach, therefore, has the potential to be applied in clinical practice.
]]>Pathophysiology doi: 10.3390/pathophysiology30040041
Authors: Magdy Y. Elsaeed Osama Mahmoud Mehanna Ezz-Eldin E. Abd-Allah Mohamed Gaber Hassan Walid Mostafa Said Ahmed Abd El Ghany A. Moustafa Gaber E. Eldesoky Amal M. Hammad Usama Bahgat Elgazzar Mohamed R. Elnady Fatma M. Abd-Allah Walaa M. Shipl Amr Mohamed Younes Mostafa Rizk Magar Ahmed E. Amer Mohamed Ali Mahmoud Abbas Khaled Saleh Ali Elhamaky Mohammed Hussien Mohammed Hassan
Background: As the impacts of diabetes-induced reproductive damage are now evident in young people, we are now in urgent need to devise new ways to protect and enhance the reproductive health of diabetic people. The present study aimed to evaluate the protective effects of enalapril (an ACE inhibitor) and paricalcitol (a vitamin D analog), individually or in combination, on streptozotocin (STZ)-diabetes-induced testicular dysfunction in rats and to identify the possible mechanisms for this protection. Material and methods: This study was carried out on 50 male Sprague-Dawley rats; 10 normal rats were allocated as a non-diabetic control group. A total of 40 rats developed diabetes after receiving a single dose of STZ; then, the diabetic rats were divided into four groups of equivalent numbers assigned as diabetic control, enalapril-treated, paricalcitol-treated, and combined enalapril-and-paricalcitol-treated groups. The effects of mono and combined therapy with paricalcitol and enalapril on testicular functions, sperm activity, glycemic state oxidative stress, and inflammatory parameters, as well as histopathological examinations, were assessed in comparison with the normal and diabetic control rats. Results: As a result of diabetes induction, epididymal sperm count, sperm motility, serum levels of testosterone, follicle-stimulating hormone (FSH) as well as luteinizing hormone (LH), and the antioxidant enzyme activities, were significantly decreased, while abnormal sperm (%), insulin resistance, nitric oxide (NO), malondialdehyde (MDA), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) were significantly increased, along with severe distortion of the testicular structure. Interestingly, treatment with paricalcitol and enalapril, either alone or in combination, significantly improved the sperm parameters, increased antioxidant enzyme activities in addition to serum levels of testosterone, FSH, and LH, reduced insulin resistance, IL-6, and TNF-α levels, and finally ameliorated the diabetes-induced testicular oxidative stress and histopathological damage, with somewhat superior effect for paricalcitol monotherapy and combined therapy with both drugs compared to monotherapy with enalapril alone. Conclusions: Monotherapy with paricalcitol and its combination therapy with enalapril has a somewhat superior effect in improving diabetes-induced testicular dysfunction (most probably as a result of their hypoglycemic, antioxidant, anti-inflammatory, and anti-apoptotic properties) compared with monotherapy with enalapril alone in male rats, recommending a synergistic impact of both drugs.
]]>Pathophysiology doi: 10.3390/pathophysiology30040040
Authors: Miyu Okabe Yuki Miyamoto Yuta Ikoma Mikito Takahashi Remina Shirai Mutsuko Kukimoto-Niino Mikako Shirouzu Junji Yamauchi
Autism spectrum disorder (ASD) is a neurodevelopmental disorder that includes autism, Asperger’s syndrome, and pervasive developmental disorder. ASD is characterized by poor interpersonal relationships and strong attachment. The correlations between activated or inactivated gene products, which occur as a result of genetic mutations affecting neurons in ASD patients, and ASD symptoms are now of critical concern. Here, for the first time, we describe the process in which that the respective ASD-associated mutations (Arg676-to-Cys [R676C] and Ser951-to-Cys [S951C]) of semaphorin-5A (Sema5A) localize Sema5A proteins themselves around the plasma membrane in the N1E-115 cell line, a model line that can achieve neuronal morphological differentiation. The expression of each mutated construct resulted in the promotion of excessive elongation of neurite-like processes with increased differentiation protein markers; R676C was more effective than S951C. The differentiated phenotypes were very partially neutralized by an antibody, against Plexin-B3 as the specific Sema5A receptor, suggesting that the effects of Sema5A act in an autocrine manner. R676C greatly increased the activation of c-Jun N-terminal kinase (JNK), one of the signaling molecules underlying process elongation. In contrast, the blocking of JNK signaling, by a chemical JNK inhibitor or an inhibitory construct of the interaction of RhoG with Elmo1 as JNK upstream signaling molecules, recovered the excessive process elongation. These results suggest that ASD-associated mutations of Sema5A, acting through the JNK signaling cascade, lead to excessive differentiated phenotypes, and the inhibition of JNK signaling recovers them, revealing possible therapeutic targets for recovering the potential molecular and cellular phenotypes underlying certain ASD symptoms.
]]>Pathophysiology doi: 10.3390/pathophysiology30040039
Authors: Josue Enriquez Brianyell McDaniel Mims Stephanie Stroever Andrea Pires dos Santos Yava Jones-Hall Kathryn L. Furr Matthew B. Grisham
The objective of this study was to determine how housing temperature and genetic diversity affect the onset and severity of allogeneic T cell-induced tissue damage in mice subjected to reduced intensity conditioning (RIC). We found that adoptive transfer of allogeneic CD4+ T cells from inbred donors into sub-lethally irradiated inbred recipients (I→I) housed at standard housing temperatures (ST; 22–24 °C) induced extensive BM and spleen damage in the absence of injury to any other tissue. Although engraftment of T cells in RIC-treated mice housed at their thermo-neutral temperature (TNT; 30–32 °C) also developed similar BM and spleen damage, their survival was markedly and significantly increased when compared to their ST counterparts. In contrast, the adoptive transfer of allogeneic T cells into RIC-treated outbred CD1 recipients failed to induce disease in any tissue at ST or TNT. The lack of tissue damage was not due to defects in donor T cell trafficking to BM or spleen but was associated with the presence of large numbers of B cells and myeloid cells within these tissues that are known to contain immunosuppressive regulatory B cells and myeloid-derived suppressor cells. These data demonstrate, for the first time, that housing temperature affects the survival of RIC-treated I→I mice and that RIC-conditioned outbred mice are resistant to allogeneic T cell-induced BM and spleen damage.
]]>Pathophysiology doi: 10.3390/pathophysiology30040038
Authors: Maria Y. Boboshko Irina V. Savenko Ekaterina S. Garbaruk Veronika M. Knyazeva Marina J. Vasilyeva
Prematurity is one of the most crucial risk factors negatively affecting the maturation of the auditory system. Children born preterm demonstrate high rates of hearing impairments. Auditory processing difficulties in preterm children might be a result of disturbances in the central auditory system development and/or sensory deprivation due to peripheral hearing loss. To investigate auditory processing in preterm children, we utilized a set of psychoacoustic tests to assess temporal processing and speech intelligibility. A total of 241 children aged 6–11 years old (136 born preterm and 105 healthy full-term children forming the control group) were assessed. The preterm children were divided into three groups based on their peripheral hearing status: 74 normal hearing (NH group); 30 children with bilateral permanent sensorineural hearing loss (SNHL group) and 32 children with bilateral auditory neuropathy spectrum disorder (ANSD group). The results showed significantly worse performance in all tests in premature children compared with full-term children. NH and SNHL groups showed significant age-related improvement in speech recognition thresholds in noise that might signify a “bottom-up” auditory processing maturation effect. Overall, all premature children had signs of auditory processing disorders of varying degrees. Analyzing and understanding the auditory processing specificity in preterm children can positively contribute to the more effective implementation of rehabilitation programs.
]]>Pathophysiology doi: 10.3390/pathophysiology30040037
Authors: Aleksey Maksimovich Radovskiy Andrey Evgenevich Bautin Alexander Olegovich Marichev Victor Vasilyevich Osovskikh Natalia Yuryevna Semenova Zoya Evgenyevna Artyukhina Lada Aleksandrovna Murashova Vsevolod Alexandrovich Zinserling
Objective. To evaluate the effect of NO added to the sweep gas of the oxygenator during cardiopulmonary bypass (CPB) on the liver and kidneys in pigs. Methods. An experiment was carried out on 10 pigs undergoing cardiac surgery using CPB. NO was added to the sweep gas of the oxygenator at a concentration of 100 ppm for the animals in the experimental group (CPB-NO, n = 5). Animals in the control group (CPB-contr, n = 5) did not receive NO in the sweep gas of the oxygenator. The CPB lasted 4 h, followed by postoperative monitoring for 12 h. To assess the injury to the liver and kidneys, the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin, creatinine, and neutrophil gelatinase-associated lipocalin (NGAL) were determined initially, at weaning from the CPB, and 6 and 12 h after weaning from the CPB. The glomerular filtration rate (GFR) was evaluated initially, at weaning from the CPB, and 6 and 12 h after weaning from the CPB. A pathomorphological study of the liver and kidneys was performed using semiquantitative morphometry. Results. The long four-hour period of CPB deliberately used in our experiment caused liver and kidney injury. In the CPB-contr group, an increase in the ALT concentration was found: 43 (34; 44) U/L at baseline to 82 (53; 99) U/L 12 h after CPB, p < 0.05. The AST concentration in the CPB-contr group increased from 25 (17; 26) U/L at baseline to 269 (164; 376) U/L 12 h after CPB, p < 0.05. We found no significant increase in the ALT and AST concentrations in the CPB-NO group. There were no significant differences in ALT and AST concentrations between the CPB-NO and CPB-contr groups at all the study time-points. In the CPB-contr group, an increase in the creatinine level was found from 131 (129; 133) µmol/L at baseline to 273 (241; 306) µmol/L 12 h after CPB, p < 0.05. We found no significant increase in creatinine level in the CPB-NO group. Creatinine levels in the CPB-NO group were significantly lower than in the CPB-contr group 12 h after weaning from CPB: 183 (168; 196) vs. 273 (241; 306) µmol/L; p = 0.008. The GFR in the CPB-NO group was significantly higher than in the CPB-contr group 6 h after weaning from CPB: 78.9 (77.8; 82.3) vs. 67.9 (62.3; 69.2) mL/min; p = 0.016. GFR was significantly higher in the CPB-NO group than in the CPB-contr group 12 h after weaning from CPB: 67.7 (65.5; 68.0) vs. 50.3 (48.7; 54.9) mL/min; p = 0.032. We found no significant differences between the study groups in the level of NGAL. We found several differences between the groups in the pathomorphological study. Conclusions. NO added to the sweep gas of the oxygenator reduces creatinine levels and increases GFR during prolonged CPB injury. Further research is required.
]]>Pathophysiology doi: 10.3390/pathophysiology30040036
Authors: Nhi Dao Colette Cozean Oleg Chernyshev Clete Kushida Jonathan Greenburg Jonathan S. Alexander
In response to the commentary “Response to ‘Retrospective analysis of real-world data for the treatment of obstructive sleep apnea with slow maxillary expansion’” [...]
]]>Pathophysiology doi: 10.3390/pathophysiology30040035
Authors: G. Dave Singh
I found the recent article by Dao et al [...]
]]>Pathophysiology doi: 10.3390/pathophysiology30040034
Authors: Chun Shing Kwok Jacopo Tafuro Chun Wai Wong Sadie Bennett Donah Zachariah Diane Barker Adrian Morley-Davies Duwarakan Satchithananda Mark Gunning Josip A. Borovac
Despite the efforts to deliver the best evidence-based care, in-hospital death is an inevitable event among some patients hospitalized in cardiology departments. We conducted a retrospective evaluation of mortality events from inpatient admissions to the cardiology department between 2010 and 2019. Data were collected from morbidity and mortality meeting presentations that evaluated comorbidities, medical history, treatments, and causes of death for the overall cohort and according to age group and sex. There were 1182 registered deaths. The most common causes of death among patients were acute myocardial infarction (AMI, 53.0%), heart failure (HF, 11.7%), cardiac arrest (CA, 6.6%), HF with complication/defined cardiomyopathy (6.3%), and sepsis (4.4%). We observed a decline in deaths from AMI from 61.9% in 2010 to 46.7% in 2019, while there was a clear increase in deaths from HF (11.1% in 2010 to 25.9% in 2019). Compared to patients ≥65 years, younger patients were more likely to have died from CA (15.7% vs. 4.3%, p < 0.001) and other cardiac reasons (3.0% vs. 0.4%, p < 0.001). The majority of deaths were due to AMI, HF, and CA. We observed a significant declining trend in the proportion of deaths due to AMI in recent years, with an increase in deaths due to HF.
]]>Pathophysiology doi: 10.3390/pathophysiology30040033
Authors: Elena Y. Danilova Anna O. Maslova Andrey N. Stavrianidi Alexander E. Nosyrev Larisa D. Maltseva Olga L. Morozova
One of the primary challenges regarding chronic kidney disease (CKD) diagnosis is the absence of reliable methods to detect early-stage kidney damage. A metabolomic approach is expected to broaden the current diagnostic modalities by enabling timely detection and making the prognosis more accurate. Analysis performed on urine has several advantages, such as the ease of collection using noninvasive methods and its lower protein and lipid content compared with other bodily fluids. This review highlights current trends in applied analytical methods, major discoveries concerning pathways, and investigated populations in the context of urine metabolomic research for CKD over the past five years. Also, we are presenting approaches, instrument upgrades, and sample preparation modifications that have improved the analytical parameters of methods. The onset of CKD leads to alterations in metabolism that are apparent in the molecular composition of urine. Recent works highlight the prevalence of alterations in the metabolic pathways related to the tricarboxylic acid cycle and amino acids. Including diverse patient cohorts, using numerous analytical techniques with modifications and the appropriate annotation and explanation of the discovered biomarkers will help develop effective diagnostic models for different subtypes of renal injury with clinical applications.
]]>Pathophysiology doi: 10.3390/pathophysiology30030032
Authors: Henry W. Sanicola Caleb E. Stewart Patrick Luther Kevin Yabut Bharat Guthikonda J. Dedrick Jordan J. Steven Alexander
Subarachnoid hemorrhage (SAH) is a type of hemorrhagic stroke resulting from the rupture of an arterial vessel within the brain. Unlike other stroke types, SAH affects both young adults (mid-40s) and the geriatric population. Patients with SAH often experience significant neurological deficits, leading to a substantial societal burden in terms of lost potential years of life. This review provides a comprehensive overview of SAH, examining its development across different stages (early, intermediate, and late) and highlighting the pathophysiological and pathohistological processes specific to each phase. The clinical management of SAH is also explored, focusing on tailored treatments and interventions to address the unique pathological changes that occur during each stage. Additionally, the paper reviews current treatment modalities and pharmacological interventions based on the evolving guidelines provided by the American Heart Association (AHA). Recent advances in our understanding of SAH will facilitate clinicians’ improved management of SAH to reduce the incidence of delayed cerebral ischemia in patients.
]]>Pathophysiology doi: 10.3390/pathophysiology30030031
Authors: Zinab O. Doha Rosalie C. Sears
The transcription factor MYC plays a pivotal role in regulating various cellular processes and has been implicated in tumorigenesis across multiple cancer types. MYC has emerged as a master regulator governing tumor intrinsic and tumor microenvironment interactions, supporting tumor progression and driving drug resistance. This review paper aims to provide an overview and discussion of the intricate mechanisms through which MYC influences tumorigenesis and therapeutic resistance in cancer. We delve into the signaling pathways and molecular networks orchestrated by MYC in the context of tumor intrinsic characteristics, such as proliferation, replication stress and DNA repair. Furthermore, we explore the impact of MYC on the tumor microenvironment, including immune evasion, angiogenesis and cancer-associated fibroblast remodeling. Understanding MYC’s multifaceted role in driving drug resistance and tumor progression is crucial for developing targeted therapies and combination treatments that may effectively combat this devastating disease. Through an analysis of the current literature, this review’s goal is to shed light on the complexities of MYC-driven oncogenesis and its potential as a promising therapeutic target.
]]>Pathophysiology doi: 10.3390/pathophysiology30030030
Authors: Daniel García-Caballero Jonathan R. Hart Peter K. Vogt
In this article, we discuss a class of MYC-interacting lncRNAs (long non-coding RNAs) that share the following criteria: They are direct transcriptional targets of MYC. Their expression is coordinated with the expression of MYC. They are required for sustained MYC-driven cell proliferation, and they are not essential for cell survival. We refer to these lncRNAs as “MYC facilitators” and discuss two representative members of this class of lncRNAs, SNHG17 (small nuclear RNA host gene) and LNROP (long non-coding regulator of POU2F2). We also present a general hypothesis on the role of lncRNAs in MYC-mediated transcriptional regulation.
]]>Pathophysiology doi: 10.3390/pathophysiology30030029
Authors: Charles P. Daniel Maxwell J. Wagner Grant E. Borne Connor J. Plaisance Shahab Ahmadzadeh Alfonso Aquino Sahar Shekoohi Adam M. Kaye Elyse M. Cornett Alan D. Kaye
Acromegaly is a condition most commonly diagnosed in the fifth decade of life and has numerous treatment options. In this regard, Mycapssa® is the first FDA-approved oral octreotide capsule for treating acromegaly, combining the efficacy of the somatostatin receptor ligand, octreotide, with the ease of a twice-daily oral capsule. Where surgical treatment is not an option, somatostatin analogs, including octreotide, are the first line of medical treatment for acromegaly, requiring regular subcutaneous or intramuscular injections administered by a patient’s healthcare provider. Octreotide capsules (Mycapssa®) provide an alternative to these somatostatin receptor ligand injections by combining octreotide with other excipients to produce a transient permeability enhancer technology that improves paracellular transport of octreotide across the gastrointestinal wall into the small intestine. Across multiple trials, including open-label (CH-ACM-01), double-blind placebo-controlled (CHIASMA OPTIMAL), and open-label extension of the trial period (CHIASMA OPTIMAL OLE), Mycapssa® octreotide capsules maintained a consistent biochemical normalization of IGF-1 and GH levels, safety profiles similar to injected somatostatin receptor ligands, and patient preference to continued treatment with octreotide capsules. While clinical trial data supports the use of octreotide capsules (Mycapssa®) in the pharmacological management of GH and IGF-1 levels, very little data exist regarding the drug’s efficacy, tolerability, and use in female or pediatric-specific populations. A better understanding of the efficacy, application, and role of oral octreotide capsules in the long-term medical management of acromegaly in a diversity of populations is imperative to best determine the risks/benefits for the clinician.
]]>Pathophysiology doi: 10.3390/pathophysiology30030028
Authors: Erwin Astha Triyono Joni Wahyuhadi Christijogo Soemartono Waloejo Dimas Aji Perdana Nabilah Sisilia Dewanti Amal Arifi Hidayat Michael Austin Pradipta Lusida Fani Sarasati Ngurah Arie Kapindra Dharma Muhammad Ikhtiar Zaki Al Razzak Tanri Hadinata Wiranegara Nurarifah Destianizar Ali
Background: The COVID-19 pandemic has led to a rise in confirmed cases, making epidemiological studies crucial for identifying the source of transmission and developing effective treatment methods. We conducted a study on the clinical characteristics of patients with asymptomatic and mild symptoms of COVID-19 at a rescue hospital in Indonesia. Methods: This is an epidemiological study involving 6102 patients who were admitted to the Indrapura forefront hospital in Surabaya from May 2020 to February 2021. We described demographic data, clinical signs and symptoms, laboratory data, therapy, and clinical outcomes. Results: A total of 6102 patients were involved in this study, with 3664 (60.04%) being male and 2438 (39.95%) being female. The age range of 21–30 years was the most prevalent, accounting for 31.1% (1898 patients). The population had 1476 patients (24.2%) with comorbid conditions. The most prevalent comorbidity observed among these patients was hypertension, affecting 1015 individuals (16.6%). Out of the total 6006 patients observed, 40.7% (n = 2486) were asymptomatic, 54.6% (n = 3329) had mild symptoms, and 3.1% (n = 191) had moderate symptoms. All patients were administered supportive therapy without the use of antiviral medication. Out of the 6102 patients included in the study, 5923 patients (97.1%) achieved a cure, 36 patients (0.6%) are currently undergoing treatment, 142 patients (2.3%) were referred for desaturation indications (SpO2 < 94%), and one patient died due to a suspected cardiovascular event. Out of the total number of patients, 74.5% (4529 patients) had an average length of stay (LOS) of less than 10 days, while 25.6% (1563 patients) had an average length of stay of more than 10 days. Conclusion: The clinical presentation of asymptomatic and mild COVID-19 patients at a rescue hospital varies significantly based on the age and sex of patients. Cough and hyposmia are commonly observed symptoms. Supportive therapy is effective, and strict implementation of social distancing is crucial in preventing the spread of this disease from individuals who are asymptomatic or have mild symptoms.
]]>Pathophysiology doi: 10.3390/pathophysiology30030027
Authors: Barbara Illi Sergio Nasi
Myc is one of the most well-known oncogenes driving tumorigenesis in a wide variety of tissues. From the brain to blood, its deregulation derails physiological pathways that grant the correct functioning of the cell. Its action is carried out at the gene expression level, where Myc governs basically every aspect of transcription. Indeed, in addition to its role as a canonical, chromatin-bound transcription factor, Myc rules RNA polymerase II (RNAPII) transcriptional pause–release, elongation and termination and mRNA capping. For this reason, it is evident that minimal perturbations of Myc function mirror malignant cell behavior and, consistently, a large body of literature mainly focuses on Myc malfunctioning. In healthy cells, Myc controls molecular mechanisms involved in pivotal functions, such as cell cycle (and proliferation thereof), apoptosis, metabolism and cell size, angiogenesis, differentiation and stem cell self-renewal. In this latter regard, Myc has been found to also regulate tissue regeneration, a hot topic in the research fields of aging and regenerative medicine. Indeed, Myc appears to have a role in wound healing, in peripheral nerves and in liver, pancreas and even heart recovery. Herein, we discuss the state of the art of Myc’s role in tissue regeneration, giving an overview of its potent action beyond cancer.
]]>Pathophysiology doi: 10.3390/pathophysiology30030026
Authors: Alyssa Williams Rosi Bissinger Hala Shamaa Shivani Patel Lavern Bourne Ferruh Artunc Syed Qadri
Diabetes Mellitus (DM) is a complex metabolic disorder associated with multiple microvascular complications leading to nephropathy, retinopathy, and neuropathy. Mounting evidence suggests that red blood cell (RBC) alterations are both a cause and consequence of disturbances related to DM-associated complications. Importantly, a significant proportion of DM patients develop varying degrees of anemia of confounding etiology, leading to increased morbidity. In chronic hyperglycemia, RBCs display morphological, enzymatic, and biophysical changes, which in turn prime them for swift phagocytic clearance from circulation. A multitude of endogenous factors, such as oxidative and dicarbonyl stress, uremic toxins, extracellular hypertonicity, sorbitol accumulation, and deranged nitric oxide metabolism, have been implicated in pathological RBC changes in DM. This review collates clinical laboratory findings of changes in hematology indices in DM patients and discusses recent reports on the putative mechanisms underpinning shortened RBC survival and disturbed cell membrane architecture within the diabetic milieu. Specifically, RBC cell death signaling, RBC metabolism, procoagulant RBC phenotype, RBC-triggered endothelial cell dysfunction, and changes in RBC deformability and aggregation in the context of DM are discussed. Understanding the mechanisms of RBC alterations in DM provides valuable insights into the clinical significance of the crosstalk between RBCs and microangiopathy in DM.
]]>Pathophysiology doi: 10.3390/pathophysiology30030025
Authors: Choirina Windradi Tri Pudy Asmarawati Alfian Nur Rosyid Erika Marfiani Bagus Aulia Mahdi Okla Sekar Martani Giarena Giarena Esthiningrum Dewi Agustin Milanitalia Gadys Rosandy
The mortality of COVID-19 patients has left the world devastated. Many scoring systems have been developed to predict the mortality of COVID-19 patients, but several scoring components cannot be carried out in limited health facilities. Herein, the authors attempted to create a new and easy scoring system involving mean arterial pressure (MAP), PF Ratio, or SF ratio-respiration rate (SF Ratio-R), and lymphocyte absolute, which were abbreviated as MPL or MSLR functioning, as a predictive scoring system for mortality within 30 days for COVID-19 patients. Of 132 patients with COVID-19 hospitalized between March and November 2021, we followed up on 96 patients. We present bivariate and multivariate analyses as well as the area under the curve (AUC) and Kaplan–Meier charts. From 96 patients, we obtained an MPL score of 3 points: MAP < 75 mmHg, PF Ratio < 200, and lymphocyte absolute < 1500/µL, whereas the MSLR score was 6 points: MAP < 75 mmHg, SF Ratio < 200, lymphocyte absolute < 1500/µL, and respiration rate 24/min. The MPL cut-off point is 2, while the MSLR is 4. MPL and MSLR have the same sensitivity (79.1%) and specificity (75.5%). The AUC value of MPL vs. MSLR was 0.802 vs. 0.807. The MPL ≥ 2 and MSLR ≥ 4 revealed similar predictions for survival within 30 days (p < 0.05). Conclusion: MPL and MSLR scores are potential predictors of mortality in COVID-19 patients within 30 days in a resource-limited country.
]]>Pathophysiology doi: 10.3390/pathophysiology30030024
Authors: Konstantin Bogdanov Ekaterina Kudryavtseva Yulia Fomicheva Irina Churkina Elza Lomaia Larisa Girshova Yuri Osipov Andrey Zaritskey
Mutations in the FLT3 gene not only lead to abnormalities in its structure and function, but also affect the expression of other genes involved in leukemogenesis. This study evaluated the expression of genes that are more characteristic of neuroblastoma but less studied in leukemia. N-MYC oncogene expression was found to be more than 3-fold higher in primary AML patients carrying the FLT3-ITD mutation compared to carriers of other mutations as well as patients with normal karyotype (p = 0.03946). In contrast to the expression of several genes (C-MYC, SPT16, AURKA, AURKB) directly correlated to the allelic load of FLT3-ITD, the expression of the N-MYC oncogene is extremely weakly related or independent of it (p = 0.0405). Monitoring of N-MYC expression in some patients with high FLT3-ITD allelic load receiving therapy showed that a decrease in FLT3-ITD allelic load is not always accompanied by a decrease in N-MYC expression. On the contrary, N-MYC expression may remain elevated during the first three months after therapy, which is additional evidence of the emergence of resistance to therapy and progression of AML.
]]>Pathophysiology doi: 10.3390/pathophysiology30030023
Authors: Hadi Askarifirouzjaei Leila Khajoueinejad Elena Wei Sruti Cheruvu Carlos Ayala Ning Chiang Thomas Theis Dongming Sun Mehdi Fazeli Wise Young
Rats manifest a condition called hemorrhagic cystitis after spinal cord injury (SCI). The mechanism of this condition is unknown, but it is more severe in male rats than in female rats. We assessed the role of sex regarding hemorrhagic cystitis and pathological chronic changes in the bladder. We analyzed the urine of male and female Sprague-Dawley and Fischer 344 rats after experimental spinal cord contusion, including unstained microscopic inspections of the urine, differential white blood cell counts colored by the Wright stain, and total leukocyte counts using fluorescent nuclear stains. We examined bladder histological changes in acute and chronic phases of SCI, using principal component analysis (PCA) and clustered heatmaps of Pearson correlation coefficients to interpret how measured variables correlated with each other. Male rats showed a distinct pattern of macroscopic hematuria after spinal cord injury. They had higher numbers of red blood cells with significantly more leukocytes and neutrophils than female rats, particularly hypersegmented neutrophils. The histological examination of the bladders revealed a distinct line of apoptotic umbrella cells and disrupted bladder vessels early after SCI and progressive pathological changes in multiple bladder layers in the chronic phase. Multivariate analyses indicated immune cell infiltration in the bladder, especially hypersegmented neutrophils, that correlated with red blood cell counts in male rats. Our study highlights a hitherto unreported sex difference of hematuria and pathological changes in males and females’ bladders after SCI, suggesting an important role of immune cell infiltration, especially neutrophils, in SCI-induced hemorrhagic cystitis.
]]>Pathophysiology doi: 10.3390/pathophysiology30020022
Authors: Alexandra Nikolaeva Maria Pospelova Varvara Krasnikova Albina Makhanova Samvel Tonyan Yurii Krasnopeev Evgeniya Kayumova Elena Vasilieva Aleksandr Efimtsev Anatoliy Levchuk Gennadiy Trufanov Mark Voynov Maxim Shevtsov
Vestibulo-atactic syndrome (VAS), which represents a combination of motor and vestibular disorders, can be manifested as a clinical complication of breast cancer treatment and has a significant impact on patients’ quality of life. The identification of novel potential biomarkers that might help to predict the onset of VAS and its progression could improve the management of this group of patients. In the current study, the levels of intercellular cell adhesion molecule 1 (ICAM-1), platelet/endothelial cell adhesion molecule 1 (PECAM-1), NSE (neuron-specific enolase), and the antibodies recognizing NR-2 subunit of NMDA receptor (NR-2-ab) were measured in the blood serum of BC survivor patients with vestibulo-atactic syndrome (VAS) and associated with the brain connectome data obtained via functional magnetic resonance imaging (fMRI) studies. A total of 21 patients were registered in this open, single-center trial and compared to age-matched healthy female volunteers (control group) (n = 17). BC patients with VAS demonstrated higher serum levels of ICAM-1, PECAM-1, and NSE and a lower value of NR-2-ab, with values of 654.7 ± 184.8, 115.3 ± 37.03, 49.9 ± 103.9, and 0.5 ± 0.3 pg/mL, respectively, as compared to the healthy volunteers, with 230.2 ± 44.8, 62.8 ± 15.6, 15.5 ± 6.4, and 1.4 ± 0.7 pg/mL. According to the fMRI data (employing seed-to-voxel and ROI-to-ROI methods), in BC patients with VAS, significant changes were detected in the functional connectivity in the areas involved in the regulation of postural-tonic reflexes, the coordination of movements, and the regulation of balance. In conclusion, the detected elevated levels of serum biomarkers may reveal damage to the CNS neurons and endothelial cells that is, in turn, associated with the change in the brain connectivity in this group of patients.
]]>Pathophysiology doi: 10.3390/pathophysiology30020021
Authors: Anastasia Sklifasovskaya Mikhail Blagonravov Madina Azova Vyacheslav Goryachev
Antioxidant protection is one of the key reactions of cardiomyocytes (CMCs) in response to myocardial damage of various origins. The thioredoxin interacting protein (TXNIP) is an inhibitor of thioredoxin (TXN). Over the recent few years, TXNIP has received significant attention due to its wide range of functions in energy metabolism. In the present work, we studied the features of the redox-thiol systems, in particular, the amount of TXNIP and glutathione synthetase (GS) as markers of oxidative damage to CMCs and antioxidant protection, respectively. This study was carried out on 38-week-old Wistar-Kyoto rats with insulin-dependent diabetes mellitus (DM) induced by streptozotocin, on 38- and 57-week-old hypertensive SHR rats and on a model of combined hypertension and DM (38-week-old SHR rats with DM). It was found that the amount of TXNIP increased in 57-week-old SHR rats, in diabetic rats and in SHR rats with DM. In 38-week-old SHR rats, the expression of TXNIP significantly decreased. The expression of GS was significantly higher compared with the controls in 57-week-old SHR rats, in DM rats and in the case of the combination of hypertension and DM. The obtained data show that myocardial damage caused by DM and hypertension are accompanied by the activation of oxidative stress and antioxidant protection.
]]>Pathophysiology doi: 10.3390/pathophysiology30020020
Authors: Amal Arifi Hidayat Vania Azalia Gunawan Firda Rachmawati Iragama Rizky Alfiansyah Decsa Medika Hertanto Artaria Tjempakasari Mochammad Thaha
Acute kidney injury (AKI) is associated with a worse prognosis in coronavirus disease 2019 (COVID-19) patients. Identification of AKI, particularly in COVID-19 patients, is important for improving patients’ management. The study aims to assess risk factors and comorbidities of AKI in COVID-19 patients. We systematically searched PubMed and DOAJ databases for relevant studies involving confirmed COVID-19 patients with data on risk factors and comorbidities of AKI. The risk factors and comorbidities were compared between AKI and non-AKI patients. A total of 30 studies involving 22385 confirmed COVID-19 patients were included. Male (OR: 1.74 (1.47, 2.05)), diabetes (OR: 1.65 (1.54, 1.76)), hypertension (OR: 1.82 (1.12, 2.95)), ischemic cardiac disease (OR: 1.70 (1.48, 1.95)), heart failure (OR: 2.29 (2.01, 2.59)), chronic kidney disease (CKD) (OR: 3.24 (2.20, 4.79)), chronic obstructive pulmonary disease (COPD) (OR: 1.86 (1.35, 2.57)), peripheral vascular disease (OR: 2.34 (1.20, 4.56)), and history of nonsteroidal anti-inflammatory drugs (NSAID) (OR: 1.59 (1.29, 1.98)) were independent risk factors associated with COVID-19 patients with AKI. Patients with AKI presented with proteinuria (OR: 3.31 (2.59, 4.23)), hematuria (OR: 3.25 (2.59, 4.08)), and invasive mechanical ventilation (OR: 13.88 (8.23, 23.40)). For COVID-19 patients, male gender, diabetes, hypertension, ischemic cardiac disease, heart failure, CKD, COPD, peripheral vascular disease, and history of use of NSAIDs are associated with a higher risk of AKI.
]]>Pathophysiology doi: 10.3390/pathophysiology30020019
Authors: Carolina Ochoa Phillip C. S. R. Kilgore Nadejda Korneeva Eric Clifford Steven A. Conrad Marjan Trutschl Jacquelyn M. Bowers Thomas Arnold Urska Cvek
There are several pathophysiological outcomes associated with substance abuse including metabolic disbalance, neurodegeneration, and disordered redox. Drug use in pregnant women is a topic of great concern due to developmental harm which may occur during gestation and the associated complications in the neonate after delivery. We sought to determine what the trajectory of drug use is like in children aged 0–4 years and mothers of neonates. Urine drug screen (UDS) results were obtained of our target demographic during 1998–2011 and 2012–2019 from LSU Health Sciences Center in Shreveport (LSUHSC-S). Statistical analysis was performed using R software. We observed an increase in cannabinoid-positive UDS results in both Caucasian (CC) and African American (AA) groups between 1998–2011 and 2012–2019 periods. Cocaine-positive UDS results decreased in both cohorts. CC children had higher UDS positive results for opiates, benzodiazepines, and amphetamines, while AA children had a higher percentage for illicit drugs such as cannabinoids and cocaine. Neonate’s mothers had similar UDS trends to that in children during 2012–2019. Overall, while percentage of positive UDS results for both AA and CC 0–4 year old children started to decline for opiate, benzodiazepine, and cocaine during 2012–2019, cannabinoid- and amphetamine (CC)-positive UDS steadily increased. These results suggest a shift in the type of drug use by mothers from opiates, benzodiazepines, and cocaine to cannabinoids and/or amphetamines. We also observed that 18-year-old females who tested positive for opiates, benzodiazepine, or cocaine had higher than average chances of testing positive for cannabinoids later in life.
]]>Pathophysiology doi: 10.3390/pathophysiology30020018
Authors: Liudmila Gerasimova-Meigal Alexander Meigal Maria Gerasimova Anna Sklyarova Ekaterina Sirotinina
The primary aim of the study was to assess cerebral circulation in healthy young subjects during an ultra-short (45 min) session of ground-based microgravity modeled by “dry” immersion (DI), with the help of a multifunctional Laser Doppler Flowmetry (LDF) analyzer. In addition, we tested a hypothesis that cerebral temperature would grow during a DI session. The supraorbital area of the forehead and forearm area were tested before, within, and after a DI session. Average perfusion, five oscillation ranges of the LDF spectrum, and brain temperature were assessed. Within a DI session, in the supraorbital area most of LDF parameters remained unchanged except for a 30% increase in respiratory associated (venular) rhythm. The temperature of the supraorbital area increased by up to 38.5 °C within the DI session. In the forearm area, the average value of perfusion and its nutritive component increased, presumably due to thermoregulation. In conclusion, the results suggest that a 45 min DI session does not exert a substantial effect on cerebral blood perfusion and systemic hemodynamics in young healthy subjects. Moderate signs of venous stasis were observed, and brain temperature increased during a DI session. These findings must be thoroughly validated in future studies because elevated brain temperature during a DI session can contribute to some reactions to DI.
]]>Pathophysiology doi: 10.3390/pathophysiology30020017
Authors: Nhi Dao Colette Cozean Oleg Chernyshev Clete Kushida Jonathan Greenburg Jonathan S. Alexander
In addition to mandibular advancement devices, dental expansion appliances are an important clinical approach for achieving an increased intra-oral space that promotes airflow and lessens the frequency or severity of apneic events in patients diagnosed with obstructive sleep apnea (OSA). It has been thought that dental expansion in adults must be preceded by oral surgery; however, in this paper, we examine the results of a new technique for slow maxillary expansion without any surgical procedures. The palatal expansion device, DNA (Daytime-Nighttime Appliance), was reviewed in this retrospective study, particularly regarding its effects on measurements of transpalatal width, airway volume, and apnea-hypopnea indices (AHI) as well as its common modalities and complications. The DNA effectively reduced AHI by 46% (p = 0.00001) and significantly increased both airway volume and transpalatal width (p < 0.00001). After DNA treatment, 80% of patients showed some improvement in AHI scores with 28% of patients having their OSA symptoms completely resolved. Compared to the use of mandibular appliances, this approach is intended to create a sustained improvement in airway management that can reduce or eliminate dependence on continuous positive airway pressure (CPAP) or other OSA treatment devices.
]]>Pathophysiology doi: 10.3390/pathophysiology30020016
Authors: Muhammad Vitanata Arfijanto Tri Pudy Asmarawati Bramantono Bramantono Musofa Rusli Brian Eka Rachman Bagus Aulia Mahdi Nasronudin Nasronudin Usman Hadi
Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) ribonucleic acid (RNA) shedding is an important parameter for determining the optimal length of isolation period required for coronavirus disease 2019 (COVID-19) patients. However, the clinical (i.e., patient and disease) characteristics that could influence this parameter have yet to be determined. In this study, we aim to explore the potential associations between several clinical features and the duration of SARS-CoV-2 RNA shedding in patients hospitalized with COVID-19. A retrospective cohort study involving 162 patients hospitalized for COVID-19 in a tertiary referral teaching hospital in Indonesia was performed from June to December 2021. Patients were grouped based on the mean duration of viral shedding and were compared based on several clinical characteristics (e.g., age, sex, comorbidities, COVID-19 symptoms, severity, and therapies). Subsequently, clinical factors potentially associated with the duration of SARS-CoV-2 RNA shedding were further assessed using multivariate logistic regression analysis. As a result, the mean duration of SARS-CoV-2 RNA shedding was found to be 13 ± 8.44 days. In patients with diabetes mellitus (without chronic complications) or hypertension, the duration of viral shedding was significantly prolonged (≥13 days; p = 0.001 and p = 0.029, respectively). Furthermore, patients with dyspnea displayed viral shedding for longer durations (p = 0.011). The multivariate logistic regression analysis reveals that independent risk factors associated with the duration of SARS-CoV-2 RNA shedding include disease severity (adjusted odds ratio [aOR] = 2.94; 95% CI = 1.36–6.44), bilateral lung infiltrates (aOR = 2.79; 95% CI = 1.14–6.84), diabetes mellitus (aOR = 2.17; 95% CI = 1.02–4.63), and antibiotic treatment (aOR = 3.66; 95% CI = 1.74–7.71). In summary, several clinical factors are linked with the duration of SARS-CoV-2 RNA shedding. Disease severity is positively associated with the duration of viral shedding, while bilateral lung infiltrates, diabetes mellitus, and antibiotic treatment are negatively linked with the duration of viral shedding. Overall, our findings suggest the need to consider different isolation period estimations for specific clinical characteristics of patients with COVID-19 that affect the duration of SARS-CoV-2 RNA shedding.
]]>Pathophysiology doi: 10.3390/pathophysiology30020015
Authors: Elena Zelikovna Golukhova Inessa Viktorovna Slivneva Inga Yur’evna Farulova Ivan Ivanovich Skopin Damir Ildarovich Marapov Dar’ya Vladimirovna Murysova Yuliya Dmitrievna Pirushkina Irina Vasilyevna Volkovskaya
Aim of the study: The aim of this study was to perform a comparative analysis of severity of discordant aortic stenosis (AS) assessment using multiposition scanning and the standard apical window. Materials and Methods: All patients (n = 104) underwent preoperative transthoracic echocardiography (TTE) and were ranked according to the degree of AS severity. The reproducibility feasibility of the right parasternal window (RPW) was 75.0% (n = 78). The mean age of the patients was 64 years, and 40 (51.3%) were female. In 25 cases, low gradients were identified from the apical window not corresponding to the visual structural changes in the aortic valve, or disagreement between the velocity and calculated parameters was detected. Patients were divided into two groups: concordant AS (n = 56; 71.8%) and discordant AS (n = 22; 28.2%). Three individuals were excluded from the discordant AS group due to the presence of moderate stenosis. Results: Based on the comparative analysis of transvalvular flow velocities obtained from multiposition scanning, the concordance group showed agreement between the velocity and calculated parameters. We observed an increase in the mean transvalvular pressure gradient (ΔPmean) and peak aortic jet velocity (Vmax), ΔPmean in 95.5% of patients, velocity time integral of transvalvular flow (VTI AV) in 90.9% of patients, and a decrease in aortic valve area (AVA) and indexed AVA in 90.9% of patients after applying RPW in all patients with discordant AS. The use of RPW allowed the reclassification of AS severity from discordant to concordant high-gradient AS in 88% of low-gradient AS cases. Conclusion: Underestimation of flow velocity and overestimation of AVA using the apical window may lead to misclassification of AS. The use of RPW helps to match the degree of AS severity with the velocity characteristics and reduce the number of low-gradient AS cases.
]]>Pathophysiology doi: 10.3390/pathophysiology30020014
Authors: Gatot Soegiarto Dewajani Purnomosari
In recent years, the elderly has become a rapidly growing proportion of the world’s population as life expectancy is extending. Immunosenescence and inflammaging contribute to the increased risk of chronic non-communicable and acute infectious diseases. Frailty is highly prevalent in the elderly and is associated with an impaired immune response, a higher propensity to infection, and a lower response to vaccines. Additionally, the presence of uncontrolled comorbid diseases in the elderly also contributes to sarcopenia and frailty. Vaccine-preventable diseases that threaten the elderly include influenza, pneumococcal infection, herpes zoster, and COVID-19, which contribute to significant disability-adjusted life years lost. Previous studies had shown that conventional vaccines only yielded suboptimal protection that wanes rapidly in a shorter time. This article reviews published papers on several vaccination strategies that were developed for the elderly to solve these problems: more immunogenic vaccine formulations using larger doses of antigen, stronger vaccine adjuvants, recombinant subunit or protein conjugated vaccines, newly developed mRNA vaccines, giving booster shots, and exploring alternative routes of administration. Included also are several publications on senolytic medications under investigation to boost the immune system and vaccine response in the elderly. With all those in regard, the currently recommended vaccines for the elderly are presented.
]]>Pathophysiology doi: 10.3390/pathophysiology30020013
Authors: Nicole Hall Nhi Dao Cameron Hewett Sara Oberle Andrew Minagar Kariann Lamon Carey Ford Bruce E. Blough J. Steven Alexander Kevin S. Murnane
To avoid criminal prosecution, clandestine chemists produce designer stimulants that mimic the pharmacological and psychoactive effects of conventional stimulants, such as methamphetamine. Following persistent or high-dose exposure, both acute vasoconstriction and loss of vascular homeostasis are reported dangers of conventional stimulants, and designer stimulants may pose even greater dangers. To compare the effects of a conventional stimulant and two designer stimulants on vascular contraction, this study examined the direct effects of 1,3-benzodioxolylbutanamine (BDB) and N-butylpentylone in comparison to methamphetamine on the function of human brain vascular smooth muscle cells (HBVSMCs). HBVSMCs suspended in collagen gels were exposed to varying concentrations of each drug, and the degree of constriction was assessed over one week. The MTT assay was used to measure the impact of the three drugs on the cellular metabolic activity as a marker of cellular toxicity. The highest concentration tested of either methamphetamine or N-butylpentylone produced a loss of HBVSMC contractility and impaired cellular metabolism. BDB showed a similar pattern of effects, but, uniquely, it also induced vasoconstrictive effects at substantially lower concentrations. Each drug produced direct effects on HBVSMC contraction that may be a mechanism by which the cardiovascular system is damaged following high-dose or persistent exposure, and this could be exacerbated by any sympathomimetic effects of these compounds in whole organisms. BDB appears to impact HBVSMC function in ways distinct from methamphetamine and N-butylpentylone, which may present unique dangers.
]]>Pathophysiology doi: 10.3390/pathophysiology30020012
Authors: Stefanus Gunawan Kandinata Soebagijo Adi Soelistijo Agung Pranoto Erwin Astha Triyono
Previous studies have yielded inconsistent results on whether glycated hemoglobin (HbA1c) and random blood glucose (RBG) are associated with mortality of coronavirus disease 2019 (COVID-19) patients with type 2 diabetes mellitus (T2DM). This study aimed to assess the association of HbA1c and RBG with mortality among COVID-19 patients with T2DM. A retrospective study was conducted on 237 patients with COVID-19 and T2DM (survival (n = 169) and non-survival groups (n = 68)). Data on socio-demography, comorbidities, clinical symptoms, laboratory examination, and mortality were collected. Patients in the non-survival group had an older age range as compared with those in the survival group (60 (52.3–65.0) vs. 56.0 (48.5–61.5) years, p = 0.009). There was no statistical gender difference between the two groups. After matching was done, chronic kidney disease, NLR, d-dimer, procalcitonin, and random blood glucose were higher in the non-survival group compared to the survival group (p < 0.05). HbA1c levels were similar in survivors and non-survivors (8.7% vs. 8.9%, p=0.549). The level of RBG was independently associated with mortality of COVID-19 patients with T2DM (p = 0.003, adjusted OR per 1-SD increment 2.55, 95% CI: 1.36–4.76). In conclusion, RBG was associated with the mortality of COVID-19 patients with T2DM, but HbA1c was not.
]]>Pathophysiology doi: 10.3390/pathophysiology30020011
Authors: Lacee K. Collins Matthew W. Cole Timothy L. Waters Michael Iloanya Patrick A. Massey William F. Sherman
Aging causes a reduction in testosterone and estrogen, which is linked to diminished bone mineral density. Hormone replacement therapy and its effect on the outcome of joint arthroplasties is unclear. The purpose of this study was to analyze the impact of testosterone replacement therapy (TRT) and estrogen replacement therapy (ERT) on the medical and joint outcomes of total hip (THA) and total knee arthroplasties (TKA). A retrospective cohort study was conducted using the PearlDiver database. Patients who received TRT or ERT perioperatively were matched to controls. Rates of 90-day medical complications and 2-year joint complications were queried. Patients who received TRT had an increased risk of revision, periprosthetic joint infection, and pooled joint complications within 2 years following a THA and increased rates of septic and aseptic revisions, and aseptic loosening after TKA compared to the control cohort. Patients receiving ERT had increased rates of aseptic loosening and pooled joint complications within 2 years following THA and increased rates of all-cause revisions and pooled joint complications after TKA. Patients who received TRT demonstrated significantly higher rates of revision rates and PJI. Patients who received perioperative ERT were significantly more likely to have increased risks of revision rates and joint infections.
]]>Pathophysiology doi: 10.3390/pathophysiology30020010
Authors: Samvel Tonyan Maria Pospelova Varvara Krasnikova Olga Fionik Tatyana Alekseeva Konstantin Samochernykh Nataliya Ivanova Tatyana Vavilova Elena Vasilieva Albina Makhanova Aleksandra Nikolaeva Tatyana Bukkieva Stephanie Combs Maxim Shevtsov
Damage to the peripheral nervous system (PNS) is a common complication of breast cancer (BC) treatment, with 60 to 80% of breast cancer survivors experiencing symptoms of PNS damage. In the current study, the levels of brain-derived neurotrophic factor (BDNF), galectin-3 (Gal-3), and neurotrophin-3 (NT-3) were measured in the blood serum of BC patients by ELISA as potential biomarkers that might indicate the PNS damage. Sixty-seven patients were enrolled in this multi-center trial and compared to the aged-matched healthy female volunteers (control group) (n = 25). Intergroup comparison of biomarker levels (i.e., Gal-3 and BDNF) did not show significant differences in any of the studied subgroups. However, intriguingly, NT-3 levels were significantly higher in BC patients as compared to healthy volunteers, constituting 14.85 [10.3; 18.0] and 5.74 [4.56; 13.7] pg/mL, respectively (p < 0.001). In conclusion, NT-3 might be employed as a potential biomarker in BC patients with clinical manifestations of PNS damage. However, further studies to validate its correlation to the degree of peripheral nervous system lesions are of high value.
]]>Pathophysiology doi: 10.3390/pathophysiology30020009
Authors: Kaka Renaldi Marcellus Simadibrata Nur Rahadiani Diah Rini Handjari Alida Roswita Harahap Kuntjoro Harimurti Nasrul Zubir Lianda Siregar Imelda Maria Loho Evlina Suzanna Bonita Prawirodihardjo Heriawaty Hidajat Budi Widodo Alphania Rahniayu Renaningtyas Tambun Andy William Dadang Makmun
Chronic inflammation is a crucial driver of carcinogenesis in pancreatic ductal adenocarcinoma (PDAC). Several studies have investigated the prognostic significance of cyclooxygenase−2 (COX−2) expression in PDAC patients, obtaining conflicting results. Nuclear factor kappa−B (NF−κB), specificity protein 1 (Sp1), and c−Jun are known as the transcription factors of the COX2 gene. This exploratory observational study investigated the association of the NF−κB, COX−2, Sp1, and c−Jun expressions with patient survival in PDAC. We used the immunohistochemical method to detect the PDAC tissue expressions of NF−κB (RelA/p65), COX−2, Sp1, and c−Jun. The expressions of these proteins were correlated with the overall survival (OS) and other clinicopathological characteristics of PDAC patients. We obtained 53 PDAC specimens from resections and biopsies. There were significant correlations between the four proteins’ expressions in the PDAC tissues. The expression of the cytoplasmic (aHR = 0.31; 95% CI 0.11–0.90; p = 0.032) or nuclear NF−κB (aHR = 0.22; 95% CI 0.07–0.66; p = 0.007) was independently associated with a better prognosis in the PDAC patients. COX−2, Sp1, and c−Jun showed no significant association with a prognosis in the PDAC patients. The PDAC patients who expressed NF−κB had a better prognosis than the other patients, which suggests that the role of inflammation in PDAC is more complex than previously thought.
]]>Pathophysiology doi: 10.3390/pathophysiology30020008
Authors: Madeline Gautreaux Steven Kautz Zashiana Martin Edward Morgan R. Shane Barton Matthew Dubose Hayden McBride Giovanni F. Solitro
Total hip arthroplasty is a widely performed operation allowing disabled patients to improve their quality of life to a degree greater than any other elective procedure. Planning for a THA requires adequate patient assessment and preoperative characterizations of acetabular bone loss via radiographs and specific classification schemes. Some surgeons may be inclined to ream at a larger diameter thinking it would lead to a more stable press-fit, but this could be detrimental to the acetabular wall, leading to intraoperative fracture. In the attempt to reduce the incidence of intraoperative fractures, the current study aims to identify how increased reaming diameter degrades and weakens the acetabular rim strength. We hypothesized that there is proportionality between the reaming diameter and the reduction in acetabular strength. To test this hypothesis, this study used bone surrogates, templated from CT scans, and reamed at different diameters. The obtained bone surrogate models were then tested using an Intron 8874 mechanical testing machine (Instron, Norwood, MA) equipped with a custom-made fixture. Analysis of variance (ANOVA) was used to identify differences among reamed diameters while linear regression was used to identify the relationship between reamed diameters and acetabular strength. We found a moderate correlation between increasing reaming diameter that induced thinning of the acetabular wall and radial load damage. For the simplified acetabular model used in this study, it supported our hypothesis and is a promising first attempt in providing quantitative data for acetabular weakening induced by reaming.
]]>Pathophysiology doi: 10.3390/pathophysiology30010007
Authors: Iman Aolymat Ma’mon M. Hatmal Amin N. Olaimat
Cells employ a well-preserved physiological stress response mechanism, termed the heat shock response, to activate a certain type of molecular chaperone called heat shock proteins (HSPs). HSPs are activated by transcriptional activators of heat shock genes known as heat shock factors (HSFs). These molecular chaperones are categorized as the HSP70 superfamily, which includes HSPA (HSP70) and HSPH (HSP110) families; the DNAJ (HSP40) family; the HSPB family (small heat shock proteins (sHSPs)); chaperonins and chaperonin-like proteins; and other heat-inducible protein families. HSPs play a critical role in sustaining proteostasis and protecting cells against stressful stimuli. HSPs participate in folding newly synthesized proteins, holding folded proteins in their native conformation, preventing protein misfolding and accumulation, and degrading denatured proteins. Ferroptosis is a recently identified type of oxidative iron-dependent cell demise. It was coined recently in 2012 by Stockwell Lab members, who described a special kind of cell death induced by erastin or RSL3. Ferroptosis is characterized by alterations in oxidative status resulting from iron accumulation, increased oxidative stress, and lipid peroxidation, which are mediated by enzymatic and non-enzymatic pathways. The process of ferroptotic cell death is regulated at multiple, and it is involved in several pathophysiological conditions. Much research has emerged in recent years demonstrating the involvement of HSPs and their regulator heat shock factor 1 (HSF1) in ferroptosis regulation. Understanding the machinery controlling HSF1 and HSPs in ferroptosis can be employed in developing therapeutic interventions for ferroptosis occurrence in a number of pathological conditions. Therefore, this review comprehensively summarized the basic characteristics of ferroptosis and the regulatory functions of HSF1 and HSPs in ferroptosis.
]]>Pathophysiology doi: 10.3390/pathophysiology30010006
Authors: Anatoly Brazhnikov Natalya Zotova Liliya Solomatina Alexey Sarapultsev Alexey Spirin Evgeni Gusev
Background: Amniotic fluid embolism (AFE) is one of the main causes of maternal mortality in developed countries. The most critical AFE variants may be considered from the perspective of systemic inflammation (SI), a general pathological process that includes high levels of systemic inflammatory response, neuroendocrine system distress, microthrombosis, and multiple organ dysfunction syndrome (MODS). This research work aimed to characterize the dynamics of super-acute SI using four clinical case studies of patients with critical AFE. Methods: In all the cases, we examined blood coagulation parameters, plasma levels of cortisol, troponin I, myoglobin, C-reactive protein, IL-6, IL-8, IL-10, and TNF-α, and calculated the integral scores. Results: All four patients revealed the characteristic signs of SI, including increased cytokine, myoglobin, and troponin I levels, changes in blood cortisol, and clinical manifestations of coagulopathy and MODS. At the same time, the cytokine plasma levels can be characterized not only as hypercytokinemia, and not even as a “cytokine storm”, but rather as a “cytokine catastrophe” (an increase of thousands and tens of thousands of times in proinflammatory cytokine levels). AFE pathogenesis involves rapid transition from the hyperergic shock phase, with its high levels of a systemic inflammatory response over to the hypoergic shock phase, characterized by the mismatch between low systemic inflammatory response values and the patient’s critical condition. In contrast to septic shock, in AFE there is a much more rapid succession of SI phases. Conclusion: AFE is one of the most compelling examples for studying the dynamics of super-acute SI.
]]>Pathophysiology doi: 10.3390/pathophysiology30010005
Authors: Yurii Frenkel Valerii Cherno Heorhii Kostenko Hitesh Chopra Rupesh K. Gautam Vitalii Kostenko
This study aims to investigate the effect of resveratrol on systemic inflammatory response and metabolic disorder in rats fed a high-fructose high-lipid diet (HFHLD) and exposed to round-the-clock lighting (RCL). 21 adult male Wistar rats were randomly divided into 3 groups: control (group 1, n = 7); HFHLD for 8 weeks + round-the-clock lighting (RCL) (group 2, n = 7); HFHLD + RCL + Resveratrol (in a daily dose of 5 mg/kg intragastrically (group 3, n = 7). Results show that the combined effect of HFHLD and RCL reduces the serum melatonin (p < 0.001) and accelerates pro-inflammatory activities, oxidative stress, and metabolic disorder. There is a significant increase in the serum tumour necrosis factor-alpha (TNF-α) and C-reactive protein (CRP) (both p < 0.001), blood malondialdehyde—thiobarbituric acid adducts (MDA-TBA2) (p < 0.001), serum glucose (p < 0.01), insulin concentration, and the homeostatic model assessment insulin resistance (HOMA-IR) index (both p < 0.001), serum with very low-density lipoprotein (VLDL), and triacylglycerol (TAG) (both p < 0.001). At the same time, the decrease in the serum high-density lipoprotein (HDL) level (p < 0.001) is observed in the HFHLD + RCL group compared to the control. In the HFHLD + RCL + Resveratrol group, hypomelatonaemia (p < 0.001), pro-inflammatory actions, oxidative stress, and metabolic disorder were mitigated. Resveratrol can cause a significant rise in the serum melatonin and reduce serum TNF-α and CRP levels (both p < 0.001), blood MDA-TBA2 (p < 0.001), serum glucose (both p < 0.01), insulin concentration, and HOMA-IR (both p < 0.001), serum VLDL and TAG (both p < 0.001) compared to the group 2, while serum HDL level increases (p < 0.01). Resveratrol attenuates pro-inflammatory responses and prevents considerable metabolic disorder in rats fed HFHLD under RCL.
]]>Pathophysiology doi: 10.3390/pathophysiology30010004
Authors: Alice Ordean Meara Tubman-Broeren
The prevalence of opioid use among pregnant people has been increasing over the past few decades, with a parallel increase in the rate of neonatal abstinence syndrome. Opioid agonist treatment (OAT) including methadone and buprenorphine is the recommended management method for opioid use disorders during pregnancy. Methadone has been extensively studied during pregnancy; however, buprenorphine was introduced in the early 2000s with limited data on the use of different preparations during pregnancy. Buprenorphine-naloxone has been incorporated into routine practice; however, only a few studies have investigated the use of this medication during pregnancy. To determine the safety and efficacy of this medication, we conducted a systematic review of maternal and neonatal outcomes among buprenorphine-naloxone-exposed pregnancies. The primary outcomes of interest were birth parameters, congenital anomalies, and severity of neonatal abstinence syndrome. Secondary maternal outcomes included the OAT dose and substance use at delivery. Seven studies met the inclusion criteria. Buprenorphine-naloxone doses ranged between 8 and 20 mg, and there was an associated reduction of opioid use during pregnancy. There were no significant differences in gestational age at delivery, birth parameters, or prevalence of congenital anomalies between buprenorphine-naloxone-exposed neonates and those exposed to methadone, buprenorphine monotherapy, illicit opioids, or no opioids. In studies comparing buprenorphine-naloxone to methadone, there were reduced rates of neonatal abstinence syndrome requiring pharmacotherapy. These studies demonstrate that buprenorphine-naloxone is a safe and effective opioid agonist treatment for pregnant people with OUD. Further large-scale, prospective data collection is required to confirm these findings. Patients and clinicians may be reassured about the use of buprenorphine-naloxone during pregnancy.
]]>Pathophysiology doi: 10.3390/pathophysiology30010003
Authors: Myadagmaa Jaalkhorol Oyunbileg Dulamsuren Amarsaikhan Dashtseren Enkh-Amgalan Byambajav Nansalmaa Khaidav Badrangui Bat-Orgil Anar Bold Enkhdulguun Amgalan Anujin Chuluunbaatar Ikuo Tsunoda
Mongolia is located at 45° north latitude in the center of the Asian continent, and about 80% of the territory is at 1000 m above sea level. Epidemiologically, multiple sclerosis (MS) has not been investigated in Mongolia, although there have been a few MS case reports. We investigated the characteristics of MS in Mongolia for the first time, focusing on the association between MS-related parameters and depression levels. We initiated cross-sectional analyses, using data from 27 MS patients aged 20 to 60 years in Ulaanbaatar, Mongolia. The patients completed a questionnaire on their lifestyles and clinical information. We classified the MS patients on the basis of disability levels using the expanded disability status scale (EDSS) scores: 11.1% mild disability and 88.9% moderate to severe disability (median EDSS score, 5.5). We also classified the patients on the basis of depression levels using the 9-item patient health questionnaire (PHQ-9) scores: 44.4% mild depression, 40.7% moderate depression, and 14.8% severe depression (mean PHQ-9’s score, 9.96 ± 5.05). We used multivariate logistical regression analyses to identify predictors of EDSS or PHQ-9 scores. Disability levels were associated with vision and balance problems. Depression levels were associated with corticosteroid treatment; no patients were treated with disease-modifying drugs (DMDs). The odds ratios for disease onset age and treatment duration were associated with EDSS scores. In conclusion, MS onset age and treatment duration were independent predicting factors influencing the level of disability. Appropriate DMD treatment would lower the disability and depression levels.
]]>Pathophysiology doi: 10.3390/pathophysiology30010002
Authors: Pathophysiology Editorial Office Pathophysiology Editorial Office
High-quality academic publishing is built on rigorous peer review [...]
]]>Pathophysiology doi: 10.3390/pathophysiology30010001
Authors: Cua Thi Hong Trinh Dung Ngoc Tran Linh Thi Thao Nguyen Nghia Tin Tran Minh Trinh Gia Nguyen Vy Tran Phuong Nguyen Nhung Thi Hong Vu Khanh Duy Dang Kha Van Vo Hoa Chieu Chau Phi Thi Phi Phan Mai Huynh Truc Phuong
Nasopharyngeal carcinoma (NPC) is the most common cancer among head and neck cancers in Vietnam. We aimed to identify the rate of a 30 bp deletion mutation of the LMP1-EBV gene in nasopharyngeal biopsy tissue samples, the HLA genotypes of NPC patients, and the relationship between these two targets. Patients with NPC at Can Tho Oncology Hospital from September 2014 to December 2018 were selected. A length of 30 bp of the del-LMP1-EBV gene was analyzed using a PCR technique, and the HLA genotypes in patients’ blood samples were analyzed with PCR-SSO technology. HLA-B*15 gene carriers had the highest risk of 30 bp LMP1-EBV gene deletion mutation, which was found in 51 out of 70 patients (72.9%). Carriers of the HLA-B*15 allele had a 4.6-fold increased risk of a 30 bp del-LMP1-EBV gene compared with non-carriers of this allele. The initial identification of NPC was related to the 30 bp del-LMP1-EBV gene and high frequencies of the -A*02, -B*15, -DRB1*12, -DQB1*03, and -DQA1*01 HLA alleles. Our study results suggest an association of the 30 bp del-LMP1-EBV gene and the HLA-B*15 allele with NPC susceptibility.
]]>Pathophysiology doi: 10.3390/pathophysiology29040052
Authors: Gaganpreet Kaur Wendy Leskova Norman R. Harris
Purpose. Previous studies suggest that the endothelial glycocalyx adds to vascular resistance, inhibits thrombosis, and is critical for regulating homogeneous blood flow and ensuring uniform red blood cell (RBC) distribution. However, these functions and consequences of the glycocalyx have not been examined in the retina. We hypothesize that the endothelial glycocalyx is a critical regulator of retinal hemodynamics and perfusion and decreases the propensity for retinal thrombus formation. Methods. Hyaluronidase and heparinase, which are endothelial glycocalyx-degrading enzymes, were infused into mice. Fluorescein isothiocyanate–dextran (2000 kDa) was injected to measure lumen diameter, while RBC velocity and distribution were measured using fluorescently labeled RBCs. The diameters and velocities were used to calculate retinal blood flow and shear rates. Mean circulation time was calculated by measuring the difference between arteriolar and venular mean transit times. Rose Bengal dye was infused, followed by illumination with a green light to induce thrombosis. Results. The acute infusion of hyaluronidase and heparinase led to significant increases in both arteriolar (7%) and venular (16%) diameters in the retina, with a tendency towards increased arteriolar velocity. In addition, the degradation caused a significant decrease in the venular shear rate (14%). The enzyme infusion resulted in substantial increases in total retinal blood flow (26%) and retinal microhematocrit but no changes in the mean circulation time through the retina. We also observed an enhanced propensity for retinal thrombus formation with the removal of the glycocalyx. Conclusions. Our data suggest that acute degradation of the glycocalyx can cause significant changes in retinal hemodynamics, with increases in vessel diameter, blood flow, microhematocrit, pro-thrombotic conditions, and decreases in venular shear rate.
]]>Pathophysiology doi: 10.3390/pathophysiology29040051
Authors: Nurina Febriyanti Ayuningtyas Fatma Yasmin Mahdani Togu Andrie Simon Pasaribu Muhammad Chalim Visilmi Kaffah Putri Ayna Arvind Babu Rajendra Santosh Luigi Santacroce Meircurius Dwi Condro Surboyo
Oral carcinogenesis is also dependent on the balance of the oral microbiota. Candida albicans is a member oral microbiota that acts as an opportunistic pathogen along with changes in the epithelium that can predispose to premalignancy and/or malignancy. This systematic review uses the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines to analyze the role of Candida albicans in the process of oral carcinogenesis. Eleven articles qualified inclusion criteria, matched keywords, and provided adequate information about the carcinogenesis parameters of Candida albicans in oral cancer. Candida albicans in oral carcinogenesis can be seen as significant virulent factors for patients with oral squamous cell carcinoma (OSCC) or potentially malignant disorder (OPMD) with normal adjacent mucosa. Candida albicans have a role in the process of oral carcinogenesis concerning morphological phenotype changes in cell structure and genotype and contribute to the formation of carcinogenic substances that can affect cell development towards malignancy.
]]>Pathophysiology doi: 10.3390/pathophysiology29040050
Authors: Babu Raja Maharjan Susan V. McLennan Stephen M. Twigg Paul F. Williams
Transforming growth factor beta (TGFβ) is a versatile cytokine. Although a profibrotic role of TGFβ is well established, its effect on tissue inhibitor of metalloproteinase (TIMPs) and inflammatory mediators are incompletely described. This study investigates the profibrotic and pro-inflammatory role of TGFβ1 during adipocyte differentiation. NIH3T3L1 cells were used for the in vitro study and were differentiated by adding a standard differentiation mix either with rosiglitazone (R-Diff) or without (S-Diff). Recombinant TGFβ1 (2 ng/mL) was added to the undifferentiated preadipocyte during the commitment stage and at the terminal differentiation stage. TGFβ1 treatment significantly decreased adiponectin mRNA at both early commitment (>300 fold) and terminal differentiated cells [S-Diff (~33%) or R-Diff (~20%)]. TGFβ1 upregulated collagen VI mRNA and its regulators connective tissue growth factor (CCN2/CTGF), TIMP1 and TIMP3 mRNA levels in undifferentiated preadipocytes and adipocytes at commitment stage. But in the terminal differentiated adipocytes, changes in mRNA and protein of collagen VI and TIMP3 mRNA were not observed despite an increase in CCN2/CTGF, TIMP1 mRNA. Although TGFβ1 upregulated interleukin-6 (IL6) and monocyte chemoattractant protein-1 (MCP1) mRNA at all stages of differentiation, decreased tumor necrosis factor-α (TNFα) mRNA was observed early in adipocyte differentiation. This study highlights the complex role of TGFβ1 on extracellular matrix (ECM) remodeling and inflammatory markers in stimulating both synthetic and inhibitory markers of fibrosis at different stages of adipocyte differentiation.
]]>Pathophysiology doi: 10.3390/pathophysiology29040049
Authors: Abodunrin Adebayo Ojetola Jerome Ndudi Asiwe Wale Johnson Adeyemi Dare Joshua Ogundipe Adesoji Adedipe Fasanmade
Diets rich in fats and fructose are associated with the pathogenesis of oxidative stress-induced non-alcoholic fatty liver disease. Therefore, we investigated the effect of D-ribose-L-cysteine (DRLC) in high-fructose high-fat (HFHF) diet-fed rats. Twenty rats (n = 5), divided into four groups, were simultaneously exposed to HFHF and/or DRLC (250 mg/kg) orally during the 8 weeks of the study. Results showed that HFHF precipitated pro-inflammation and selective disruption of the oxidative stress markers. There were significant decreases in the level of antioxidants such as superoxide dismutase (SOD), glutathione peroxidase (GPX), total antioxidant capacity (TAC), hepatic SOD and GPX. Significant increases in serum levels of uric acid (UA), tumour necrosis factor-alpha (TNF-α), C-reactive protein (CRP) and hepatic Xanthine oxidase (XO) were observed in the HFHF compared to the control. In the HFHF + DRLC group, oxidative stress was mitigated due to differences in serum levels of SOD, GPX, TAC, TNF-α, liver SOD, and XO relative to control. The administration of DRLC alone caused significant reductions in malondialdehyde, UA and CRP and a significant increase in SOD compared to the control. DRLC prevents hepatic and systemic oxidative stress and pro-inflammatory events in HFHF diet-fed rats.
]]>Pathophysiology doi: 10.3390/pathophysiology29040048
Authors: Zakariya H. Nawasreh Mohammad A. Yabroudi Ahmad A. Darwish Wesam A. Debes Khaldoon M. Bashaireh
Background: The factors contributing to soccer injuries and their influence on the occurrence of injury are controversial and inconclusive. This study aimed to determine the association between player characteristics and playing factors with injuries in professional soccer players. Methods: One hundred and fifty-two professional soccer players completed a self-administered questionnaire that asked about demographic information and injury profile, the type of playing surface on which they sustained their injury, medical treatment, and the time lost due to soccer injury at the end of the soccer season. Results: The injury rate was 44.74% (n = 68; males: 61.50% (n = 56), females: 19.70% (n = 12)). Players’ age (OR: 1.15, 95%CI: 1.05–1.25, p < 0.002) and BMI (OR: 1.21, 95%CI: 1.06–1.38, p < 0.003) were significantly associated with soccer injuries. After adjusting for age and BMI, players’ sex (OR: 5.39, 95%CI: 2.11–13.75, p < 0.001), previous soccer injury (OR: 3.308, 95%CI: 2.307–29.920, p < 0.001), and playing surfaces (OR: 11.07, 95%CI: 4.53–27.03, p < 0.001) were the significant predictors of soccer injuries. Conclusion: Players’ age, BMI, sex, previous soccer injury, and playing surface were associated with injuries among professional soccer players. Old male athletes with high BMI, previous soccer injuries, and playing on natural grass were more likely to sustain soccer injuries than young female players with low BMI who had no previous injuries and played on synthetic surfaces.
]]>Pathophysiology doi: 10.3390/pathophysiology29040047
Authors: Jaksa Zanchi Dino Miric Lovel Giunio Anteo Bradaric Slujo Mislav Lozo Duje Erceg Duje Orsulic Josip A. Borovac
A spontaneous coronary artery dissection (SCAD) during the postpartum period is a serious medical emergency and the most important non-atherosclerotic cause of coronary artery disease (CAD) in this population. While conservative management is recommended in most SCAD scenarios, cases complicated by hemodynamic instability or cardiogenic shock are particularly challenging and might be amenable only with invasive percutaneous or cardiothoracic surgical management. Herein, we present a case of a 35-year-old otherwise healthy woman that suffered an intense emotional stress event and was subsequently admitted with crushing chest pain to the emergency department. The initial electrocardiogram showed dynamic changes suggesting anterolateral ST-elevation myocardial infarction. She gave birth to a healthy child 3 months before the current presentation. Diagnostic angiography found no occlusive CAD but instead an extensive intramural hematoma originating from the left main artery dissection and extending to the whole left coronary circulation was observed. Hemodynamic instability and hypotension soon followed, and the patient went into cardiogenic shock. The heart team opted for conservative and supportive intensive care management without surgical or percutaneous intervention. This decision ultimately led to the successful extubation of the patient and the achievement of hemodynamic stability. The patient was eventually safely discharged home without any permanent disability.
]]>Pathophysiology doi: 10.3390/pathophysiology29040046
Authors: Tatyana Bukkieva Maria Pospelova Aleksandr Efimtsev Olga Fionik Tatyana Alekseeva Konstantin Samochernykh Elena Gorbunova Varvara Krasnikova Albina Makhanova Aleksandra Nikolaeva Samvel Tonyan Anna Lepekhina Anatoliy Levchuk Gennadiy Trufanov Serik Akshulakov Maxim Shevtsov
Complex breast cancer (BC) treatment can cause various neurological and psychiatric complications, such as postmastectomy pain syndrome, vestibulocerebellar ataxia, and depression, which can lead to microstructural damage of the white matter tracts of the brain. The purpose of the study is to assess microstructural changes in the white matter tracts of the brain in BC survivors using diffusion tensor imaging (DTI). Single DTI scans were performed on patients (n = 84) after complex BC treatment (i.e., surgery, chemotherapy and/or radiation therapy) and on the control group (n = 40). According to the results, a decrease in the quantitative anisotropy (FDR ≤ 0.05) was revealed in the bilateral corticospinal tracts, cerebellar tracts, corpus callosum, fornix, left superior corticostriatal and left corticopontine parietal in patients after BC treatment in comparison to the control group. A decrease in the quantitative anisotropy (FDR ≤ 0.05) was also revealed in the corpus callosum and right cerebellar tracts in patients after BC treatment with the presence of postmastectomy pain syndrome and vestibulocerebellar ataxia. The use of DTI in patients after BC treatment reveals microstructural properties of the white matter tracts in the brain. The results will allow for the improvement of treatment and rehabilitation approaches in patients receiving treatment for breast cancer.
]]>Pathophysiology doi: 10.3390/pathophysiology29040045
Authors: Cristina Vila Zárate Candelaria Martín González Ruimán José González Álvarez Iván Soto Darias Beatriz Díaz Pérez Pedro Abreu González Vicente Medina Arana Antonio Martínez Riera
Cytokines are expressed by various cells after several stimuli such as surgical tissue damage, producing a systemic inflammatory response (SIR). C-reactive protein (CRP) is used extensively in clinical practice after operative injury, but proinflammatory cytokines, iron status, albumin, neutrophil-to-lymphocyte (N/L) ratio and hemoglobin, as acute phase reactants, have been poorly documented. This study aims to show how they behave after surgery, comparing laparoscopic (LC) versus open cholecystectomy (OC). In total, 55 patients were included in a prospective non-randomized form to undergo a cholecystectomy: 8 patients OC (50% females) and 47 patients LC (68% females). Before (A1) and 24 h after surgery (A2), blood samples were taken for an ordinary analysis and IL6, IL8 and TNFα determination. There were no differences between LC and OC groups concerning age, CRP, IL6 and TNFα at day A1. In the LC group at day A2, CRP, IL6, IL8, TNF, ferritin, leukocytes and N/L ratio increased; hemoglobin, lymphocytes, prothrombin and albumin decreased (p < 0.05). In the OC group at day A2, only IL6 (p < 0,07), ferritin, leukocytes, N/L ratio and CRP (p < 0.05) increased; serum iron, hemoglobin, lymphocytes and albumin (p < 0.05) decreased. At day A2, OC vs. LC group, higher values were observed in IL6, ferritin and CRP (p ≤ 0.05), and lesser values were observed in serum iron and prothrombin (p < 0.05). In conclusion, classic markers of inflammation are altered after surgery, in a milder way in laparoscopic surgery. Ferritin can be used as an inflammatory marker, as has been described in COVID-19 infection.
]]>Pathophysiology doi: 10.3390/pathophysiology29030044
Authors: Pooja Veerareddy Nhi Dao Jungmi W. Yun Karen Y. Stokes Elizabeth Disbrow Christopher G. Kevil Urska Cvek Marjan Trutschl Philip Kilgore Murali Ramanathan Robert Zivadinov Jonathan S. Alexander
Multiple sclerosis (MS) is a leading cause of neurodegenerative disability in younger individuals. When diagnosed early, MS can be managed more effectively, stabilizing clinical symptoms and delaying disease progression. The identification of specific serum biomarkers for early-stage MS could facilitate more successful treatment of this condition. Because MS is an inflammatory disease, we assessed changes in enzymes of the endothelial hydrogen sulfide (H2S) pathway in response to inflammatory cytokines. Blotting analysis was conducted to detect Cystathionine γ-lyase (CSE), Cystathionine beta synthase (CBS), and 3-mercaptopyruvate sulfurtransferase (MST) in human brain microvascular endothelial apical and basolateral microparticles (MPs) and cells following exposure to tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ). CSE was increased in MPs and cells by exposure to TNF-α/IFN-γ; CBS was elevated in apical MPs but not in cells or basolateral MPs; MST was not significantly affected by cytokine exposure. To test how our findings relate to MS patients, we evaluated levels of CSE, CBS, and MST in serum samples from healthy control and MS patients. We found significantly decreased levels of CBS and MST (p = 0.0004, 0.009) in MS serum samples, whereas serum levels of CSE were marginally increased (p = 0.06). These observations support increased CSE and lower CBS and MST expression being associated with the vascular inflammation in MS. These changes in endothelial-derived sulfide enzymes at sites of inflammation in the brain may help to explain sulfide-dependent changes in vascular dysfunction/neuroinflammation underlying MS. These findings further support the use of serum samples to assess enzymatic biomarkers derived from circulating MPs. For example, “liquid biopsy” can be an important tool for allowing early diagnosis of MS, prior to the advanced progression of neurodegeneration associated with this disease.
]]>Pathophysiology doi: 10.3390/pathophysiology29030043
Authors: Meircurius Dwi Condro Surboyo Lakshman Samaranayake Arvind Babu Rajendra Santosh Nurina Febriyanti Ayuningtyas Sisca Meida Wati Retno Pudji Rahayu Francisco Urbina Winni Langgeng Kuntari Sesaria Junita Mega Rahma Syahnia Karlina Puspasari Adiastuti Endah Parmadiati Diah Savitri Ernawati
The pigmentation of the fungiform papillae of the tongue is a rare idiopathic condition in which only the fungiform papillae appear hyperpigmented. In the absence of any reviews on the subject, we conducted a systematic review of the aetiopathogenesis and pathophysiology of pigmented fungiform papillae (PFP) of the tongue, including its demographic and histopathological features, trying to outline a possible aetiology. The preferred reporting items for systematic reviews and meta-analyses (PRISMA) was performed using PubMed, Scopus, EMBASE databases and manual searches, for publications between January 1974 and July 2022. Inclusion criteria were case reports defining patients’ characteristics, their general medical and dental conditions, histopathological and/or immunohistochemical findings, all with a final definitive diagnosis of PFP. Overall, 51 studies comprising 69 cases of PFP which included histopathological descriptions were reviewed. Prominent features consisted of hyperpigmentation of melanocytes, melanophages, chromatophores, and a lymphocytic infiltrate in the subepidermal area of the fungiform papillae. On special staining, PFP contained melanin, not iron or hemosiderin. On immunohistochemistry, immune-reactive CD3+ T lymphocytes, S-100 and Sox10, but non-immune-reactive melan-A intraepithelial melanocytes were noted in some studies. The presence of hyperpigmented melanocytes and melanophages, with non-immune-reactive melan-A, suggests that PFP are a benign and physiological form of pigmentation. The inflammatory infiltrates described in some papillary lesions could possibly be due to traumatic events during mastication. Nevertheless, the true reasons for the hyperpigmentation of the fungiform papillae are as of yet elusive, and remain to be determined.
]]>Pathophysiology doi: 10.3390/pathophysiology29030042
Authors: Varvara Krasnikova Maria Pospelova Olga Fionik Tatyana Alekseeva Konstantin Samochernykh Nataliya Ivanova Nikita Trofimov Tatyana Vavilova Elena Vasilieva Albina Makhanova Samwel Tonyan Alexandra Nikolaeva Evgeniya Kayumova Maxim Shevtsov
Various complications from a breast cancer treatment, in the pathogenesis of which excessive tissue fibrosis plays a leading role, are a common pathology. In this study, the levels of TGF-β1, VEGFR-2, and TIMP-2 were determined by the immuno-enzyme serum analysis for patients during the long-term period after breast cancer treatment as potential markers of fibrosis. The single-center study enrolled 92 participants, which were divided into two age-matched groups: (1) 67 patients following breast cancer treatment, and (2) 25 healthy female volunteers. The intergroup analysis demonstrated that the patients after breast cancer treatment showed a decrease in the serum levels of TGF-β1 (U = 666, p < 0.001) and TIMP-2 (U = 637, p < 0.001) as compared to the group of healthy volunteers. The levels of VEGFR-2 in these groups were comparable (U = 1345, p = 0.082). It was also found that the type of treatment, the presence of lymphedema, shoulder joint contracture, and changes in lymphoscintigraphy did not affect the levels of TGF-β1, VEGFR-2, and TIMP-2 within the group of patients after breast cancer treatment. These results may indicate that these biomarkers do not play a leading role in the maintenance and progression of fibrosis in the long-term period after breast cancer treatment. The reduced levels of TGF-β1 and TIMP-2 may reflect endothelial dysfunction caused by the antitumor therapy.
]]>Pathophysiology doi: 10.3390/pathophysiology29030041
Authors: Skender Topi Lucrezia Bottalico Ioannis Alexandros Charitos Marica Colella Marina Di Domenico Raffaele Palmirotta Luigi Santacroce
The use of innovative approaches to elucidate the pathophysiological mechanisms of autoimmune diseases, as well as to further study of the factors which can have either a positive or negative effect on the course of the disease, is essential. In this line, the development of new molecular techniques and the creation of the Human Genome Program have allowed access to many more solutions to the difficulties that exist in the identification and characterization of the microbiome, as well as changes due to various factors. Such innovative technologies can rekindle older hypotheses, such as molecular mimicry, allowing us to move from hypothesis to theory and from correlation to causality, particularly regarding autoimmune diseases and dysbiosis of the microbiota. For example, Prevotella copri appears to have a strong association with rheumatoid arthritis; it is expected that this will be confirmed by several scientists, which, in turn, will make it possible to identify other mechanisms that may contribute to the pathophysiology of the disease. This article seeks to identify new clues regarding similar correlations between autoimmune activity and the human microbiota, particularly in relation to qualitative and quantitative microbial variations therein.
]]>Pathophysiology doi: 10.3390/pathophysiology29030040
Authors: Daniel W. Flowers Wayne Brewer Katy Mitchell Jennifer Ellison Clifton Frilot
The treatment of patients with knee osteoarthritis is typically focused on the involved lower extremity. There is a gap in the literature concerning the effectiveness of core stabilization training on the treatment of patients with knee osteoarthritis. This investigation aimed to determine whether core stabilization improved the gait and functional ability of patients with knee osteoarthritis. Eighteen participants with knee osteoarthritis completed the six-week core stabilization intervention. Participants completed the gait motion analysis and the Knee Injury and Osteoarthritis Outcome Score to assess self-perceived function, pre- and post-intervention. Gait speed improved (p = 0.006, d = 0.59), while the external knee adduction moment decreased (p = 0.034, d = −0.90). Moreover, self-reported function improved (p < 0.001, d = 1.26). The gait speed and external knee adduction moment changes met minimal detectable change thresholds, while gait speed also met the minimal clinically important difference. A six-week core stabilization program can thus improve gait speed and reduce the external knee adduction moment, which is tied to disease progression. Increased functional scores post-intervention indicate an important clinical improvement. Core stabilization training is a safe and potentially effective treatment option for this population.
]]>Pathophysiology doi: 10.3390/pathophysiology29030039
Authors: Leonid P. Churilov Muslimbek G. Normatov Vladimir J. Utekhin
Molecular mimicry between human and microbial/viral/parasite peptides is common and has long been associated with the etiology of autoimmune disorders provoked by exogenous pathogens. A growing body of evidence accumulated in recent years suggests a strong correlation between SARS-CoV-2 infection and autoimmunity. The article analyzes the immunogenic potential of the peptides shared between the SARS-CoV-2 spike glycoprotein (S-protein) and antigens of human endocrinocytes involved in most common autoimmune endocrinopathies. A total of 14 pentapeptides shared by the SARS-CoV-2 S-protein, thyroid, pituitary, adrenal cortex autoantigens and beta-cells of the islets of Langerhans were identified, all of them belong to the immunoreactive epitopes of SARS-CoV-2. The discussion of the findings relates the results to the clinical correlates of COVID-19-associated autoimmune endocrinopathies. The most common of these illnesses is an autoimmune thyroid disease, so the majority of shared pentapeptides belong to the marker autoantigens of this disease. The most important in pathogenesis of severe COVID-19, according to the authors, may be autoimmunity against adrenals because their adequate response prevents excessive systemic action of the inflammatory mediators causing cytokine storm and hemodynamic shock. A critique of the antigenic mimicry concept is given with an assertion that peptide sharing is not a guarantee but only a prerequisite for provoking autoimmunity based on the molecular mimicry. The latter event occurs in carriers of certain HLA haplotypes and when a shared peptide is only used in antigen processing
]]>Pathophysiology doi: 10.3390/pathophysiology29030038
Authors: Supaporn Kulthinee Naohiro Yano Shougang Zhuang Lijiang Wang Ting C. Zhao
Histone deacetylases (HDACs) are a superfamily of enzymes that catalyze the removal of acetyl functional groups from lysine residues of histone and non-histone proteins. There are 18 mammalian HDACs, which are classified into four classes based on the primary homology with yeast HDACs. Among these groups, Class I and II HDACs play a major role in lysine deacetylation of the N-terminal histone tails. In mammals, HDACs play a pivotal role in the regulation of gene transcription, cell growth, survival, and proliferation. HDACs regulate the expression of inflammatory genes, as evidenced by the potent anti-inflammatory activity of pan-HDAC inhibitors, which were implicated in several pathophysiologic states in the inflammation process. However, it is unclear how each of the 18 HDAC proteins specifically contributes to the inflammatory gene expression. It is firmly established that inflammation and its inability to converge are central mechanisms in the pathogenesis of several cardiovascular diseases (CVDs). Emerging evidence supports the hypothesis that several different pro-inflammatory cytokines regulated by HDACs are associated with various CVDs. Based on this hypothesis, the potential for the treatment of CVDs with HDAC inhibitors has recently begun to attract attention. In this review, we will briefly discuss (1) pathophysiology of inflammation in cardiovascular disease, (2) the function of HDACs in the regulation of atherosclerosis and cardiovascular diseases, and (3) the possible therapeutic implications of HDAC inhibitors in cardiovascular diseases. Recent studies reveal that histone deacetylase contributes critically to mediating the pathophysiology of inflammation in cardiovascular disease. HDACs are also recognized as one of the major mechanisms in the regulation of inflammation and cardiovascular function. HDACs show promise in developing potential therapeutic implications of HDAC inhibitors in cardiovascular and inflammatory diseases.
]]>Pathophysiology doi: 10.3390/pathophysiology29030037
Authors: Irina V. Belyaeva Anna N. Kosova Andrei G. Vasiliev
The authors would like to make the following correction to the published paper [...]
]]>Pathophysiology doi: 10.3390/pathophysiology29030036
Authors: Anton V. Barsukov Alexander E. Korovin Leonid P. Churilov Ekaterina V. Borisova Dmitry V. Tovpeko
Low-intensity systemic inflammation is an important element of heart failure pathogenesis. The aim of this study is to assess proinflammatory status serum indicators (C-reactive protein (CRP), tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6)) in middle-aged males (M) and females (F) with essential hypertension (HTN) depending on left ventricular (LV) diastolic dysfunction (LVDD). The main group comprised 55 M and 49 F with the first- to second-severity grade HTN with mild heart failure and a preserved LV ejection fraction ≥50%. Patients had sinus rhythm, first or second-severity degree LVDD, LV hypertrophy, left atrium dilatation, and NT-proBNP > 125 pg/mL. Comparison group: 30 hypertensives without cardiac dysfunction; control group: 31 normotensives. Quantitative features were compared using the Mann–Whitney test, median χ2, ANOVA module. Spearman’s rank correlation coefficients were determined to identify the relationship between the proinflammatory pattern and exercise tolerance. Hypertensive M had markedly higher CRP, TNF-α, and IL-6 levels compared to F. All mean values corresponded to reference range. In patients with second-degree LVDD, CRP, TNF-α, and IL-6 levels were significantly greater than in subjects with first-degree LVDD (both within M and within F samples). Significant negative associations between CRP, IL-6, and TNF-α levels and the 6 min walk test existed in hypertensive M and F. The study demonstrated a close relationship between the proinflammatory pattern and LVDD and exercise tolerance indicators, regardless of the hypertensive patient’s sex.
]]>Pathophysiology doi: 10.3390/pathophysiology29030035
Authors: Marco Cascella Maria Rosaria Muzio Federica Monaco Davide Nocerino Alessandro Ottaiano Francesco Perri Massimo Antonio Innamorato
Pain and nociception are different phenomena. Nociception is the result of complex activity in sensory pathways. On the other hand, pain is the effect of interactions between nociceptive processes, and cognition, emotions, as well as the social context of the individual. Alterations in the nociceptive route can have different genesis and affect the entire sensorial process. Genetic problems in nociception, clinically characterized by reduced or absent pain sensitivity, compose an important chapter within pain medicine. This chapter encompasses a wide range of very rare diseases. Several genes have been identified. These genes encode the Nav channels 1.7 and 1.9 (SCN9A, and SCN11A genes, respectively), NGFβ and its receptor tyrosine receptor kinase A, as well as the transcription factor PRDM12, and autophagy controllers (TECPR2). Monogenic disorders provoke hereditary sensory and autonomic neuropathies. Their clinical pictures are extremely variable, and a precise classification has yet to be established. Additionally, pain insensitivity is described in diverse numerical and structural chromosomal abnormalities, such as Angelman syndrome, Prader Willy syndrome, Chromosome 15q duplication syndrome, and Chromosome 4 interstitial deletion. Studying these conditions could be a practical strategy to better understand the mechanisms of nociception and investigate potential therapeutic targets against pain.
]]>Pathophysiology doi: 10.3390/pathophysiology29030034
Authors: Krasimir Kostov Alexander Blazhev
The increased glycation of elastin is an important factor in vascular changes in diabetes. Using the ELISA method, we determined serum levels of IgM and IgG autoantibodies to advanced glycation end products of vascular elastin (anti-AGE EL IgM and anti-AGE EL IgG) in 59 hypertensive patients with type 2 diabetes (T2D) and 20 healthy controls. Serum levels of matrix metalloproteinases-2 and -9 (MMP-2 and MMP-9) and the C-reactive protein (CRP) were also determined. The levels of anti-AGE EL IgM antibodies in the T2D group were similar to those in the control group, while those of anti-AGE EL IgG antibodies were significantly higher (p = 0.017). Significant positive correlations were found between the levels of anti-AGE EL IgM antibodies and MMP-2 (r = 0.322; p = 0.013) and between the levels of anti-AGE EL IgG antibodies and CRP (r = 0.265; p = 0.042). Our study showed that elevated anti-AGE EL IgG antibody levels may be an indicator of the enhanced AGE-modification and inflammatory-mediated destruction of vascular elastin in hypertensive patients with T2D. Anti-AGE EL IgM antibodies may reflect changes in vascular MMP-2 activity, and their elevated levels may be a sign of early vascular damage.
]]>Pathophysiology doi: 10.3390/pathophysiology29030033
Authors: Naim Mahroum Yehuda Shoenfeld
The pathophysiological mechanisms involved in chronic disorders such as complex regional pain syndrome, fibromyalgia, chronic fatigue syndrome, silicone breast implant–related symptoms, and post-COVID syndrome have not been clearly defined. The course of the pain in some of the syndromes, the absence of evident tissue damage, and the predominance of alterations in the autonomic nervous system are shared similarities between them. The production of autoantibodies following a trigger in the syndromes was previously described, for instance, trauma in complex regional pain syndrome, infectious agents in fibromyalgia, chronic fatigue syndrome, and post-COVID syndrome, and the immune stimulation by silicone in women with breast implants. In fact, the autoantibodies produced were shown to be directed against the autonomic nervous system receptors, leading to the amplification of the perception of pain alongside various clinical symptoms seen during the clinical course of the syndromes. Therefore, we viewed autoantibodies targeting the autonomic nervous system resulting in autonomic dysfunction as likely the most comprehensive explanation of the pathophysiology of the disorders mentioned. Based on this, we aimed to introduce a new concept uniting complex regional pain syndrome, fibromyalgia, chronic fatigue syndrome, silicone breast implant–related symptoms, and post-COVID syndrome, namely “autoimmune autonomic dysfunction syndromes”. Due to its etiological, pathophysiological, and clinical implications, the suggested term would be more precise in classifying the syndromes under one title. The new title would doubtlessly facilitate both laboratory and clinical studies aimed to improve diagnosis and make treatment options more directed and precise.
]]>Pathophysiology doi: 10.3390/pathophysiology29030032
Authors: Gul Habib Khalid Mahmood Haji Gul Muhammad Tariq Qurat Ul Ain Azam Hayat Mujaddad Ur Rehman
The global spread of the coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has infected humans in all age groups, deteriorated host immune responses, and caused millions of deaths. The reasons for individuals succumbing to COVID-19 were not only the SARS-CoV-2 infection but also associated bacterial infections. Antibiotics were largely used to prevent bacterial infections during COVID-19 illness, and many bacteria became resistant to conventional antibiotics. Although COVID-19 was considered the main culprit behind the millions of deaths, bacterial coinfections and superinfections were the major factors that increased the mortality rate in hospitalized patients. In the present study, we assessed the pathophysiology of methicillin-resistant Staphylococcus aureus (MRSA) superinfection in COVID-19 patients in Pakistan. A total of 3492 COVID-19 hospitalized patients were screened among which 224 strain were resistant to methicillin; 110 strains were tazobactam-resistant; 53 strains were ciprofloxacin-resistant; 23 strains were gentamicin-resistant; 11 strains were azithromycin-resistant; 3 strains were vancomycin-resistant. A high frequency of MRSA was detected in patients aged ≥50 with a prevalence of 7.33%, followed by patients aged >65 with a prevalence of 5.48% and a 5.10% prevalence in patients aged <50. In addition, pneumonia was detected in the COVID-19-associated MRSA (COVID-MRSA) that showed decreased levels of lymphocytes and albumin and increased the mortality rate from 2.3% to 25.23%. Collectively, an MRSA superinfection was associated with increased mortality in COVID-19 after 12 to 18 days of hospitalization. The study assessed the prevalence of MRSA, mortality rate, pneumonia, and the emergence of antibiotic resistance as the main outcomes. The study summarized that COVID-MRSA aggravated the treatment and recovery of patients and suggested testing MRSA as critical for hospitalized patients.
]]>Pathophysiology doi: 10.3390/pathophysiology29030031
Authors: Ruth Solomon Jan Pieter Hommen Francesco Travascio
The anterior cruciate ligament (ACL) is a commonly injured ligament in the knee. Bone tunnel widening is a known phenomenon after soft-tissue ACL reconstruction and etiology and the clinical relevance has not been fully elucidated. Osteoconductive compounds are biomaterials providing an appropriate scaffold for bone formation such as a demineralized bone matrix. Osteoinductive materials contain growth factors stimulating bone lineage cells and bone growth. A possible application of osteoinductive/osteoconductive (OIC) material is in ACL surgery. We hypothesized that OIC placed in ACL bone tunnels: (1) reduces tunnel widening, (2) improves graft maturation, and (3) reduces tunnel ganglion cyst formation. To test this hypothesis, this study evaluated the osteogenic effects of demineralized bone matrix (DBM) and platelet-rich plasma (PRP) on tunnel widening, graft maturation, and ganglion cyst formation. This was a randomized controlled clinical trial pilot study. A total of 26 patients that elected to have ACL reconstruction surgery were randomized between the OIC and control group. Measurements of tunnel expansion and graft-tunnel incorporation were conducted via the quantitative image analysis of MRI scans performed at six months after surgery for both groups. No patients had adverse post-operative reactions or infections. The use of OIC significantly reduced tunnel widening (p < 0.05) and improved graft maturation (p < 0.05). Patients treated with OIC had a significantly lower prevalence of ganglion cyst compared to the control group (p < 0.05). The use of OIC has measurable effects on the reduction of tunnel widening, improved graft maturation, and decreased size of ganglion cyst after ACL reconstruction. This study explored the utilization of biologics to minimize bone tunnel widening in ACL reconstruction surgery.
]]>Pathophysiology doi: 10.3390/pathophysiology29030030
Authors: Phillip Gu Eric Clifford Andrew Gilman Christopher Chang Elizabeth Moss David I. Fudman Phillip Kilgore Urska Cvek Marjan Trutschl J. Steven Alexander Ezra Burstein Moheb Boktor
Low socioeconomic status (SES) is associated with greater morbidity and increased healthcare resource utilization (HRU) in IBD. We examined whether a financial assistance program (FAP) to improve healthcare access affected outcomes and HRU in a cohort of indigent IBD patients requiring biologics. IBD patients (>18 years) receiving care at a ‘safety-net’ hospital who initiated biologics as outpatients between 1 January 2010 and 1 January 2019 were included. Patients were divided by FAP status. Patients without FAP had Medicare, Medicaid, or commercial insurance. Primary outcomes were steroid-free clinical remission at 6 and 12 months. Secondary outcomes were surgery, hospitalization, and ED utilization. Multivariate logistic regression was used to calculate odds ratio (OR) and 95% confidence interval (CI). Decision tree analysis (DTA) was also performed. We included 204 patients with 258 new biologic prescriptions. FAP patients had less complex Crohn’s disease (50.7% vs. 70%, p = 0.033) than non-FAP patients. FAP records indicated fewer prior surgeries (19.6% vs. 38.4% p = 0.003). There were no statistically significant differences in remission rates, disease duration, or days between prescription and receipt of biologics. In multivariable logistic regression, adjusting for baseline demographics and disease severity variables, FAP patients were less likely to undergo surgery (OR: 0.28, 95% CI [0.08–0.91], p = 0.034). DTA suggests that imaging utilization may shed light on surgical differences. We found FAP enrollment was associated with fewer surgeries in a cohort of indigent IBD patients requiring biologics. Further studies are needed to identify interventions to address healthcare disparities in IBD.
]]>Pathophysiology doi: 10.3390/pathophysiology29030029
Authors: Ha Hong Nguyen Ha Hai Tran Le Thi Nguyen Thang Nguyen Nhut Anh Nguyen Mai Tuyet Vi Kien Trung Nguyen
Background: Dyslipidemia is highly prevalent in patients with chronic kidney disease (CKD), and the relationship between dyslipidemia and renal function in these patients remains controversial. Our objectives were to determine the triglycerides/HDL-cholesterol ratio (TG/HDL-C), evaluate the correlation between TG/HDL-C and the urine albumin/creatinine ratio (ACR), and estimate the glomerular filtration rate (eGFR) according to MDRD in CKD patients. Methods: A descriptive cross-sectional study was conducted on 152 patients with CKD at the Endocrine Clinic, the University of Medicine and Pharmacy Hospital, Ho Chi Minh City, Vietnam. Study subjects were medically examined and recorded information on the data collection form. Subjects were tested for total cholesterol, triglycerides, HDL-C, LDL-C, urea, creatinine and albumin, urine creatinine, and eGFR according to the MDRD formula. Data were analyzed using SPSS Statistics version 20.0. Results: The average age was 58.08 ± 15.69 years, and the overweight and obesity rate was 54%. Most patients had comorbidities, among which the most common diseases were hypertension and diabetes mellitus. Among the subjects, 57.3% were CKD stage 3 patients, and ACR was in the range of 30–300 mg/g. According to the classification of CKD using GFR and ACR categories, 40.8% of patients were at very high risk. The average TG/HDL-C ratio was 5.09 ± 4.26. There was a medium negative correlation between TG/HDL-C and eGFR (R = 0.44, p < 0.01) and a weak positive correlation between TG/HDL-C and ACR (R = 0.34, p < 0.01). Conclusions: The TG/HDL-C ratio was a risk factor associated with CKD and was noticeable in monitoring and assessing the risk of progression of CKD.
]]>Pathophysiology doi: 10.3390/pathophysiology29030028
Authors: Celeste Manfredi Lorenzo Spirito Francesco Paolo Calace Raffaele Balsamo Marco Terribile Marco Stizzo Lorenzo Romano Luigi Napolitano Gianluigi Califano Luigi Cirillo Giovanni Maria Fusco Claudia Rosati Carmelo Quattrone Carmine Sciorio Massimiliano Creta Nicola Longo Marco De Sio Davide Arcaniolo
Intravesical chemotherapy may cause chemical cystitis and related lower urinary tract symptoms (LUTS). The aims of this study were to evaluate the efficacy and safety of an oral preparation of hyaluronic acid (HA), chondroitin sulfate (CS), curcumin, and quercetin (Ialuril® Soft Gels) to reduce the severity of LUTS in patients with a history of bladder cancer (BCa) undergoing intravesical chemotherapy. We designed a monocentric, randomized, double-blind, placebo-controlled pilot trial. Patients referred to our institute between November 2016 and March 2018 were enrolled. All subjects had non-muscle-invasive BCa and received intravesical chemotherapy with mitomycin C (MMC). Patients were randomized 1:1 in two groups (intervention vs. control). All subjects underwent oral administration (Ialuril® Soft Gels or placebo) starting one week before the first weekly instillation and ending 30 days after the last one, subsequently starting one week before each monthly instillation and ending 14 days after it. International prostate symptom score (IPSS) and 0-100 visual analogue scale (VAS) were used to assess the efficacy of the treatment. Adverse events were also described. Patients were evaluated at baseline and after 1, 4, 7, and 13 months of intravesical chemotherapy. A total of 34 patients were enrolled. The median IPSS score was significantly lower in the intervention group compared to the control group at 4 (13 vs. 17 points; p = 0.038), 7 (10 vs. 18 points; p < 0.001), and 13 (10 vs. 17 points; p = 0.002) months. The median VAS score was significantly lower in the intervention group compared to the control group at 7 (22 vs. 37 points; p = 0.021) and 13 (20 vs. 35 points; p = 0.024) months. No AE specifically related to supplement or placebo was recorded. Oral formulation of HA, CS, quercetin, and curcumin could be an effective and safe supportive therapy against chemical cystitis in patients receiving intravesical chemotherapy for BCa.
]]>Pathophysiology doi: 10.3390/pathophysiology29030027
Authors: Vladimir Shvartz Eleonora Khugaeva Yuri Kryukov Maria Sokolskaya Artak Ispiryan Elena Shvartz Andrey Petrosyan Elizaveta Dorokhina Leo Bockeria Olga Bockeria
Background: Acute kidney injury (AKI) is among the expected complications of cardiac surgery. Statins with pleiotropic anti-inflammatory and antioxidant effects may be effective in the prevention of AKI. However, the results of studies on the efficacy and safety of statins are varied and require further study. Methods: We conducted a retrospective cohort study to evaluate long-term preoperative intake of atorvastatin and rosuvastatin on the incidence of AKI, based on the “Kidney Disease: Improving Global Outcomes” (KDIGO) criteria in the early postoperative period after coronary artery bypass graft surgery (CABG). We performed propensity score matching to compare the findings in our study groups. The incidence of AKI was assessed on day 2 and day 4 after the surgery. Results: The analysis included 958 patients after CABG. After 1:1 individual matching, based on propensity score, the incidence of AKI was comparable both on day 2 after the surgery (7.4%) between the atorvastatin group and rosuvastatin group (6.5%) (OR: 1.182; 95%Cl 0.411–3.397; p = 0.794), and on postoperative day 4 between the atorvastatin group (3.7%) and the rosuvastatin group (4.6%) (OR: 0.723, 95%Cl 0.187–2.792; p = 0.739). Additionally, there were no statistically significant differences in terms of incidence of AKI after 1:1 individual matching, based on propensity score, between the rosuvastatin group and the control group both on postoperative day 2 (OR: 0.692; 95%Cl 0.252–1.899; p = 0.611) and day 4 (OR: 1.245; 95%Cl 0.525–2.953; p = 0.619); as well as between the atorvastatin group and the control group both on postoperative day 2 (OR: 0.549; 95%Cl 0.208–1.453; p = 0.240) and day 4 (OR: 0.580; 95%Cl 0.135–2.501; p = 0.497). Conclusion: Long-term statin use before CABG did not increase the incidence of postoperative AKI. Further, we revealed no difference in the incidence of post-CABG AKI between the atorvastatin and rosuvastatin groups.
]]>Pathophysiology doi: 10.3390/pathophysiology29030026
Authors: I Made Putra Juliawan Febie Putra Suwana Jimmy Yanuar Annas Muhammad Firman Akbar Widjiati Widjiati
Polycystic ovary syndrome (PCOS), a common hormonal disorder in women of reproductive age, is associated with a poor and unhealthy diet. This study aimed to investigate the effect of a high sucrose and cholic acid (HSCA) diet in the presence of PCOS-like phenotypes. Female Wistar rats were divided into HSCA and normal diet groups for four weeks, each with twenty rats. Body weight was assessed before and after the study. Blood and fecal samples were obtained to measure HOMA-IR and testosterone level (ELISA) and Enterobacteriaceae isolates grown on MacConkey Agar. Obtained ovarian tissues were H&E-stained. HSCA rats demonstrated a reduction in Enterobacteriaceae colonies (median 4.75 × 105 vs. 2.47 × 104/CFU, p < 0.001) and an elevated HOMA-IR (mean 2.94 ± 1.30 vs. 4.92 ± 0.51, p < 0.001), as well as an increase in testosterone level (median 0.65 vs. 3.00 ng/mL, p < 0.001), despite no statistical differences in the change in body weight (mean −2.31 ± 14.42 vs. −3.45 ± 9.32, p = 0.769). In H&E staining, HSCA rats had a reduction in preovulatory follicle count (median 0.50 vs. 0.00, p = 0.005). The HSCA diet caused insulin resistance and high testosterone levels, which contribute to the development of PCOS, and affected folliculogenesis by altering follicular maturation, but had no effect on ovulation.
]]>Pathophysiology doi: 10.3390/pathophysiology29030025
Authors: Hiroaki Matsushita Yohei Misumi Teruaki Masuda Masamitsu Okada Fumika Inoue Mitsuharu Ueda Yukio Ando
Transthyretin (TTR), the precursor protein for amyloidogenic TTR (ATTR) amyloidosis, forms tetramers and escapes glomerular filtration by binding with thyroxine and retinol-binding protein. However, variant TTRs are unstable as tetramers, so monomeric TTR has become the precursor protein of amyloid deposits, via protein misfolding. The aim of the study was to evaluate the utility of urinary TTR in the diagnosis of ATTRv amyloidosis. Urinary samples from healthy volunteers, ATTRv V50M amyloidosis patients, and asymptomatic carriers of the ATTRv V50M gene were analysed using ELISA. To analyse the different forms of TTR secreted to the urine, we performed Western blotting and mass spectrometry. Urinary TTR concentrations were significantly higher in the ATTRv V50M amyloidosis patients than they were in the healthy volunteers and asymptomatic carriers of the gene. Although the TTR concentrations were negligible in the healthy volunteers, they were correlated with disease progression and urinary albumin concentrations in the ATTRv V50M amyloidosis patients. The Western blotting and mass spectrometry revealed the presence of monomeric wild-type and variant TTRs in the urine. Urinary TTR concentrations may become a more sensitive biomarker of ATTRv progression than albumin.
]]>Pathophysiology doi: 10.3390/pathophysiology29030024
Authors: Praveen Raman Mishra Akash Bharti Ridhi Arora Irfan Ahmad Mir V. P. S. Punia
Introduction: Hepatitis C virus (HCV) infection is a serious global public health problem. It is estimated that 2% to 3% of the world’s population is infected with the virus. It was found that chronic hepatitis C is an independent predictor of the development of type 2 diabetes mellitus. Infection with HCV or the inflammatory response to HCV infection likely contributes to the development of insulin resistance (IR), which increases the risk of developing type 2 diabetes in the long term. This study aimed to assess the insulin resistance in hepatitis C and its correlation with various metabolic parameters. Materials and Methods: This cross-sectional observational study was conducted at a tertiary care hospital in North India in the Department of Internal Medicine with hepatitis C-positive patients attending an out-patient or in-patient department. We took a total of 100 patients aged > 18 years and divided them into two groups: Group A with hepatitis C (cases) and Group B without hepatitis C (controls). There were a total of 50 hepatitis C patients and 50 patients without hepatitis C. Results: A total of 100 patients were included in the present study after obtaining informed consent. There was a significantly higher level of serum ferritin and insulin in group A patients than group B patients. There was a positive correlation of insulin resistance with the serum insulin, ferritin levels, cholesterol, LDL and triglyceride level and a negative correlation with the serum HDL level. The incidence of insulin resistance was positively correlated with changes in fibrosis in the liver due to the hepatitis C infection. Conclusions: From our study, we found that there is an increased incidence of insulin resistance in the patients with hepatitis-C infection, and insulin resistance is associated with the presence of altered hepatic function test results.
]]>Pathophysiology doi: 10.3390/pathophysiology29020023
Authors: Shrey Kumar Srivastav Irfan Ahmad Mir Naman Bansal Pankaj Kumar Singh Rashmi Kumari Ajoy Deshmukh
Metabolic syndrome (MS) is a cluster of conditions including central obesity, hypertriglyceridemia, low HDL cholesterol, hyperglycaemia, and hypertension with a prevalence rate of 20–25% of the world’s adult population. Metabolic syndrome is often characterized by insulin resistance, which some have suggested is a major supportive connection between physical inactivity and MS. Various studies suggest that moderately elevated iron and ferritin levels are associated with an increased prevalence of metabolic syndrome and are markers of insulin resistance. Increased body iron stores are associated with the development of glucose intolerance, type 2 diabetes mellitus, and insulin resistance syndrome (IRS). This is a hospital-based cross-sectional observational study, which was conducted in the department of internal medicine of a tertiary care hospital in northern India. The study was conducted from 1 January 2019 to 30 June 2020 and included 100 patients and 100 controls. All subjects in the age group of 35–65 years were enrolled and investigated as per the study design. Metabolic syndrome patients were diagnosed according to the modified National Cholesterol Education Program Adult Treatment Panel-III (NCEP ATP-III) with BMI > 23 kg/m2. All baseline investigations were undertaken, including serum ferritin levels. Insulin resistance (IR) was calculated using the homeostasis model assessment IR (HOMA-IR) formula. We found a positive association between an increase in serum ferritin with the prevalence of metabolic syndrome and its clinical parameter. The serum ferritin level was positively correlated with the level of insulin resistance and inversely correlated with the insulin level of the patients.
]]>Pathophysiology doi: 10.3390/pathophysiology29020022
Authors: Irina V. Belyaeva Anna N. Kosova Andrei G. Vasiliev
Tuberculosis remains a common and dangerous chronic bacterial infection worldwide. It is long-established that pathogenesis of many autoimmune diseases is mainly promoted by inadequate immune responses to bacterial agents, among them Mycobacterium tuberculosis. Tuberculosis is a multifaceted process having many different outcomes and complications. Autoimmunity is one of the processes characteristic of tuberculosis; the presence of autoantibodies was documented by a large amount of evidence. The role of autoantibodies in pathogenesis of tuberculosis is not quite clear and widely disputed. They are regarded as: (1) a result of imbalanced immune response being reactive in nature, (2) a critical part of TB pathogenicity, (3) a beginning of autoimmune disease, (4) a protective mechanism helping to eliminate microbes and infected cells, and (5) playing dual role, pathogenic and protective. There is no single autoimmunity-mechanism development in tuberculosis; different pathways may be suggested. It may be excessive cell death and insufficient clearance of dead cells, impaired autophagy, enhanced activation of macrophages and dendritic cells, environmental influences such as vitamin D insufficiency, and genetic polymorphism, both of Mycobacterium tuberculosis and host.
]]>Pathophysiology doi: 10.3390/pathophysiology29020021
Authors: Vsevolod A. Zinserling Natalia Yu Semenova Anastasia E. Bikmurzina Natalia M. Kruglova Oksana V. Rybalchenko Alexander G. Markov
In spite of intensive studies of different aspects of a new coronavirus infection, many issues still remain unclear. In a screening analysis of histopathology in l200 lethal cases, authors succeeded in performing a wide spectrum of immune histochemical reactions (CD2, CD 3, CD 4, CD 5, CD 7, CD 8, CD14, CD 20, CD 31, CD 34, CD 56, CD 57, CD 68, CD 163, collagen 1,3, spike protein SARS-CoV-2, caspase-3, MLCM; ACE2 receptor, occludin, and claudin-1 and -3) and electron microscopy. The results of the histological and IHC studies of deceased people with varying degrees of severity of coronavirus infection confirmed the ability of these pathogens to cause cytoproliferative changes, primarily in epithelial and endothelial cells. Lesions of various organs are possible, while the reasons for significant differences in organotropy remain unclear. Severe respiratory failure in COVID-19 in humans is associated with a very peculiar viral pneumonia. In the pathogenesis of COVID-19, the most important role is played by lesions of the microcirculatory bed, the genesis of which requires further study, but direct viral damage is most likely. Endothelial damage can be associated with both thrombosis in vessels of various calibers, leading to characteristic complications, and the development of DIC syndrome with maximal kidney damage. Such lesions can be the basis of clinically diagnosed septic shock, while usually there are no morphological data in favor of classical sepsis caused by bacteria or fungi. A massive infiltration of the lung tissue and other organs, mainly by T lymphocytes, including those with suppressor properties, makes it necessary to conduct a differential diagnosis between the morphological manifestation of the protective cellular immune response and direct viral lesions but does not exclude the hypothesis of an immunopathological component of pathogenesis. In many of the deceased, even in the absence of clear clinical symptoms, a variety of extrapulmonary lesions were also detected. The mechanism of their development probably has a complex nature: direct lesions associated with the generalization of viral infection and vascular disorders associated with endothelial damage and having an autoimmune nature. Many aspects of the pathogenesis of coronavirus infection require further comprehensive study.
]]>Pathophysiology doi: 10.3390/pathophysiology29020020
Authors: Aristo Vojdani Elroy Vojdani Avi Rosenberg Yehuda Shoenfeld
In our continuing examination of the role of exposomes in autoimmune disease, we use this review to focus on pathogens. Infections are major contributors to the pathophysiology of autoimmune diseases through various mechanisms, foremost being molecular mimicry, when the structural similarity between the pathogen and a human tissue antigen leads to autoimmune reactivity and even autoimmune disease. The three best examples of this are oral pathogens, SARS-CoV-2, and the herpesviruses. Oral pathogens reach the gut, disturb the microbiota, increase gut permeability, cause local inflammation, and generate autoantigens, leading to systemic inflammation, multiple autoimmune reactivities, and systemic autoimmunity. The COVID-19 pandemic put the spotlight on SARS-CoV-2, which has been called “the autoimmune virus.” We explore in detail the evidence supporting this. We also describe how viruses, in particular herpesviruses, have a role in the induction of many different autoimmune diseases, detailing the various mechanisms involved. Lastly, we discuss the microbiome and the beneficial microbiota that populate it. We look at the role of the gut microbiome in autoimmune disorders, because of its role in regulating the immune system. Dysbiosis of the microbiota in the gut microbiome can lead to multiple autoimmune disorders. We conclude that understanding the precise roles and relationships shared by all these factors that comprise the exposome and identifying early events and root causes of these disorders can help us to develop more targeted therapeutic protocols for the management of this worldwide epidemic of autoimmunity.
]]>Pathophysiology doi: 10.3390/pathophysiology29020019
Authors: Iviana P. Yovchevska Alexandar B. Trenovski Maria H. Atanasova Martin N. Georgiev Radka K. Tafradjiiska-Hadjiolova Simeon D. Lazarov Plamen H. Yovchevski
In the current pandemic of coronavirus disease (COVID-19), the identification of the patients admitted with severe infection–who are disposed to a high risk of acute respiratory distress syndrome (ARDS) development, is of a major significance for the determination of the appropriate therapeutic strategy. Laboratory records in admission were retrospectively reviewed from 493 cases of severe COVID-19 divided into two groups: Group 1 with ARDS and Group 2 without ARDS. The platelet distribution width (PDW) difference between Group 1 and Group 2 is significant–15.10 ± 2.08 fl for those who developed ARDS versus 12.94 ± 2.12 fl for those without ARDS. The sensitivity and the specificity of this parameter is lower than that of D-dimer. After grouping of the PDW values into intervals and combining them with the rate of increase in D-dimer (D-PDWf index) to form a forecasting index, a significant increase in the specificity and sensitivity of the two parameters is identified–area under the ROC curve (AUC) is 0.874 for D-PDWf index, with respective AUC for PDW 0.768 and AUC for D-dimer 0.777. Conclusion: PDW is a significant predictive parameter at admission for subsequent development of ARDS in patients, with increased significance in combination with the degree of increase in D-dimer.
]]>Pathophysiology doi: 10.3390/pathophysiology29020018
Authors: Allison Derise Carey Ford Nazar Hafiz Sudha Pandit Aditya Vyas Samuel Igbinedion James Morris Paul Jordan Qiang Cai Jonathan Steven Alexander
Legalization/decriminalization of cannabis will increase the numbers of patients who have had recent exposure to recreational or medical cannabis. Currently, little has been reported about potential interactions between cannabis use and Propofol anesthesia e.g., for oropharyngeal procedures. We describe three cases of ‘cannabis-induced hypersalivation after propofol’ (CHAP) and present our institutions’ experience with this unique pharmacological combination. Increased hypersalivation may complicate procedures and represent a procedural risk of suffocation. We evaluate possible pharmacological interactions that might underlie this phenomenon and consider management options going forward.
]]>Pathophysiology doi: 10.3390/pathophysiology29020017
Authors: Ajay Kumar Pal Prateek Sharma Alishan Zia Deepali Siwan Dipali Nandave Mukesh Nandave Rupesh K. Gautam
Cancer cells undergo transient EMT and MET phenomena or vice versa, along with the parallel interplay of various markers, often correlated as the determining factor in decoding metabolic profiling of breast cancers. Moreover, various cancer signaling pathways and metabolic changes occurring in breast cancer cells modulate the expression of such markers to varying extents. The existing research completed so far considers the expression of such markers as determinants regulating the invasiveness and survival of breast cancer cells. Therefore, this manuscript is crosstalk among the expression levels of such markers and their correlation in regulating the aggressiveness and invasiveness of breast cancer. We also attempted to cover the possible EMT-based metabolic targets to retard migration and invasion of breast cancer.
]]>Pathophysiology doi: 10.3390/pathophysiology29020016
Authors: Olga Danilenko Natalia Gavrilova Leonid Churilov
Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is considered to be associated with post-viral complications and mental stress, but the role of autoimmunity also remains promising. A comparison of autoimmune profiles in chronic fatigue of different origin may bring insights on the pathogenesis of this disease. Thirty-three patients with CFS/ME were divided into three subgroups. The first group included Herpesviridae carriers (group V), the second group included stress-related causes of chronic fatigue (distress, group D), and the third group included idiopathic CFS/ME (group I). Were evaluated thirty-six neural and visceral autoantigens with the ELISA ELI-test (Biomarker, Russia) and compared to 20 healthy donors, either without any fatigue (group H), or “healthy but tired” (group HTd) with episodes of fatigue related to job burnout not fitting the CFS/ME criteria. β2-glycoprotein-I autoantibodies were increased in CFS/ME patients, but not in healthy participants, that alludes the link between CFS/ME and antiphospholipid syndrome (APS) earlier suspected by Berg et al. (1999). In CFS/ME patients, an increase in levels of autoantibodies towards the non-specific components of tissue debris (double-stranded DNA, collagen) was shown. Both CFS and HTd subgroups had elevated level of autoantibodies against serotonin receptors, glial fibrillary acidic protein and protein S100. Only group V showed an elevation in the autoantibodies towards voltage-gated calcium channels, and only group D had elevated levels of dopamine-, glutamate- and GABA-receptor autoantibodies, as well as NF200-protein autoantibodies. Therefore, increased autoimmune reactions to the multiple neural antigens and to adrenal medullar antigen, but not to other tissue-specific somatic ones were revealed. An increase in autoantibody levels towards some neural and non-tissue-specific antigens strongly correlated with a CFS/ME diagnosis. Autoimmune reactions were described in all subtypes of the clinically significant chronic fatigue. Visceral complaints in CFS/ME patients may be secondary to the neuroendocrine involvement and autoimmune dysautonomia. CFS may be closely interrelated with antiphospholipid syndrome, that requires further study.
]]>Pathophysiology doi: 10.3390/pathophysiology29020015
Authors: Vittorio Abruzzese Caecilia H. C. Sukowati Claudio Tiribelli Ilenia Matera Angela Ostuni Faustino Bisaccia
The ATP-binding cassette sub-family C member 6 transporter (ABCC6) is mainly found in the basolateral plasma membrane of hepatic and kidney cells. In hepatocarcinoma HepG2 cells, ABCC6 was involved in cell migration. In the present study, we investigated the role of ABCC6 in colon cancer evaluating the effect of Quercetin and Probenecid, inhibitors of the ectonucleotidase NT5E and ABCC6, respectively, on migration rate of Caco2 and HT29 cell lines. Both drugs reduced cell migration analyzed by scratch test. Gene and protein expression were evaluated by quantitative reverse-transcription PCR (RT-qPCR) and Western blot, respectively. In Caco2 cells, in which ABCC6 is significantly expressed, the addition of ATP restored motility, suggesting the involvement of P2 receptors. Contrary to HT29 cells, where the expression of ABCC6 is negligible but remarkable to the level of NT5E, no effect of ATP addition was detected, suggesting a main role on their migration by the phosphatidylinositol 3′-kinase (PI3K)/Akt system. Therefore, in some colon cancers in which ABCC6 is overexpressed, it may have a primary role in controlling the extracellular purinergic system by feeding it with ATP, thus representing a potential target for a therapy aimed at mitigating invasiveness of those type of cancers.
]]>Pathophysiology doi: 10.3390/pathophysiology29020014
Authors: Elena Zelikovna Golukhova Inessa Viktorovna Slivneva Maxim Leonidovich Mamalyga Damir Ildarovich Marapov Mikhail Nikolaevich Alekhin Mikhail Mikhailovich Rybka Irina Vasilevna Volkovskaya
Cardiopulmonary disorders cause a significant increase in the risk of adverse events in patients with COVID-19. Therefore, the development of new diagnostic and treatment methods for comorbid disorders in COVID-19 patients is one of the main public health challenges. The aim of the study was to analyze patient survival and to develop a predictive model of survival in adults with COVID-19 infection based on transthoracic echocardiography (TTE) parameters. We conducted a prospective, single-center, temporary hospital-based study of 110 patients with moderate to severe COVID-19. All patients underwent TTE evaluation. The predictors of mortality we identified in univariate and multivariable models and the predictive performance of the model were assessed using receiver operating characteristic (ROC) analysis and area under the curve (AUC). The predictive model included three factors: right ventricle (RV)/left ventricle (LV) area (odds ratio (OR) = 1.048 per 1/100 increase, p = 0.03), systolic pulmonary artery pressure (sPAP) (OR = 1.209 per 1 mm Hg increase, p < 0.001), and right ventricle free wall longitudinal strain (RV FW LS) (OR = 0.873 per 1% increase, p = 0.036). The AUC-ROC of the obtained model was 0.925 ± 0.031 (95% confidence interval (95% CI): 0.863–0.986). The sensitivity (Se) and specificity (Sp) measures of the models at the cut-off point of 0.129 were 93.8% and 81.9%, respectively. A binary logistic regression method resulted in the development of a prognostic model of mortality in patients with moderate and severe COVID-19 based on TTE data. It may also have additional implications for early risk stratification and clinical decision making in patients with COVID-19.
]]>Pathophysiology doi: 10.3390/pathophysiology29020013
Authors: Noemi Cerón-Pisa Amanda Iglesias Hanaa Shafiek Aina Martín-Medina Margalida Esteva-Socias Josep Muncunill Aarne Fleischer Javier Verdú Borja G. Cosío Jaume Sauleda
Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory disease commonly induced by cigarette smoke. The expression of miRNAs can be altered in patients with COPD and could be used as a biomarker. We aimed to identify a panel of miRNAs in bronchoalveolar lavage (BAL) to differentiate COPD patients from smokers and non-smokers with normal lung function. Accordingly, forty-five subjects classified as COPD, smokers, and non-smokers (n = 15 per group) underwent clinical, functional characterization and bronchoscopy with BAL. The mean age of the studied population was 61.61 ± 12.95 years, BMI 25.72 ± 3.82 Kg/m2, FEV1/FVC 68.37 ± 12.00%, and FEV1 80.07 ± 23.63% predicted. According to microarray analysis, three miRNAs of the most upregulated were chosen: miR-320c, miR-200c-3p, and miR-449c-5p. These miRNAs were validated by qPCR and were shown to be differently expressed in COPD patients. ROC analysis showed that these three miRNAs together had an area under the curve of 0.89 in differentiating COPD from controls. Moreover, in silico analysis of candidate miRNAs by DIANA-miRPath showed potential involvement in the EGFR and Hippo pathways. These results suggest a specific 3-miRNA signature that could be potentially used as a biomarker to distinguish COPD patients from smokers and non-smoker subjects.
]]>Pathophysiology doi: 10.3390/pathophysiology29010012
Authors: Walter Serra Alfredo Chetta
In pulmonary hypertension (PH), the development of right ventricular (RV) dilatation and RV failure are signs of accelerated progression of the disease, resulting in an increased risk of cardiac death. Even the noninvasive assessment of systolic blood pressure in the pulmonary artery undertaken by echocardiography does not provide a measure of ventricle–pulmonary interaction. Some studies have shown the potential for echocardiography to indirectly evaluate pulmonary vascular resistance (PVR) and the acceleration time of pulmonary outflow (PAAT). We used systolic pulmonary artery pressure (sPAP) and pulmonary vascular resistance to develop an sPAP/PAAT ratio (strength/surface unit)/(time) for this study. From January 2017 to December 2018, 60 healthy subjects and 63 patients with systemic scleroderma (Ssc) (60 females, 3 males), 27 with PH and 36 without PH at two-dimensional echocardiographic/Doppler, were screened. In normal subjects, the mean sPAP/PAAT ratio was 0.26 ± 0.063, which indicated optimal pulmonary arterial ventricle coupling and biventricular function. The data derived from the analysis of the Ssc patients showed that those presenting pre-capillary PH at cardiac catheterization had an sPAP/PAAT ratio of 0.40 ± 0.05. There was a significant correlation between sPAP/PAAT with Walk Distance (WD) and PVR, but not with TAPSE. Interobserver variability was less than 5%. The sPAP/PAAT ratio is a new parameter that may indicate pulmonary vascular afterload and interaction, both in normal subjects and in patients with Ssc and PH.
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