J. Clin. Med., Volume 8, Issue 12 (December 2019) – 207 articles

We aimed to investigate whether perioperative magnesium sulfate administration was associated with the incidence of chronic persistent postoperative pain (PPP) following total knee arthroplasty (TKA). This retrospective observational study was performed at a single tertiary academic hospital. We reviewed the medical records of adult patients who were admitted between August 2012 and July 2017. Patients who received magnesium sulfate during surgery were the magnesium group. The presence of PPP, one year after TKA, was evaluated using a binary logistic regression analysis. A total of 924 patients were included in the analysis, and 148 patients (16.0%) experienced PPP one year after TKA. In the multivariable model, the magnesium group had a 62% lower rate of PPP one year after TKA compared to the control group (odds ratio (OR): 0.38, 95% confidence interval (CI): 0.16 to 0.90; p = 0.027). This finding was similar in the sensitivity analysis using propensity score adjustment (OR: 0.38, 95% CI: 0.16 to 0.93; p = 0.036). We showed that perioperative magnesium sulfate administration was associated with a lower rate of PPP one year after TKA. Our results suggest that magnesium sulfate administered perioperatively is effective for the alleviation of acute and chronic pain after surgery. Full article

Inflammation and immune activation play an important role in the pathogenesis of cardiac remodelling in patients with heart failure. The aim of this study was to assess whether biomarkers of inflammation and immune activation are linked to disease severity and the prognosis of heart failure patients. In 149 patients (65.8% men, median age 49.7 years) with heart failure from nonischaemic cardiomyopathy, the biomarkers neopterin and C-reactive protein were tested at the time of diagnosis. Patients were followed-up for a median of 58 months. During follow-up, nineteen patients died, five had a heart transplantation, two needed a ventricular assistance device, and twenty-one patients had to be hospitalised because of heart failure decompensation. Neopterin concentrations correlated with N-terminal prohormone of brain natriuretic peptide (NT-proBNP) concentrations (rs = 0.399, p < 0.001) and rose with higher New York Heart Association (NYHA) class (I: 5.60 nmol/L, II: 6.90 nmol/L, III/IV: 7.80 nmol/L, p = 0.033). Higher neopterin levels were predictive for an adverse outcome (death or hospitalisation due to HF decompensation), independently of age and sex and of established predictors in heart failure such as NYHA class, NT-proBNP, estimated glomerular filtration rate (eGFR), and left ventricular ejection fraction (LV-EF) (HR 2.770; 95% CI 1.419–5.407; p = 0.003). Patients with a neopterin/eGFR ratio ≥ 0.133 (as a combined marker for immune activation and kidney function) had a more than eightfold increased risk of reaching an endpoint compared to patients with a neopterin/eGFR ratio ≤0.065 (HR 8.380; 95% CI 2.889–24.308; p < 0.001). Neopterin is associated with disease severity and is an independent predictor of prognosis in patients with heart failure. Full article

This article presents the results of intraoperative fluorescent diagnostics via the endoscopic system for assessing the quality of photodynamic therapy (PDT) of head and neck cancer. The diagnosis and PDT procedures were performed on the five patients with malignant neoplasms of the vocal cords, lateral surface of the tongue, and trachea and cancer of the left parotid salivary gland. Molecular form of chlorin E6 (Ce6) was intravenously administered with a 1.0–1.1 mg/kg concentration for PDT. Fluorescent diagnostics (FD) was conducted before PDT and after PDT procedures. Control of PDT efficiency was carried out by evaluating the photobleaching of the drug (photosensitizer). The method of intraoperative fluorescent imaging allows determining the exact location of the tumor and its boundaries. The assessment of photosensitizer photobleaching in real time regime allows making quick decisions during PDT procedure, which helps improving the quality of patients’ treatment. The results showed the convenience of endoscopic fluorescent video system in various nosologies of head and neck cancer. Therefore, this diagnostic approach will improve the effectiveness of cancer treatment. Full article

We investigated the effectiveness and safety of direct oral anticoagulants (DOACs) for secondary prevention in patients with atrial fibrillation (AF), particularly focusing on subgroups of patients with severe, disabling, and recent stroke. Using the Korean National Health Insurance Service claims database between January 2010 and April 2018, we selected OAC-naïve patients with non-valvular AF and a history of stroke. Cumulative risks for recurrent stroke, major bleeding, composite outcome (recurrent stroke + major bleeding), and mortality were compared between DOAC and warfarin groups. Among 61,568 patients, 28,839 and 32,729 received warfarin and DOACs, respectively. Compared with warfarin, DOACs were associated with lower risks of recurrent stroke (hazard ratio (HR) 0.67, 95% confidence interval (CI) 0.62–0.72), major bleeding (HR 0.73, 95% CI 0.66–0.80), composite outcome (HR 0.69, 95% CI 0.65–0.73), and mortality. DOAC use resulted in a consistent trend of improved outcomes in the subgroups of patients with severe, disabling, and recent stroke. In conclusion, DOACs were associated with lower risks of recurrent stroke, major bleeding, composite clinical outcomes, and mortality in patients with AF and a history of stroke. These results were consistent across all types of DOACs and subgroups of patients with severe, disabling, and recent stroke. Full article

Both environmental and genetic factors contribute to relative species abundance and metabolic characteristics of the intestinal microbiota. The intestinal microbiota and accompanying microbial metabolites differ substantially in those who are obese or have other metabolic disorders. Accumulating evidence from germ-free mice and antibiotic-treated animal models suggests that altered intestinal gut microbiota contributes significantly to metabolic disorders involving impaired glucose and lipid metabolism. This review will summarize recent findings on potential mechanisms by which the microbiota affects intestinal lipid and lipoprotein metabolism including microbiota dependent changes in bile acid metabolism which affects bile acid signaling by bile acid receptors FXR and TGR5. Microbiota changes also involve altered short chain fatty acid signaling and influence enteroendocrine cell function including GLP-1/GLP-2-producing L-cells which regulate postprandial lipid metabolism. Full article

Background: Although most cases of Parkinson´s disease (PD) are idiopathic with unknown cause, an increasing number of genes and genetic risk factors have been discovered that play a role in PD pathogenesis. Many of the PD-associated proteins are involved in mitochondrial quality control, e.g., PINK1, Parkin, and LRRK2, which were recently identified as regulators of mitochondrial-endoplasmic reticulum (ER) contact sites (MERCs) linking mitochondrial homeostasis to intracellular calcium handling. In this context, Miro1 is increasingly recognized to play a role in PD pathology. Recently, we identified the first PD patients carrying mutations in RHOT1, the gene coding for Miro1. Here, we describe two novel RHOT1 mutations identified in two PD patients and the characterization of the cellular phenotypes. Methods: Using whole exome sequencing we identified two PD patients carrying heterozygous mutations leading to the amino acid exchanges T351A and T610A in Miro1. We analyzed calcium homeostasis and MERCs in detail by live cell imaging and immunocytochemistry in patient-derived fibroblasts. Results: We show that fibroblasts expressing mutant T351A or T610A Miro1 display impaired calcium homeostasis and a reduced amount of MERCs. All fibroblast lines from patients with pathogenic variants in Miro1, revealed alterations of the structure of MERCs. Conclusion: Our data suggest that Miro1 is important for the regulation of the structure and function of MERCs. Moreover, our study supports the role of MERCs in the pathogenesis of PD and further establishes variants in RHOT1 as rare genetic risk factors for neurodegeneration. Full article

Pancreatic ductal adenocarcinoma (PDA) is notorious for its poor prognosis. The current mainstay of treatment for PDA is surgical resection followed by adjuvant chemotherapy. However, it is difficult to predict the post-operative outcome because of the lack of reliable markers. The single-nucleotide polymorphism (SNP) of N-acetylgalactosaminyltransferase14 (GALNT14) has been proven to predict the progression-free survival (PFS), overall survival (OS) and response to chemotherapy in various types of gastrointestinal (GI) cancers. However, its role in PDA has not been studied. This study aims to investigate whether the GALNT14 SNP genotype can be a prognostic marker for PDA. A cohort of one hundred and three PDA patients having received surgical resection were retrospectively enrolled. GALNT14 genotypes and the clinicopathological parameters were correlated with postoperative prognosis. The genotype analysis revealed that 19.4%, 60.2% and 20.4% of patients had the GALNT14 “TT”, “TG” and “GG” genotypes, respectively. The patients with the “GG” genotype had a mean OS time of 37.1 months (95% confidence interval [CI]: 18.2–56.1) and those with the “non-GG” genotype had a mean OS time of 16.1 months (95% CI: 13.1–19.2). Kaplan–Meier analysis showed that the “GG” genotype had a significantly better OS compared to the “non-GG” genotype (p = 0.005). However, there was no significant difference between the “GG” and “non-GG” genotypes in PFS (p = 0.172). The baseline characteristics between patients with the “GG” and “non-GG” genotypes were compared, and no significant difference was found. Univariate followed by multivariate Cox proportional hazard models demonstrated the GALNT14 “GG” genotype, negative resection margin, and locoregional disease as independent predictors for favorable OS (p = 0.003, p = 0.037, p = 0.021, respectively). Sensitivity analysis was performed in each subgroup to examine the relationship of GALNT14 with different clinicopathological variables and no heterogeneity was found. The GALNT14 “GG” genotype is associated with favorable survival outcome, especially OS, in patients with resected PDA and could serve as a prognostic marker. Full article

Little data is available regarding complications associated with resection arthroplasty in the treatment of hip periprosthetic joint infection (PJI). We assessed complications during and after two-stage revision using resection arthroplasty. In this retrospective study, 93 patients undergoing resection arthroplasty for hip PJI were included. Patients were assigned to a prosthesis-free interval of ≤10 weeks (group 1; 49 patients) or >10 weeks (group 2; 44 patients). The complication rates between groups were compared using the chi-squared test. The revision-free and infection-free survival was estimated using a Kaplan–Meier survival analysis. Seventy-one patients (76%) experienced at least one local complication (overall 146 complications). Common complications were blood loss during reimplantation (n = 25) or during explantation (n = 23), persistent infection (n = 16), leg length discrepancy (n = 13) and reinfection (n = 9). Patients in group 1 experienced less complications after reimplantation (p = 0.012). With increasing severity of acetabular bone defects, higher incidence of complications (p = 0.008), periprosthetic bone fractures (p = 0.05) and blood loss (p = 0.039) was observed. The infection-free survival rate at 24 months was 93.9% in group 1 and 85.9% in group 2. The indication for resection arthroplasty needs to be evaluated carefully, considering the high rate of complications and reduced mobility, particularly if longer prosthesis-free intervals are used. Full article

Purpose: The objective of this prospective randomized clinical trial (RCT) was to analyze and compare the clinical behavior of three types of prosthesis supported by single implants in the posterior region after three years of functional loading. Materials and methods: Seventy-five implants were divided into three groups according to the type of prosthetic restoration: screw-retained crown (group GS); cemented crown without finishing line (biologically oriented preparation technique) (group GBOPT); and conventional cemented crown with finishing line (group GCC). After three years in function, clinical parameters (presence of keratinized mucosa, probing depths, bleeding on probing, and radiographic bone loss) were compared between the three experimental groups. The possible correlation between soft tissue clinical parameters and bone loss was also analyzed. Results: Statistical analysis found significant differences in clinical parameters between the different types of crown, with the cemented restoration without finishing line (BOPT) presenting fewer complications and better peri-implant health outcomes including: significantly different KMW data (mm), with significant differences between groups GBOPT and GCC (p < 0.001, Kruskal–Wallis test), with GBOPT obtaining larger quantities of keratinized mucosa (KM); statistically significant differences in probing depth (PD) values between groups GBOPT and GCC (p = 0.010, Kruskal–Wallis test); significant differences in bleeding on probing (BOP) between groups GBOPT and GCC (p = 0.018, Chi² test) in favor of GBOPT. Conclusions: Soft tissue behavior around implants is related to the type of prosthetic restoration used, with cemented prostheses with BOPT presenting better peri-implant soft tissue behavior. Full article

(1) Background: A lesion within the dentato-rubro-olivary pathway (DROP) in the posterior fossa can cause secondary neurodegeneration of the inferior olivary nucleus: so-called hypertrophic olivary degeneration (HOD). The clinical syndrome of HOD occurs slowly over months and may be overlooked in progressive neuro-oncological diseases. Posterior fossa tumors are often located near these strategic structures. The goal of this study was to analyze the systematics of HOD occurrence in neuro-oncological patients. (2) Methods: The neuroradiological database of the university healthcare center was scanned for HOD-related terms from 2010 to 2019. After excluding patients with other causes of HOD, 12 datasets from neuro-oncological patients were analyzed under predetermined criteria. (3) Results: Patients received multimodal tumor treatments including neurosurgery, radiotherapy, and chemotherapy. HOD occurred both unilaterally (left n = 4; right n = 5) and bilaterally (n = 3). Though the mass effect of posterior fossa tumors had already affected strategic structures of the DROP, none of the patients showed signs of HOD on MRI until therapeutic measures including neurosurgery affecting the DROP were applied. HOD was visible on MRI within a median of 6 months after the neurosurgical intervention. In 67%, the presumed underlying surgical lesion in the DROP lay in the contralateral dentate nucleus. (4) Conclusion: In a selected cohort of neuro-oncological patients, therapeutic lesions within the DROP were associated with HOD occurrence. Full article

Background: Cesarean deliveries represent a large percentage of deliveries worldwide. Patients undergoing repeat cesarean deliveries are known to have increased risks for surgical complications. However, little is known regarding potential differences in pain. We sought to compare postoperative opioid consumption and pain scores in opioid naïve patients undergoing primary versus repeat non-emergent cesarean delivery. Methods: This was a retrospective cohort study. Patient inclusion criteria included: having a non-emergent cesarean delivery, receiving a spinal procedure for surgical anesthesia without general anesthesia, and following the same postoperative pain management protocols. Exclusion criteria included: history of opioid tolerance, illicit drug use, or prior, non-obstetric, major abdominal surgery. The primary outcome marker was total morphine equivalents consumed 0–72 h post-procedure compared between the primary versus repeat cesarean delivery groups. Secondary outcome markers were opioid consumption and pain scores in 24-h period increments for the first 72 h postoperatively. Results: 1617 patients were screened. 217 primary and 377 repeat cesarean deliveries met criteria for comparison. Reduced opioid consumption was demonstrated for the total opioid consumption 0–72 h for the repeat cesarean delivery group (median = 35) compared to the primary cesarean delivery group (median = 58), p = 0.0005. When divided into 24-h periods, differences were demonstrated for the 24–48 and 48–72 h periods but not the 0–24 h period. Pain scores did not differ statistically. Conclusion: Opioid naïve obstetric patients who undergo non-emergent repeat cesarean delivery demonstrate lower opioid consumption in the postoperative period. Providers should be aware of this potential difference in order to better educate patients and provide adequate pain management. Highlights: The study reviewed differences in opioid consumption between primary and repeat cesarean deliveries. All patients received the same protocol for spinal dosage and pain management. Repeat cesarean deliveries were associated with lower opioid consumption. Full article

Continuous positive airway pressure (CPAP) is an effective treatment for obstructive sleep apnea. However, the success of this treatment is hampered by nonadherence in half of the treated patients. Moreover, in clinical trials, poor adherence reduces adequate exposure required to determine its true effect. There is growing evidence that behavioral interventions, in addition to education, are a promising approach to improving adherence. Behavioral interventions include the use of cognitive behavioral therapy and motivational enhancement therapy designed to elevate a patient’s self-efficacy. The abundance of data obtained by CPAP tracking systems enables daily surveillance of use, and this telemonitoring along with telehealth allows the provider to quickly intervene when nightly CPAP use falls below thresholds or mask leaks are present. Telehealth reaches a large number of patients who may not be able to regularly attend a clinic, providing support and reinforcement. Peer support may also be useful in improving adherence. Not all obstructive sleep apnea patients present with the same phenotype, and can, therefore, be clustered into several groupings. Which intervention is most successful with a given phenotype or cluster remains unexplored. Comprehensive adherence management requires a team approach with the unique contribution of different professionals. Full article

There has been an alarming increase in the incidence of Type 2 Diabetes Mellitus (T2DM) worldwide. Uncontrolled T2DM can lead to alterations in the immune system, increasing the risk of susceptibility to infections such as Mycobacterium tuberculosis (M. tb). Altered immune responses could be attributed to factors such as the elevated glucose concentration, leading to the production of Advanced Glycation End products (AGE) and the constant inflammation, associated with T2DM. This production of AGE leads to the generation of reactive oxygen species (ROS), the use of the reduced form of nicotinamide adenine dinucleotide phosphate (NADPH) via the Polyol pathway, and overall diminished levels of glutathione (GSH) and GSH-producing enzymes in T2DM patients, which alters the cytokine profile and changes the immune responses within these patients. Thus, an understanding of the intricate pathways responsible for the pathogenesis and complications in T2DM, and the development of strategies to enhance the immune system, are both urgently needed to prevent co-infections and co-morbidities in individuals with T2DM. Full article

Background: The outcome after weaning from postcardiotomy venoarterial extracorporeal membrane oxygenation (VA-ECMO) is poor. In this study, we investigated the prognostic impact of arterial lactate levels at the time of weaning from postcardiotomy VA. Methods: This analysis included 338 patients from the multicenter PC-ECMO registry with available data on arterial lactate levels at weaning from VA-ECMO. Results: Arterial lactate levels at weaning from VA-ECMO (adjusted OR 1.426, 95%CI 1.157–1.758) was an independent predictor of hospital mortality, and its best cutoff values was 1.6 mmol/L (<1.6 mmol/L, 26.2% vs. ≥ 1.6 mmol/L, 45.0%; adjusted OR 2.489, 95%CI 1.374–4.505). When 261 patients with arterial lactate at VA-ECMO weaning ≤2.0 mmol/L were analyzed, a cutoff of arterial lactate of 1.4 mmol/L for prediction of hospital mortality was identified (<1.4 mmol/L, 24.2% vs. ≥1.4 mmol/L, 38.5%, p = 0.014). Among 87 propensity score-matched pairs, hospital mortality was significantly higher in patients with arterial lactate ≥1.4 mmol/L (39.1% vs. 23.0%, p = 0.029) compared to those with lower arterial lactate. Conclusions: Increased arterial lactate levels at the time of weaning from postcardiotomy VA-ECMO increases significantly the risk of hospital mortality. Arterial lactate may be useful in guiding optimal timing of VA-ECMO weaning. Full article

MicroRNAs (miRNAs) can provide insight into the pathophysiological states of ocular tissues such as proliferative diabetic retinopathy (PDR). In this study, differences in miRNA expression in vitreous from PDR patients with and without incidence of recurrent vitreous hemorrhage (RVH) after the initial pars-plana vitrectomy (PPV) were analyzed, with the aim of identifying biomarkers for RVH. Fifty-four consented vitreous samples were analyzed from patients undergoing PPV for PDR, of which eighteen samples underwent a second surgery due to RVH. Ten of the sixty-six expressed miRNAs (miRNAs-19a, -20a, -22, -27a, -29a, -93, -126, -128, -130a, and -150) displayed divergences between the PDR vitreous groups and to the control. A significant increase in the miRNA-19a and -27a expression was determined in PDR patients undergoing PPV as compared to the controls. miRNA-20a and -93 were significantly upregulated in primary PPV vitreous samples of patients afflicted with RVH. Moreover, this observed upregulation was not significant between the non-RVH and control group, thus emphasizing the association with RVH incidence. miRNA-19a and -27a were detected as putative vitreous biomarkers for PDR, and elevated levels of miRNA-20a and -93 in vitreous with RVH suggest their biomarker potential for major PDR complications such as recurrent hemorrhage incidence. Full article

While relapsing–remitting is the most prevalent course of multiple sclerosis, the prognostic/predictive markers of the worsening of symptomatology are still debated. With reference to other diseases, the study of the circadian activity rhythm, according to the theoretical framework of the two-process model of sleep regulation and applying functional linear modeling, proved to be useful to identify a possible marker. The usefulness of the study of circadian activity rhythm in multiple sclerosis is strengthened by recent findings indicating a potential involvement of circadian factors in the multifactorial etiopathology of the disorder. The aim of the present study was to verify whether circadian activity rhythm of early relapsing–remitting multiple sclerosis patients presents specific alterations, through functional linear modeling. Thirty-five relapsing–remitting multiple sclerosis patients (24 females; mean age ± SD = 31.51 ± 7.74) and 35 healthy controls (24 females; mean age ± SD = 31.29 ± 8.02) were enrolled. They wore an actigraph around the non-dominant wrist for one week. Relapsing–remitting multiple sclerosis patients showed a peak in motor activity around 5:00 a.m., higher than that of healthy controls. The timing of the peak in motor activity in the patients could be explained according to the hyperactive hypothalamus-pituitary-adrenal axis and higher cortisol awakening response reported in these patients. Full article

The risk of chronic kidney disease (CKD) following severe acute kidney injury (AKI) in critically ill patients is well documented, but not after less severe AKI. The main objective of this study was to evaluate the long-term incidence of CKD after non-severe AKI in critically ill patients. This prospective single-center observational three-years follow-up study was conducted in the medical intensive care unit in Bordeaux’s hospital (France). From 2013 to 2015, all patients with severe (kidney disease improving global outcomes (KDIGO) stage 3) and non-severe AKI (KDIGO stages 1, 2) were enrolled. Patients with prior eGFR < 90 mL/min/1.73 m² were excluded. Primary outcome was the three-year incidence of CKD stages 3 to 5 in the non-severe AKI group. We enrolled 232 patients. Non-severe AKI was observed in 112 and severe AKI in 120. In the non-severe AKI group, 71 (63%) were male, age was 62 ± 16 years. The reason for admission was sepsis for 56/112 (50%). Sixty-two (55%) patients died and nine (8%) were lost to follow-up. At the end of the follow-up the incidence of CKD was 22% (9/41); Confidence Interval (CI) _95% (9.3–33.60)% in the non-severe AKI group, tending to be significantly lower than in the severe AKI group (44% (14/30); CI _95% (28.8–64.5)%; p = 0.052). The development of CKD three years after non-severe AKI, despite it being lower than after severe AKI, appears to be a frequent event highlighting the need for prolonged follow-up. Full article

Background: Malignant gliomas are highly invasive and extremely difficult to treat tumours with poor prognosis and outcomes. Photodynamic therapy (PDT), mediated by Gleolan®, has been studied previously with partial success in treating these tumours and extending lifetime. We aim to determine whether combining PDT using ALA-protoporphyrin IX (PpIX) with a liposomal formulation of the clinical epidermal growth factor receptor (EGFR) inhibitor, lapatinib, would increase the anti-tumour PDT efficacy. Methods: Lapatinib was given in vitro and in vivo 24 h prior to PDT and for 3–5 days following PDT to elicit whether the combination provided any benefits to PDT therapy. Live-cell imaging, in vitro PDT, and in vivo studies were performed to elucidate the effect lapatinib had on PDT for a variety of glioma cell lines and as well as GSC-30 neurospheres in vivo. Results: PDT combined with lapatinib led to a significant increase in PpIX accumulation, and reductions in the LD₅₀ of PpIX mediated PDT in two EGFR-driven cell lines, U87 and U87vIII, tested (p < 0.05). PDT + lapatinib elicited stronger MRI-quantified glioma responses following PDT for two human glioma-derived tumours (U87 and GSC-30) in vivo (p < 0.05). Furthermore, PDT leads to enhanced survival in rats following treatment with lapatinib compared to lapatinib alone and PDT alone (p < 0.05). Conclusions: As lapatinib is approved for other oncological indications, a realization of its potential combination with PDT and in fluorescence-guided resection could be readily tested clinically. Furthermore, as its use would only be in acute settings, long-term resistance should not pose an issue as compared to its use as monotherapy. Full article

The central control of energy balance involves a strongly regulated neuronal network within the hypothalamus and the brainstem. In these structures, pro-opiomelanocortin (POMC) neurons are known to decrease food intake and to increase energy expenditure. Thus, leptin, a peripheral signal that relays information regarding body fat content, modulates the activity of POMC neurons. MicroRNAs (miRNAs) are short non-coding RNAs of 22–26 nucleotides that post-transcriptionally interfere with target gene expression by binding to their mRNAs. It has been demonstrated that leptin is able to modulate the expression of miRNAs (miR-383, miR-384-3p, and miR-488) that potentially target POMC mRNA. However, no study has identified the transduction pathways involved in this effect of leptin on miRNA expression. In addition, miRNAs targeting POMC mRNAs are not clearly identified. In this work, using in vitro models, we have identified and confirmed that miR-383, miR-384-3p, and miR-488 physically binds to the 3′ untranslated (3′UTR) regions of POMC mRNA. Importantly, we show that leptin inhibits these miRNAs expression by different transduction pathways. Taken together, these results allowed us to highlight the miRNA involvement in the regulation of POMC expression downstream of the leptin signaling and satiety signal integration. Full article

Study Objective: Studies have shown increased prevalence of restless legs syndrome (RLS) in sleep disordered breathing (SDB), however limited data have focused on the impact of SDB therapy on RLS. We hypothesize that positive airway pressure (PAP) will improve the International Restless Legs Syndrome (IRLS) score among SDB patients compared to patients without PAP. Methods: Patients with AHI ≥ 5 who responded positively to a RLS qualifier question from January 2010 to May 2015 were included in this retrospective study. IRLS score was used to measure RLS symptom severity. Two-sample t-tests and one-way analysis of variance were used to compare changes in IRLS score and linear regression models were created to examine IRLS change with PAP use and PAP adherence (PAP usage ≥4 h nightly for ≥70% of nights), adjusting for potential confounders. Results: In 434 patients (51.9 ± 13.4years, 50.5% female, 77.6% Caucasian; 325 PAP, 109 control), IRLS scores improved from baseline to follow-up, with the PAP group achieving significant improvement after adjustment for covariates (difference in IRLS: −1.8 (CI −3.6,0.00), p = 0.050). In self-reported PAP adherent patients, IRLS improvement was greater than controls (−5.3 ± 7.4 vs. −2.7 ± 7.6 respectively, p = 0.045), and comparable to non-adherent patients (−5.3 ± 7.4 vs. −3.0 ± 7.0, p = 0.091). Conclusions: Among SDB patients with a positive RLS qualifier, those who used PAP therapy achieved significantly greater improvement in IRLS scores than patients who did not use PAP, with more significant changes in the PAP adherent group. This is the first large clinical study to examine these relationships, providing a basis for future prospective interventional trials and informing clinicians of expected improvement in IRLS score in PAP treated SDB populations. Full article

Periodontal ligament-derived mesenchymal stem cells (hPDLSCs) possess immunomodulatory abilities which are strongly enhanced by various inflammatory cytokines. Vitamin D₃ has anti-inflammatory effects on hPDLSCs and immune cells. However, no study to date has directly compared the influence of 1,25(OH)₂D₃ on the immunomodulatory activities of hPDLSCs in the presence of different cytokines. In the present study, the effects of hPDLSCs treated with tumor necrosis factor (TNF)-α, interleukin (IL)-1β, or interferon (IFN)-γ in the presence of 1,25(OH)₂D₃ on the proliferation of allogenic CD4⁺ T lymphocyte or on the functional status of primary CD68⁺ macrophages were analyzed in coculture models. Additionally, the effects of 1,25(OH)₂D₃ on TNF-α-, IL-1β-, and IFN-γ-induced gene expression of some immunomodulatory factors in hPDLSCs were compared. Under coculture conditions, 1,25(OH)₂D₃ increased or decreased CD4⁺ T lymphocyte proliferation via hPDLSCs, depending on the cytokine. hPDLSCs primed with 1,25(OH)₂D₃ and different cytokines affected pro- and anti-inflammatory cytokine expression in macrophages variably, depending on the priming cytokine. With one exception, 1,25(OH)₂D₃ significantly reduced TNF-α-, IL-1β-, and IFN-γ-induced expression of all the investigated immunomediators in hPDLSCs, albeit to different extents. These results suggest that 1,25(OH)₂D₃ influences the immunomodulatory activities of hPDLSCs depending qualitatively and quantitatively on the presence of certain inflammatory cytokines. Full article

Sepsis is a life-threatening condition that is caused by an abnormal immune response to infection and can lead to tissue damage, organ failure, and death. Erastin is a small molecule capable of initiating ferroptotic cell death in cancer cells. However, the function of erastin in the inflammatory response during sepsis remains unknown. Here, we showed that erastin ameliorates septic shock induced by cecal ligation and puncture or lipopolysaccharides (LPS) in mice, which was associated with a reduced production of inflammatory mediators such as nitric oxide, tumor necrosis factor (TNF)-α, and interleukin (IL)-1β. Pretreatment with erastin in bone marrow-derived macrophages (BMDMs) significantly attenuated the expression of inducible nitric oxide synthase, cyclooxygenase-2, TNF-α, and IL-1β mRNA in response to LPS treatment. Furthermore, we also showed that erastin suppresses phosphorylation of IκB kinase β, phosphorylation and degradation of IκBα, and nuclear translocation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) in LPS-stimulated BMDMs. Our findings suggest that erastin attenuates the inflammatory response by suppressing the NF-κB signaling pathway, resulting in inhibition of sepsis development. This study provides new insights regarding the potential therapeutic properties of erastin in sepsis. Full article

Hypercholesterolemia and statins are risk factors for aortic stenosis (AS) and vascular calcification, respectively. Whether heterozygous subjects with familial hypercholesterolemia (HeFH) treated with statins are at risk of AS is unknown. We study the prevalence of AS, aortic valve calcification (AoVC), and aortic sclerosis (ASc) in elderly subjects with HeFH in a prolonged statin treatment. Case-control study, cases were adults ≥65 years of age with a genetic diagnosis of HeFH, LDLc >220 mg/dl, and statin treatment ≥5 years. Controls were relatives of HeFH patients, with LDLc <190 mg/dl. Participants underwent a cardiac ultrasound for aortic valve analysis. We studied 205 subjects, 112 HeFH and 93 controls, with mean age 71.8(6.5) years and 70.0(7.3) years, respectively. HeHF, with respect to controls, presented greater gradients of aortic transvalvular pressure, 7.4(7.3) mmHg versus 5.0(2.8) mmHg, and maximum aortic velocity, 1.7(0.7) m/s versus 1.5(0.4) m/s, and lower aortic valve opening area, 2.0(0.7) cm² versus 2.4(0.6) cm² (all p < 0.05). AoVC and ASc were also more prevalent in HeFH (p < 0.05 between groups). Moderate/severe AS prevalence was higher among HeFH: 7.1% versus 1.1% (age- and sex-adjusted odds ratio (OR) 8.33, p = 0.03). Independent risk factors for aortic valve disease in HeFH were age and LDLc before treatment. The number of years under statin treatment was not associated with any aortic valve measurement. Subjects ≥65 years with HeFH in prolonged statin treatment show more aortic valvular disease and higher frequency of AS than controls. Life-long elevated LDLc exposure, rather than time of exposure to statins, explains this higher risk. Full article

Goal-directed therapy based on brain-oxygen saturation (bSo₂) is controversial and hotly debated. While meta-analyses of aggregated data have shown no clinical benefit for brain near-infrared spectroscopy (NIRS)-based interventions after cardiac surgery, no network meta-analyses involving both major cardiac and noncardiac procedures have yet been undertaken. Randomized controlled trials involving NIRS monitoring in both major cardiac and noncardiac surgery were included. Aggregate-level data summary estimates of critical outcomes (postoperative cognitive decline (POCD)/postoperative delirium (POD), acute kidney injury, cardiovascular events, bleeding/need for transfusion, and postoperative mortality) were obtained. NIRS was only associated with protection against POCD/POD in cardiac surgery patients (pooled odds ratio (OR)/95% confidence interval (CI)/I²/number of studies (n): 0.34/0.14–0.85/75%/7), although a favorable effect was observed in the analysis, including both cardiac and noncardiac procedures. However, the benefit of the use of NIRS monitoring was undetectable in Bayesian network meta-analysis, although maintaining bSo₂ > 80% of the baseline appeared to have the most pronounced impact. Evidence was imprecise regarding acute kidney injury, cardiovascular events, bleeding/need for transfusion, and postoperative mortality. There is evidence that brain NIRS-based algorithms are effective in preventing POCD/POD in cardiac surgery, but not in major noncardiac surgery. However, the specific target bSo₂ threshold has yet to be determined. Full article

Many clinical trials report mesenchymal stem/stromal cells (MSCs) efficacy in various indications. Therefore, standardization of MSC production becomes necessary. MSC properties are impacted by tissue origin, especially if they are from extraembryonic tissue or adult sources. For this reason, we evaluated the impact of MSC tissue origin on production. Methods: Three productions of MSC from Wharton’s Jelly (WJ) or from bone marrow (BM) were performed according to good manufacturing practice. The identity (phenotype, differentiation, and clonogenic capacities), safety (karyotype, telomerase activity, sterility, and donor qualification), and functionality (viability, mixed lymphocyte reaction) of each cell batch were analyzed. Results: Slight differences between MSC sources were observed for phenotype, telomerase activity, and clonogenic capacities. Conclusion: Both sources have made it possible to quickly and easily obtain clinical grade MSC. However, as availability of the source is thought to be essential, WJ seems more advantageous than BM. Full article

Fibroblast growth factors 21 and 23 are used as markers of cardiometabolic disorders which are common comorbidities in psoriasis. The study aimed to evaluate the serum level of these factors in psoriatic patients and elucidate the possible interplay between disease activity, metabolic or inflammatory parameters, and systemic treatment. A total of 33 patients with active plaque-type psoriasis and 11 healthy controls were enrolled in the study. Patients were divided into subgroups based on their BMI, disease severity, and treatment. Blood samples were collected at the beginning of the study and after 3 months of systemic treatment with acitretin or methotrexate. Serum FGF21 levels in psoriatic patients were higher versus control group (p < 0.05). FGF21 levels regarding psoriasis activity were significantly increased in all three subgroups compared to the controls (p < 0.05). Regarding FGF23, no significant changes were found beside positive correlation with aspartate transferase (p < 0.05). No significant effect of systemic treatment on FGF21 and FGF23 levels was found. Interestingly, a nearly threefold decrease in FGF21 concentration after acitretin-based treatment was observed (p < 0.05). After methotrexate therapy, FGF21 levels remained unchanged. FGF21 levels might be helpful in prediction of the risk of cardiometabolic comorbidities development especially in patients with severe psoriasis and obesity. Full article

This study describes the employment of gold nanorods (AuNRs), known for their good reputation in hyperthermia-based cancer therapy, in a hybrid combination of photosensitizers (PS) and peptides (PP). We report here, the design and the synthesis of this nanosystem and its application as a vehicle for the selective drug delivery and the efficient photodynamic therapy (PDT). AuNRs were functionalized by polyethylene glycol, phototoxic pyropheophorbide-a (Pyro) PS, and a “KDKPPR” peptide moiety to target neuropilin-1 receptor (NRP-1). The physicochemical characteristics of AuNRs, the synthesized peptide and the intermediate PP-PS conjugates were investigated. The photophysical properties of the hybrid AuNRs revealed that upon conjugation, the AuNRs acquired the characteristic properties of Pyro concerning the extension of the absorption profile and the capability to fluoresce (Φ_f = 0.3) and emit singlet oxygen (Φ_Δ = 0.4) when excited at 412 nm. Even after being conjugated onto the surface of the AuNRs, the molecular affinity of “KDKPPR” for NRP-1 was preserved. Under irradiation at 652 nm, in vitro assays were conducted on glioblastoma U87 cells incubated with different PS concentrations of free Pyro, intermediate PP-PS conjugate and hybrid AuNRs. The AuNRs showed no cytotoxicity in the absence of light even at high PS concentrations. However, they efficiently decreased the cell viability by 67% under light exposure. This nanosystem possesses good efficiency in PDT and an expected potential effect in a combined photodynamic/photothermal therapy guided by NIR fluorescence imaging of the tumors due to the presence of both the hyperthermic agent, AuNRs, and the fluorescent active phototoxic PS. Full article

Background: A multi-disciplinary approach has led to an improvement in prognosis of childhood cancers. However, in parallel with the increase in survival rate, there is a greater occurrence of long-term toxicity related to antineoplastic treatment. Hypogonadism and infertility are among the most frequent endocrinological sequelae in young adult childhood cancer survivors. The aim of this study was to identify which category of patients, grouped according to diagnosis, therapy, and age at treatment, shows the worst reproductive function in adulthood. Methods: We evaluated morpho-volumetric development of the testis, endocrine function of the hypothalamic–pituitary–gonadal axis, and sperm parameters in 102 young adult childhood cancer survivors. Results: Overall, about one-third of patients showed low total testicular volume, total testosterone (TT) <3.5 ng/mL, and altered sperm count. Hodgkin’s disease, hematopoietic stem cell transplantation, and non-cranial irradiation associated to chemotherapy were risk factors for poor gonadal function. Patients treated in pubertal age showed lower total testicular volume; however, the difference was due to more gonadotoxic treatment performed in older age. Testicular volume was more predictive of spermatogenesis than follicle-stimulating hormone (FSH), while anti-Müllerian hormone (AMH) was not useful in the evaluation of testicular function of male childhood cancer survivors. Conclusions: Pre-pubertal subjects at high risk of future infertility should be candidates for testicular tissue cryopreservation. Full article

Hyperprolactinaemia is one of the most common problems in clinical endocrinology. It relates with various aetiologies (physiological, pharmacological, pathological), the clarification of which requires careful history taking and clinical assessment. Analytical issues (presence of macroprolactin or of the hook effect) need to be taken into account when interpreting the prolactin values. Medications and sellar/parasellar masses (prolactin secreting or acting through “stalk effect”) are the most common causes of pathological hyperprolactinaemia. Hypogonadism and galactorrhoea are well-recognized manifestations of prolactin excess, although its implications on bone health, metabolism and immune system are also expanding. Treatment mainly aims at restoration and maintenance of normal gonadal function/fertility, and prevention of osteoporosis; further specific management strategies depend on the underlying cause. In this review, we provide an update on the diagnostic and management approaches for the patient with hyperprolactinaemia and on the current data looking at the impact of high prolactin on metabolism, cardiovascular and immune systems. Full article

Refeeding syndrome (RFS) is the metabolic response to the switch from starvation to a fed state in the initial phase of nutritional therapy in patients who are severely malnourished or metabolically stressed due to severe illness. It is characterized by increased serum glucose, electrolyte disturbances (particularly hypophosphatemia, hypokalemia, and hypomagnesemia), vitamin depletion (especially vitamin B1 thiamine), fluid imbalance, and salt retention, with resulting impaired organ function and cardiac arrhythmias. The awareness of the medical and nursing staff is often too low in clinical practice, leading to under-diagnosis of this complication, which often has an unspecific clinical presentation. This review provides important insights into the RFS, practical recommendations for the management of RFS in the medical inpatient population (excluding eating disorders) based on consensus opinion and on current evidence from clinical studies, including risk stratification, prevention, diagnosis, and management and monitoring of nutritional and fluid therapy. Full article