The contribution of B cells to renal interstitial inflammation

Local B-cell infiltrates play a role in tissue fibrosis, neolymphangiogenesis, and renal allograft survival. We sought to characterize the B-cell infiltrates, factors involved in B-cell recruitment, and lymphangiogenesis in renal interstitial injury (ie, acute and chronic interstitial nephritis and chronic IgA nephropathy). CD20-positive B cells formed a prominent part of the interstitial infiltrating cells. Together with CD3-positive T cells, the CD20-positive B cells formed larger nodular structures. CD10-positive pre-B cells were rare, and the majority were mature CD27-positive B cells. Proliferating B cells were detected within nodular infiltrates. The level of mRNA expression of the chemokine CXCL13 was increased and correlated with CD20 mRNA in the tubulointerstitial space. CXCL13 protein was predominantly found at sites of nodular infiltrates, in association with CXCR5-positive B cells. Furthermore, sites of chronic interstitial inflammation were associated with a high number of lymphatic vessels. B-cell infiltrates form a prominent part of the interstitial infiltrates both in primary interstitial lesions and in IgA nephropathy. CXCR5-positive B cells might be recruited via the chemokine CXCL13 and seem to contribute to the formation of intrarenal lymphoid follicle-like structures. These might represent an intrarenal immune system.     

SimPEL: Simulation‐based power estimation for sequencing studies of low‐prevalence conditions

Power estimations are important for optimizing genotype‐phenotype association study designs. However, existing frameworks are designed for common disorders, and thus ill‐suited for the inherent challenges of studies for low‐prevalence conditions such as rare diseases and infrequent adverse drug reactions. These challenges include small sample sizes and the need to leverage genetic annotation resources in association analyses for the purpose of ranking potential causal genes. We present SimPEL, a simulation‐based program providing power estimations for the design of low‐prevalence condition studies. SimPEL integrates the usage of gene annotation resources for association analyses. Customizable parameters, including the penetrance of the putative causal allele and the employed pathogenic scoring system, allow SimPEL to realistically model a large range of study designs. To demonstrate the effects of various parameters on power, we estimated the power of several simulated designs using SimPEL and captured power trends in agreement with observations from current literature on low‐frequency condition studies. SimPEL, as a tool, provides researchers studying low‐frequency conditions with an intuitive and highly flexible avenue for statistical power estimation. The platform‐independent “batteries included” executable and default input files are available at https://github.com/precisionomics/SimPEL .     

Fatal Adverse Event with Dabigatran in Elderly Patient with Reduced Kidney Function

An elderly man with decreased kidney function was admitted to hospital with gastrointestinal bleeding. After remaining stable for 2 days in hospital, he became haemodynamically unstable and an adverse effect of dabigatran was suspected, but efforts to treat the patient failed and the following morning he passed away. In conjunction with the autopsy, blood samples from his hospital stay were analysed for dabigatran, revealing the highest concentration (6400 ng/mL) apparently reported to date. Supra‐therapeutic dosing was, however, never suspected. Dabigatran is largely excreted through the kidneys. A possible cause of the high dabigatran concentrations could be a rapid decrease in kidney function that seemingly occurred over a period of 2 months, sometime between his initiation of treatment (eGFR 51–55 mL/min/1.73 m²) and subsequent hospital admission (eGFR 31 mL/min/1.73 m²). The increasing dabigatran concentrations in the patient was, however, not apparent to the prescribing doctor, as therapeutic drug monitoring of dabigatran is not recommended in current guidelines and no such analyses were performed. There may be a need to evaluate blood concentrations of dabigatran, in the light of the reported differences in interindividual concentrations, along with the increased risks of thromboembolic events with lower concentrations and major bleeding events with higher concentrations. Functional assays to assess concentrations of dabigatran in blood have been developed and are available in some hospitals to be used in suspected overdoses or before emergency surgeries. Methods to determine concentrations of dabigatran specifically have also been developed and can additionally be used for therapeutic drug monitoring in an outpatient setting, especially in high‐risk individuals.     

Effects of low-level light therapy on xerostomia related to hyposalivation: a systematic review and meta-analysis of clinical trials

Lasers in Medical Science - Hyposalivation is a condition represented by a reduced salivary flow and may include symptoms such as mouth dryness (xerostomia), loss of taste, pain, dysphagia, and...     

Overexpression of oxytocin receptors in the hypothalamic PVN increases baroreceptor reflex sensitivity and buffers BP variability in conscious rats

Background and Purpose

The paraventricular nucleus (PVN) of the hypothalamus is an important integrative site for neuroendocrine control of the circulation. We investigated the role of oxytocin receptors (OT receptors) in PVN in cardiovascular homeostasis.

Experimental Approach

Experiments were performed in conscious male Wistar rats equipped with a radiotelemetric device. The PVN was unilaterally co-transfected with an adenoviral vector (Ad), engineered to overexpress OT receptors, and an enhanced green fluorescent protein (eGFP) tag. Control groups: PVN was transfected with an Ad expressing eGFP alone or untransfected, sham rats (Wt). Recordings were obtained without and with selective blockade of OT receptors (OTX), during both baseline and stressful conditions. Baroreceptor reflex sensitivity (BRS) and cardiovascular short-term variability were evaluated using the sequence method and spectral methodology respectively.

Key Results

Under baseline conditions, rats overexpressing OT receptors (OTR) exhibited enhanced BRS and reduced BP variability compared to control groups. Exposure to stress increased BP, BP variability and HR in all rats. In control groups, but not in OTR rats, BRS decreased during stress. Pretreatment of OTR rats with OTX reduced BRS and enhanced BP and HR variability under baseline and stressful conditions. Pretreatment of Wt rats with OTX, reduced BRS and increased BP variability under baseline and stressful conditions, but only increased HR variability during stress.

Conclusions and Implications

OT receptors in PVN are involved in tonic neural control of BRS and cardiovascular short-term variability. The failure of this mechanism could critically contribute to the loss of autonomic control in cardiovascular disease.     

Approach to persistent ascites after liver transplantation

Persistent ascites (PA) after liver transplantation (LT), commonly defined as ascites lasting more than 4 wk after LT, can be expected in up to 7% of patients. Despite being relatively rare, it is associated with worse clinical outcomes, including higher 1-year mortality. The cause of PA can be divided into vascular, hepatic, or extrahepatic. Vascular causes of PA include hepatic outflow and inflow obstructions, which are usually successfully treated. Regarding modifiable hepatic causes, recurrent hepatitis C and acute cellular rejection are the leading ones. Considering predictors for PA, the presence of ascites, refractory ascites, hepato-renal syndrome type 1, spontaneous bacterial peritonitis, hepatic encephalopathy, and prolonged ischemic time significantly influence the development of PA after LT. The initial approach to patients with PA should be to diagnose the treatable cause of PA. The stepwise approach in evaluating PA includes diagnostic paracentesis, ultrasound with Doppler, and an echocardiogram when a cardiac cause is suspected. Finally, a percutaneous or transjugular liver biopsy should be performed in cases where the diagnosis is unclear. PA of unknown cause should be treated with diuretics and paracentesis, while transjugular intrahepatic portosystemic shunt and splenic artery embolization are treatment methods in patients with refractory ascites after LT.     

Comprehensive Analysis of the HLA Class I and the HLA class II Alleles in Patients with Takayasu Arteritis: Relationship with Clinical Patterns and Prognosis

Background: Takayasu arteritis (TA) is a systemic vasculitis, affecting mainly the aorta and its branches. Objective: To analyze the HLA class I and class II alleles in patients with TA and explore their relationship with clinical and demographic characteristics, and potential significance in prognosis. Methods: Twenty-five, unrelated TA patients were genotyped for HLA-A, HLA-B, HLA-C, HLA-DRB1, and the HLA-DQB1 loci. The frequencies of the HLA-A, HLA-B, and the HLA-DRB1 were compared with a control group of 1992, while the HLA-C and the HLA-DQB1 were compared with a group of 159 healthy, unrelated individuals. Results: Among TA patients, 5/25 (20%) were identified as the HLA-B*52 carriers. There was a significant difference in the HLA-B*52 allele frequency in the TA patients (10%) compared with the healthy controls (1.2%). Moreover, presence of the HLA-B*52 was associated with significantly earlier disease onset, more severe clinical presentations, and a poorer response to treatment. The HLA-C*03 was detected in 32% of patients and was present exclusively in those with a clinically mild form of the TA, indicating a putative protective effect. Conclusion: These findings indicate that the HLA-B*52 allele contributes to a higher susceptibility to the TA whereas the HLA-C*03, can be a protective factor in the TA.