Coagulation,inflammation, and apoptosis: different roles for protein S and the protein S-C4b binding protein complex

Protein S (PS) has an established role as an important cofactor to activated protein C (APC) in the degradation of coagulation cofactors Va and VIIIa. This anticoagulant role is evident from the consequences of its deficiency, when there is an increased risk of venous thromboembolism. In human plasma, PS circulates approximately 40% as free PS (FPS) and 60% in complex with C4b-binding protein (C4BP). Formation of this complex results in loss of PS cofactor function, and C4BP can then modulate the anticoagulant activity of APC. It had long been predicted that the complex could act as a bridge between coagulation and inflammation due to the involvement of C4BP in regulating complement activation. This prediction was recently supported by the demonstration of binding of the PS-C4BP complex to apoptotic cells. This review aims to summarize recent findings on the structure and functions of PS, the basis and importance of its deficiency, its interaction with C4BP, and the possible physiologic and pathologic importance of the PS-C4BP interaction.     

Activation of factor XI in plasma is dependent on factor XII [see comments]

The activation of factor XI initiates the intrinsic coagulation pathway. Until recently it was believed that the main activator of factor XI is factor XIIa in conjunction with the cofactor high molecular weight kininogen on a negatively charged surface. Two recent reports have presented evidence that in a purified system factor XI is activatable by thrombin together with the soluble polyanion dextran sulfate. To assess the physiological relevance of these findings we studied the activation of factor XI in normal and factor XII-deficient plasma. We used either kaolin/cephalin or dextran sulfate as a surface for the intrinsic coagulation pathway, tissue factor to generate thrombin via the extrinsic pathway, or the addition of alpha-thrombin directly. 125I-factor XI, added to factor XI-deficient plasma at physiologic concentrations (35 nmol/L), is rapidly cleaved on incubation with kaolin. The kinetics appear to be exponential with half the maximum cleavage at 5 minutes. Similar kinetics of factor XI cleavage are seen when 40 nmol/L factor XIIa (equal to 10% of factor XII activation) is added to factor XII-deficient plasma if an activating surface is provided. Tissue factor (1:500) added to plasma did not induce cleavage of factor XI during a 90-minute incubation, although fibrin formation within 30 seconds indicated that thrombin was generated via the extrinsic pathway. Adding 1 mumol/L alpha-thrombin (equivalent to 50% prothrombin activation) directly to factor XII deficient or normal plasma (with or without kaolin/cephalin/Ca2+ or dextran sulfate) led to instantaneous fibrinogen cleavage, but again no cleavage of factor XI was observable. We conclude that in plasma surroundings factor XI is not activated by thrombin, and that proposals of thrombin initiation of the intrinsic coagulation cascade are not supportable.     

Diagnostic assessment of patients with Meniere's disease through caloric testing and the video-head-impulse test

IntroductionMeniere's disease is a labyrinth disease that usually presents with episodes of spontaneous vertigo associated with sensorineural hearing loss, tinnitus and ipsi- and unilateral aural fullness in most cases. Vestibular function tests, video-head-impulse test and the caloric test, are not specific for diagnosis of the disease, but may show alterations that help to evaluate the functional impairment.ObjectiveTo describe the results obtained at the caloric test and video-head-impulse test in patients with definite Meniere's disease and compare them between symptomatic, asymptomatic ears and those of the control group.MethodsCross-sectional and observational study including patients with definite Meniere's disease diagnosed according to the Bárány Society criteria (2015) and healthy individuals (control group) undergoing caloric test and video-head-impulse test. All subjects were assessed by neurotological anamnesis and audiological evaluation (pure-tone, vocal and immittance audiometry) to characterize the sample. The findings obtained at the caloric test and video-head-impulse test were described and compared between the symptomatic and asymptomatic ears of patients with Meniere's disease and those of the control group.ResultsThirty-two patients with definite Meniere's disease were evaluated, with a mean age of 45.7 years, mostly females (68.8%) and unilateral disease. The control group consisted of 20 healthy individuals, with a mean age of 44.7 years, mostly females (70.0%). The groups were homogeneous in relation to age and gender. The patients’ main complaint was vertigo (71.9%), and most patients had more than six episodes in the last six months (71.9%). Moderate sensorineural hearing loss was present in 38.5% of patients. The prevalence of hyporeflexia at the caloric test was higher in symptomatic (56.4%) and asymptomatic (36%) ears of patients with Meniere's disease compared to the ears of control subjects (7.5%), p < 0.001 and p = 0.004, respectively. Video-head-impulse test alterations in the lateral semicircular canals were more frequent in the symptomatic ears of patients with Meniere's disease than in the ears of control subjects (p = 0.026).ConclusionMost patients with definite Meniere's disease showed hyporeflexia at the caloric test and video-head-impulse test with normal function in the symptomatic ear. Vestibular hyporeflexia at the caloric test was more frequent in the symptomatic and asymptomatic ears of patients with Meniere's disease than in the control group. The video-head-impulse test showed more alterations in the lateral semicircular canals.     

A miRNA signature for defining aggressive phenotype and prognosis in gliomas

Gliomas represent a disparate group of tumours for which there are to date no cure. Thus, there is a recognized need for new diagnostic and therapeutic approaches based on increased understanding of their molecular nature. We performed the comparison of the microRNA （miRNA） profile of 8 WHO grade II gliomas and 24 higher grade tumours （2 WHO grade III and 22 glioblastomas） by using the Affymetrix GeneChip miRNA Array v. 1.0. A relative quantification method （RT-qPCR） with standard curve was used to confirm the 22 miRNA signature resulted by array analysis. The prognostic performances of the confirmed miRNAs were estimated on the Tumor Cancer Genome Atlas （TCGA） datasets. We identified 22 miRNAs distinguishing grade II gliomas from higher grade tumours. RT-qPCR confirmed the differential expression in the two patients＇groups for 13 out of the 22 miRNAs. The analysis of the Glioblastoma Multiforme （GBM） and Lower Grade Glioma （LGG） datasets from TCGA demonstrated the association with prognosis for 6 of those miRNAs. Moreover, in the GBM dataset miR-21 and miR-210 were predictors of worse prognosis in both univariable and multivariable Cox regression analyses （ HR 1.19, P = O. 04, and HR 1.18, P = 0. 029 respectively）. Our results support a direct contribution of miRNAs to glioma cancerogenesis and suggest that miR-21 and miR-210 may play a role in the aggressive clinical behaviour of glioblastomas.     

Low bone mineral density is associated to poor glycemic control and increased OPG expression in children and adolescents with type 1 diabetes

Aims

To investigate early alterations on bone mineral density (BMD) and RANK, RANKL and OPG mRNA expression in peripheral blood leukocytes (PBL) in children and adolescents with type 1 diabetes (T1D) and the relationship with glycemic control and bone biomarkers.

Methods

This cross-sectional study included 75 children and adolescents with T1D and 100 individuals without diabetes (normoglycemic–NG) aged 6–20 years old. T1D individuals were considered to have good (T1DG) or poor (T1DP) glycemic control according to the values of HbA1c. Phosphorus, magnesium, total and ionized calcium, osteocalcin, alkaline phosphatase and tartaric-resistant acid phosphatase (TRAP) values were determined in blood samples. BMD was measured by DEXA. RANK, RANKL and OPG mRNA expression was measured in PBL by real-time PCR.

Results

Osteocalcin values were decreased in diabetic groups in comparison to NG group (p < 0.05), and a negative correlation with both serum glucose (r = −0.265, p < 0.01) and Hb1Ac (r = −0.252, p < 0.01) in T1D group was found. BMD was lower in diabetic groups in comparison with NG group (p < 0.05) and a negative correlation was observed between BMD and both serum glucose (r = −0.357, p < 0.01) and HbA1c (r = −0.351, p < 0.01) in T1D group. OPG mRNA expression was significantly increased in T1D and T1DP groups in comparison with NG group (p < 0.05). In conclusion, children and adolescents with early onset T1D presented low bone mineral density associated to unsatisfactory glycemic control, increased OPG mRNA expression and low osteocalcin concentration.     

Mycobacterium tuberculosis Strains of the Modern Sublineage of the Beijing Family Are More Likely To Display Increased Virulence than Strains of the Ancient Sublineage

Strains of the Beijing genotype family of Mycobacterium tuberculosis are a cause of particular concern because of their increasing dissemination in the world and their association with drug resistance. Phylogenetically, this family includes distinct ancient and modern sublineages. The modern strains, contrary to the ancestral counterparts, demonstrated increasing prevalence in many world regions that suggest an enhanced bacterial pathogenicity. We therefore evaluated virulence of modern versus ancient Beijing strains with similar epidemiological and genotype characteristics. For this, we selected six strains that had very similar 24-locus mycobacterial interspersed repetitive-unit–variable-number tandem-repeat (MIRU-VNTR) typing profiles and belonged to the region of difference 181 (RD181) subgroup but differed using markers (mutT2 and mutT4 genes and NTF locus) that discriminate between modern and ancient Beijing sublineages. The strains were isolated from native patients in Brazil and Mozambique, countries with a low prevalence of Beijing strains. The virulence levels of these strains were determined in models of pulmonary infection in mice and in vitro macrophage infection and compared with that of a strain from Russia, part of the epidemic and hypervirulent Beijing clone B0/W148, and of the laboratory strain H37Rv. The results showed that two of the three modern Beijing strains were highly pathogenic, exhibiting levels of virulence comparable with that of the epidemic Russian strain. In contrast, all isolates of the ancient sublineage displayed intermediate or low virulence. The data obtained demonstrate that the strains of the modern Beijing sublineage are more likely to exhibit highly virulent phenotypes than ancient strains and suggest that genetic alterations characteristic of the modern Beijing sublineage favor selection of highly virulent bacteria.     

Does neoadjuvant therapy for pancreatic head adenocarcinoma increase postoperative morbidity? A systematic review of the literature with meta-analysis

Neoadjuvant treatment (NT) for pancreatic head cancer may allow some patients to undergo curative resection, but its impact on postoperative complications remains unclear. A systematic review and meta-analysis were performed to compare overall postoperative morbidity, pancreatic fistula, and mortality between patients who underwent upfront surgery and those who underwent neoadjuvant therapy first. Forty-five studies with 3359 patients were included. No significant differences in morbidity and mortality rates associated with NT for pancreatic head cancer were detected in this study.     

Cordocentesis and evaluation of fetal wellbeing in a very high-risk population (a very reliable index)]

In a population of 57 very high-risk pregnant women (severe clinical history and/or compromised fetus). A total of 240 tests for antepartum fetal evaluation were performed: baseline cardiotocography (CTG), biophysical profile scoring (BPS), doppler-velocimetry of umbilical artery and determination of blood gas analysis in venous umbilical cord blood obtained by cordocentesis. The results of the CTG, BPS, and umbilical artery doppler velocimetry showed a significant relation with those of pH and pO2. The sensitivity, specificity, false-abnormal value, and false-normal value of the CTG, PBS, and doppler velocimetry, used for the diagnosis of fetal acidosis, hypoxia, and asphyxia were comparable. The rate of fetal (asphyxia) was high if present severe/terminal CTG (85.0%), abnormal (4) BPS (82.0%), or absent-end diastole in umbilical artery doppler velocimetry (74.0%). The immediate complication rate due to cordocentesis procedure was minimal.