Control of the B cell-intrinsic tolerance programs by ubiquitin ligases Cbl and Cbl-b

B cell receptor (BCR) signaling plays a critical role in B cell tolerance and activation. Here, we show that mice with B cell-specific ablation of both Cbl and Cbl-b (Cbl-/-Cblb-/-) manifested systemic lupus erythematosus (SLE)-like autoimmune disease. The Cbl double deficiency resulted in a substantial increase in marginal zone (MZ) and B1 B cells. The mutant B cells were not hyperresponsive in terms of proliferation and antibody production upon BCR stimulation; however, B cell anergy to protein antigen appeared to be impaired. Concomitantly, BCR-proximal signaling, including tyrosine phosphorylation of Syk tyrosine kinase, Phospholipase C-gamma2 (PLC-gamma2), and Rho-family GTP-GDP exchange factor Vav, and Ca2+ mobilization were enhanced, whereas tyrosine phosphorylation of adaptor protein BLNK was substantially attenuated in the mutant B cells. These results suggested that the loss of coordination between these pathways was responsible for the impaired B cell tolerance induction. Thus, Cbl proteins control B cell-intrinsic checkpoint of immune tolerance, possibly through coordinating multiple BCR-proximal signaling pathways during anergy induction.     

Prevalence,Evolution, and Risk Factors for Advanced Liver Fibrosis in Adults Undergoing Intestinal Transplantation

Introduction

Intestinal failure–associated liver disease (IFALD) occurs commonly in intestinal transplant (ITx) candidates receiving parenteral nutrition (PN). The aim of this study is to establish the prevalence and risk factors for advanced liver fibrosis in adults at the time of ITx.

Methods

Retrospective chart review of all ITx was performed in adults between January 2000 and May 2014. Advanced liver fibrosis was defined as stage 3 or stage 4 fibrosis.

Results

Fifty‐three patients met the inclusion criteria. The mean age was 50.6 ± 10.9 years, and the majority were female (60.4%) and Caucasian (67.9%). The mean body mass index was 21.7 ± 3.8 kg/m² and the median duration of PN was 402 (interquartile range: 529) days. Advanced liver fibrosis at the time of ITx was found in 13 patients (24.5%). The multivariate analysis revealed that female gender and white race were significant predictors of advanced liver fibrosis. A total bilirubin >3.0 mg/dL for > a month prior to ITx was associated with an odds ratio of 8.9 for advanced fibrosis at the time of ITx but did not reach statistical significance (P = 0.055).

Conclusion

Close to one‐quarter of the ITx recipients had advanced liver fibrosis. In the current era of improved PN management, our data suggests that previously reported risk factors for IFALD, such as extreme short gut syndrome and PN duration, may have a lesser impact on development of liver fibrosis. A prolonged duration of bilirubin elevation may be associated with advanced liver fibrosis in patients with IFALD, but this requires validation in a larger cohort.     

A stand-alone peristaltic micropump based on piezoelectric actuation

Despite significant efforts to develop micropumps, cumbersome driving equipment means that the design of portable micropumps remains a challenge. This study presents a stand-alone micropump system, which includes a peristaltic micropump based on piezoelectric actuation and a driving circuit. This battery-based driving circuit comprises a 12 V battery, an ATmega 8535 microprocessor, a 12 V-to-180 V DC to DC converter using transformerless technology, three differential amplifiers, an IC 7805, a phase controller, an A/D converter, a keyboard and an LCD module. The system can produce step-function signals with voltages of up to 228 V_pp and frequencies ranging from 10 Hz to 100 kHz, as the inputs for the pump. It is portable and programmable with the package size of 22 × 12.8 × 9 cm. Additionally, this proposed system is used to design the driving signals of the pump which are 3-, 4, and 6-phase actuation sequences. This work performs the circuit testing and fluid pumping, and demonstrates the effects of actuation sequences on pump performance in terms of the dynamic behavior of the diaphragm, flow rates, back pressure and power consumption of the system. The experimental results show that the pump excited by the 6-phase sequence results in better performance compared with the 3- and 4-phase sequences, and produces a maximum flow rate of 36.8 μl/min and a maximum back pressure of 520 Pa with deionized water at 100 V _pp and 700 Hz.     

Familial association of schizophrenia symptoms retrospectively measured on a lifetime basis

OBJECTIVE: The objective of this study was to characterize the familial associations of symptoms or symptom dimensions of schizophrenia, as a component of the effort to delineate suitable phenotypic markers under the homogenous genetic control. METHODS: Clinical symptoms of the patients were evaluated on a lifetime basis, with the Korean version of the Diagnostic Interview for Genetic Studies and the Krawieka scale. Our sample consisted of 54 sibling pairs who were concordant for Diagnostic and statistical manual of mental disorder-IV schizophrenia or schizoaffective disorder. RESULTS: At the individual symptom level measured by the Diagnostic Interview for Genetic Studies, we observed a statistically significant degree of concordance within the sibling pairs for auditory hallucination (kappa=0.600, chi(2)=15.193, P=0.000). The within-sibling resemblance of this symptom was also indicated by the results of correlation analyses of individual items of the Krawiecka scale (partial correlation coefficient=0.423, P=0.005). Among the individual symptoms or symptom dimensions of the Krawiecka scale, the 'anxious' (partial correlation coefficient=0.469, P=0.001) and the 'affective dimension' (including the items of 'anxious' and 'depressed') (partial correlation coefficient=0.436, P=0.003) were also determined to indicate significant intra-pair correlations after controlling for potential confounding variables, such as sex, duration of illness, and age of onset. CONCLUSIONS: The results of this study suggest that familial factors, possibly genetic factors, contribute a liability to the development of auditory hallucinations. This symptom might then prove useful as a phenotype marker in future genetic studies.     

Compressive neuropathy of the tibial nerve and peroneal nerve by a Baker's cyst: case report

We report a case of Baker's cyst that induced compression of both the tibial and common peroneal nerves. The patient presented with calf atrophy and foot drop over a 6-month period. These signs and symptoms could have been mistaken for those of spinal origin. Based on an electrodiagnostic study and magnetic resonance imaging, compression of nerves by an asymptomatic Baker's cyst measuring 6x4 cm was confirmed. This cyst communicated with the articular joint which was also associated with a medial meniscal lesion. We treated the patient arthroscopically by performing partial medial meniscectomy, and through the posterolateral and the posteromedial portal, decompression of the Baker's cyst was performed. Approximately 6 weeks after the arthroscopic decompression, the cyst recurred. Therefore open resection was performed. At 1-year follow-up, the patient had considerable improvement in motor as well as sensory function and showed no evidence of recurrence. Although the electrodiagnostic studies showed an improvement in symptoms, the patient continued to complain of lower leg weakness owing to delayed diagnosis and cyst decompression. We believe that Baker's cysts should also be considered in the differential diagnoses of patients who present with neuromuscular dysfunction in the calf and leg.     

Incidence and Risk Factors of Neck Discomfort: A 6-month Sedentary-worker Cohort Study

Introduction: This study aimed to evaluate the six-month incidence and possible risk factors of neck discomfort among sedentary workers. Methods: Data, including demographic characteristics, work history, psychological characteristics and prevalent neck discomfort of 157 sedentary workers was collected by a questionnaire. A follow-up questionnaire was administered six months later to calculate the incidence of symptoms and related disability. Results: The six-month incidence of neck discomfort was 23.5% (12/51). The two groups of prevalent and non-prevalent subjects showed no difference in demographic data and work characteristics except for work load (p<0.05) and score in “job control” in the Job Content Questionnaire (JCQ) (p<0.05). In logistic regression, light-load work (versus no-load work, OR = 0.10, p = 0.023) and higher score of ‘job control’ in JCQ (OR = 0.86, p = 0.031) were significant protecting factors. Conclusion: The six-month incidence rates of neck discomfort in our subjects were high. Light-load work and a higher score of ‘job control’ were important preventive factors. The results provide an epidemiological basis for prevention of neck discomfort in different working populations.     

Antioxidant and pro-oxidant effects of green tea extracts in oxygen radical absorbance capacity assay

Green tea extracts (GTEs) [water (GTE-W) and 75% ethanol (GTE-E)] were investigated to characterize their propensities to act as antioxidants or as pro-oxidants by analyzing oxygen radical absorbance capacity (ORAC) and scavenging capacity for hydroxyl radical. When 2,2'-azobis(2-amidinopropane) dihydrochloride was used for the generation of peroxyl radicals, both GTE-W and GTE-E exhibited strong concentration-dependent scavenging activity through donating protons, which could be explained by their reducing property. When hydroxyl radicals were generated through the addition of Cu(2+) and H(2)O(2), GTE-W and GTE-E exhibited antioxidant activity or pro-oxidant activity, depending on their concentrations, which might be attributed to the metal chelating activity, the scavenging activity on hydroxyl radical, and/or the pro-oxidant activity to generate some reactive oxygen species. When Cu(2+) without H(2)O(2) was used as an oxidant in the assay, the copper-initiated pro-oxidant activities of GTE-W and GTE-W was consistent with the availability of (-)-epigallocatechin and (-)-epicatechin to generate hydrogen peroxide and/or hydroxyl radical. The pro-oxidant activity of GTE-W and GTE-E was demonstrated by the deoxyribose assay. These results indicate that both GTE-W and GTE-E can have pro-oxidant activity at lower concentrations and antioxidant activity at higher concentrations in the ORAC and deoxyribose assays using generated hydroxyl radicals.     

Triptolide inhibits matrix metalloproteinase-9 expression and invasion of breast cancer cells through the inhibition of NF-κB and AP-1 signaling pathways

Triptolide is a diterpenoid epoxide that is endogenously produced by the thunder god vine, Tripterygium wilfordii Hook F. Triptolide has demonstrated a variety of biological activities, including anticancer activities, in previous studies. Invasion and metastasis are the leading causes of mortality for patients with breast cancer, and the increased expression of matrix metalloproteinase-9 (MMP-9) has been shown to be associated with breast cancer invasion. Therefore, the aim of the present study was to investigate the effect of triptolide on 12-O-tetradecanoyl phorbol-13-acetate (TPA)-induced cell invasion and MMP-9 expression in breast cancer cells. The expression of signal molecules was examined by western blotting, zymography and quantitative polymerase chain reaction; an electrophoretic mobility gel shift assay was also used, and cell invasiveness was measured by an in vitro Matrigel invasion assay. The MCF-7 human breast cancer cell line was treated with triptolide at the highest concentrations at which no marked cytotoxicity was evident. The results demonstrated that triptolide decreased the expression of MMP-9 through inhibition of the TPA-induced phosphorylation of extracellular signal-regulated kinase (ERK) and the downregulation of nuclear factor-κB (NF-κB) and activator protein-1 (AP-1) activity. In addition, a Transwell assay revealed that triptolide reduced the ability of MCF-7 cells to invade Matrigel. These data demonstrate that the anti-invasive effect of triptolide is associated with the inhibition of ERK signaling and NF-κB and AP-1 activation, and suggest that triptolide may be a promising drug for breast cancer.     

Mumps outbreak in a highly vaccinated school population: assessment of secondary vaccine failure using IgG avidity measurements

From March to April 2006, an outbreak of mumps occurred in Gyeonggi, Korea. The aim of this study was to describe and discriminate between primary and secondary vaccine failure in a highly vaccinated population for mumps using IgG avidity testing. Fifteen clinical mumps cases occurred among 41 students. Among these 15 patients, 11 vaccinated patients were considered secondary vaccine failures with high IgG titers and a high avidity index (AI, > or =32%); an unvaccinated patient was considered to have primary infection with high IgG titers and low AI, and three vaccinated patients were considered as other infections with low IgG titers and low AI. Among 26 unaffected students, 5 vaccinated patients were retrospectively diagnosed as sub-clinical infection with high IgG titers and high AI; the remaining students had low IgG titers and low AI except for one previously infected student. The results of this study show that secondary vaccine failure played an important role in this mumps outbreak. Therefore, booster immunization for mumps should be considered in immunized adolescents to prevent further outbreaks.