Autoimmune hepatitis type 1 and primary biliary cirrhosis have distinct bone marrow cytokine production

We have recently reported differences in the hematopoiesis between autoimmune hepatitis type 1 (AIH-1) and primary biliary cirrhosis (PBC). In view of the notion that cytokines are regulators of hematopoiesis, we investigated in our tertiary center the cytokine production in the bone marrow (BM) of the same consecutive cohort of patients (13 AIH-1, 13 PBC, 10 healthy and 7 patients with cirrhosis due to chronic hepatitis B). Interferon-gamma (IFN-gamma), interleukin-4 (IL-4), interleukin-10 (IL-10), tumor necrosis factor-alpha (TNF-alpha) and transforming growth factor-beta (TGF-beta) were determined in the supernatants of long-term BM cultures by ELISAs. IL-4, TNF-alpha and TGF-beta were found significantly increased in the BM of PBC patients compared to AIH-1 and both control groups. AIH-1 patients had significantly higher BM IL-10 compared to PBC patients and higher IL-10, IL-4 and TNF-alpha compared to controls. BM IFN-gamma was significantly higher in PBC and AIH-1 patients compared to controls. In AIH-1 patients, IL-10 was positively correlated with CD34+, CD34+/CD38- and CD34+/CD38+ cell proportions. In conclusion, the BM cytokine microenvironment of PBC and AIH-1 patients differs significantly compared to that of healthy individuals and cirrhotic patients of non-autoimmune etiology. Differences were also found between patients with PBC and AH-1. The implication of BM in the pathogenesis of autoimmune liver diseases is possible and needs further investigation.     

Serum procalcitonin levels in chronic hepatitis C patients under pegylated interferon-alpha plus ribavirin treatment.

OBJECTIVES: To evaluate the alterations of serum procalcitonin (PCT) levels in patients with chronic hepatitis C during pegylated interferon-alpha (PEG-IFNa) plus ribavirin (RIB) treatment and to correlate them with clinical and virological outcomes. STUDY DESIGN: Fifty-two consecutive patients (29 males, age=41.2+/-14.7 years) with chronic HCV-related liver disease (six cirrhotics) were evaluated for PCT levels at baseline and during the treatment course (at week 12, 24, 48 and 72) with PEG-IFNa plus RIB. Sustained virological response (SVR) was confirmed by undetectable serum HCV-RNA at the end of treatment and again 6 months after completion of treatment. RESULTS: Two patients exhibited culture-proved bacterial infections during the treatment course. Thirty-six patients (69.2%) exhibit SVR and 16 (30.8%) were non-responders. Serum PCT levels remained within normal limits (0.1-0.5 ng/mL) in all treated patients throughout the follow-up period except those two who exhibited bacterial infections during the treatment course. Virological responders exhibited significant decline of serum PCT levels over time compared to non-responders (p<0.001), even when adjusted for multiple baseline parameters (p=0.037). CONCLUSION: Serum PCT levels decline in chronic hepatitis C patients during PEG-IFNa plus RIB treatment, especially in the sustained virological responder group, while they elevate only when bacterial infections complicate the treatment course.     

Obscurin: a multitasking muscle giant

Obscurin (~800 kDa) is the third member of a family of giant proteins expressed in vertebrate striated muscle, along with titin (3–3.7 MDa) and nebulin (~800 kDa). Like its predecessors, it is a multidomain protein composed of tandem adhesion modules and signaling domains. Unlike titin and nebulin, which are integral components of sarcomeres, obscurin is concentrated at the peripheries of Z-disks and M-lines, where it is appropriately positioned to communicate with the surrounding myoplasm. This unique distribution allows obscurin to bind small ankyrin 1, an integral component of the sarcoplasmic reticulum (SR) membrane. Obscurin also associates with the contractile apparatus through its binding to titin, sarcomeric myosin and perhaps other proteins of the contractile apparatus. Overexpression of the COOH-terminus of obscurin in primary myotubes has a dramatic and specific effect on the organization of sarcomeric myosin, indicating a role in the organization and regular assembly of A-bands. Given its ability to associate tightly, selectively and periodically with the periphery of the myofibril, its high affinity for an integral membrane protein of the SR and its close association with thick filaments, we speculate that obscurin is ideally suited to play key roles in modulating the organization and assembly of both the myofibril and the SR.     

Molecular genetics of familial parkinsonism

Parkinson's disease (PD) is a progressive, neurodegenerative disorder associated with tremor, rigidity, bradykinesia, and postural instability. There exists a familial form of PD that is indistinguishable from the sporadic form. In addition, there exists a class of syndromes classified as parkinsonism-plus syndromes (PPS), in which parkinsonism is an essential but not the only phenotypic characteristic. The etiology of PD remains unclear. Both environmental and genetic factors contribute to the disease pathogenesis. Recent progress in the molecular genetics of parkinsonism has demonstrated that six different chromosomal regions are associated with forms of familial parkinsonism. Mutations in four candidate genes have been identified and include both point mutations and deletions. Both gain-of-function and loss-of-function mutational mechanisms have been implicated. The molecular genetic characterization has led to a new classification of PD and PPS based on the type of genetic defect. Understanding the mechanisms by which these mutations lead to disease should provide further insights into the etiology of parkinsonism.     

An Early Warning System for Hypoglycemic/Hyperglycemic Events Based on Fusion of Adaptive Prediction Models

Introduction

Early warning of future hypoglycemic and hyperglycemic events can improve the safety of type 1 diabetes mellitus (T1DM) patients. The aim of this study is to design and evaluate a hypoglycemia/hyperglycemia early warning system (EWS) for T1DM patients under sensor-augmented pump (SAP) therapy.

Methods

The EWS is based on the combination of data-driven online adaptive prediction models and a warning algorithm. Three modeling approaches have been investigated: (i) autoregressive (ARX) models, (ii) auto-regressive with an output correction module (cARX) models, and (iii) recurrent neural network (RNN) models. The warning algorithm performs postprocessing of the models′ outputs and issues alerts if upcoming hypoglycemic/hyperglycemic events are detected. Fusion of the cARX and RNN models, due to their complementary prediction performances, resulted in the hybrid autoregressive with an output correction module/recurrent neural network (cARN)-based EWS.

Results

The EWS was evaluated on 23 T1DM patients under SAP therapy. The ARX-based system achieved hypoglycemic (hyperglycemic) event prediction with median values of accuracy of 100.0% (100.0%), detection time of 10.0 (8.0) min, and daily false alarms of 0.7 (0.5). The respective values for the cARX-based system were 100.0% (100.0%), 17.5 (14.8) min, and 1.5 (1.3) and, for the RNN-based system, were 100.0% (92.0%), 8.4 (7.0) min, and 0.1 (0.2). The hybrid cARN-based EWS presented outperforming results with 100.0% (100.0%) prediction accuracy, detection 16.7 (14.7) min in advance, and 0.8 (0.8) daily false alarms.

Conclusion

Combined use of cARX and RNN models for the development of an EWS outperformed the single use of each model, achieving accurate and prompt event prediction with few false alarms, thus providing increased safety and comfort.     

Successful intravenous regional sympathetic blockade (Bier's Block) with guanethidine and lidocaine in a patient with advanced Buerger's Disease (thromboangiitis obliterans)--a case report

A 65-year-old man, a heavy smoker with Buerger's disease (thromboangiitis obliterans), presented to this department with persistent severe ischemic rest pain at the fingers of his right hand, not responding to oral treatment with vasodilators and analgesics. Critical blood flow was discovered in the middle, ring, and little finger, with ischemic ulcerations apparent in the fingertips of these 3 fingers. The distal phalanx of the little finger had been amputated 6 months before because of gangrenous necrosis. In an attempt to avoid further disabling amputations, the patient received 3 series of Bier's block sessions with guanethidine and lidocaine according to a specific protocol. Marked increase in finger blood flow was induced even after the first series, and complete disappearance of both fingertip ulcerations and ischemic rest pain was achieved. No side effects were observed. The above-described method in a patient with advanced Buerger's disease resulted in excellent pain relief and full restoration of both blood flow and function of the affected fingers.