Persistence of autoantibodies against recombinant mitochondrial and nuclear pore proteins after orthotopic liver transplantation for primary biliary cirrhosis

Primary biliary cirrhosis is an autoimmune disease characterized by high titer autoantibodies predominantly against mitochondrial antigens PDC-E2, BCOADC-E2 and OGDC-E2. Currently orthotopic liver transplant (OLT) is the major form of treatment for end-stage primary biliary cirrhosis (PBC), but it is still unclear whether the autoimmune response continues post-transplantation. In this study we took advantage of a well-defined collection of sera collected serially before and after liver transplantation. We assayed these sera for quantitative and isotype-specific titers of antibodies against a set of recombinant mitochondrial autoantigens. We also studied reactivity to gp210. Serum samples were taken before transplantation and at intervals of 6 months, 1, 2, and 3 years after OLT. Before OLT 24/35 patients were AMA-positive, including seven out of the 35 to PDC-E2 alone, eight to both PDC-E2 and OGDC-E2, six to both PDC-E2 and BCOADC-E2, two to BCOADC-E2 alone and one to OGDC-E2. Following OLT, the frequency of sera that responded to PDC-E2 alone increased from seven to 12/35. Similarly, reactivity to BCOADC-E2 slightly increased from two to four out of 35. However, there was an overall decrease in sera that responded to more than one antigen. Neither Ig isotype nor subclass of the autoimmune response changed following OLT. Findings with gp210 were similar, in that reactivity to gp210 was found in nine out of 35 patients pre-OLT; following OLT the frequency decreased to seven out of 35 patients. Overall, the titers of AMAs decline slightly during the first year post-OLT, but are equivalent to pre-OLT values by 6 months. Moreover, the antibody subclass/ isotype remained unchanged. These data suggest that the removal of a diseased PBC liver has little, if any, impact on the serological characteristics of PBC. Moreover, it provides information regarding the natural history of PBC, particularly on the long latency time for disease development.     

HCV genotypes in patients with liver disease of different stages and severity

AIMS/MATERIAL: Hepatitis C virus (HCV) genotyping was performed in 213 anti-HCV-positive patients with chronic liver disease ranging from minimal histological changes to hepatocellular carcinoma. One hundred and twenty-two patients had non-cirrhotic chronic active or persistent hepatitis (including 29 who were asymptomatic with persistently normal ALT levels) (chronic liver disease group). The other 91 had hepatocellular carcinoma and, in all but three cases, cirrhosis (hepatocellular carcinoma group). RESULTS: The overall prevalence of HCV variants was: 54.9% type 1b, 37.8% type 2, 2.5% type 1a, 2.0% type 3a, 2.0% type 4a. The genotype distribution showed no relation to the stage (chronic liver disease vs. hepatocellular carcinoma) or severity (chronic active vs. chronic persistent hepatitis) of the liver disease, or to the duration of the disease (<10 years vs. >10 years). Within the hepatocellular carcinoma group, the duration of type-1b disease was similar to that of type-2 infections. Ages at the time of infection and genotype were both independently associated with progression to cirrhosis and hepatocellular carcinoma, but multivariate analysis revealed that the effect of age was much stronger than that of genotype 1b. CONCLUSIONS: The predominance of HCV type 1b in this study reflects the higher frequency of this variant in our area. Our findings indicate that infections caused by each HCV genotype are capable of progressing to hepatocellular carcinoma.     

Xenobiotics Delivered by Electronic Nicotine Delivery Systems: Potential Cellular and Molecular Mechanisms on the Pathogenesis of Chronic Kidney Disease

Chronic kidney disease (CKD) is characterized as sustained damage to the renal parenchyma, leading to impaired renal functions and gradually progressing to end-stage renal disease (ESRD). Diabetes mellitus (DM) and arterial hypertension (AH) are underlying diseases of CKD. Genetic background, lifestyle, and xenobiotic exposures can favor CKD onset and trigger its underlying diseases. Cigarette smoking (CS) is a known modified risk factor for CKD. Compounds from tobacco combustion act through multi-mediated mechanisms that impair renal function. Electronic nicotine delivery systems (ENDS) consumption, such as e-cigarettes and heated tobacco devices, is growing worldwide. ENDS release mainly nicotine, humectants, and flavorings, which generate several byproducts when heated, including volatile organic compounds and ultrafine particles. The toxicity assessment of these products is emerging in human and experimental studies, but data are yet incipient to achieve truthful conclusions about their safety. To build up the knowledge about the effect of currently employed ENDS on the pathogenesis of CKD, cellular and molecular mechanisms of ENDS xenobiotic on DM, AH, and kidney functions were reviewed. Unraveling the toxic mechanisms of action and endpoints of ENDS exposures will contribute to the risk assessment and implementation of proper health and regulatory interventions.     

A voice over IP service architecture for integrated communications

The rapid evolution of Internet telephony has introduced new service implementation paradigms. The authors propose a service architecture that integrates circuit based telecommunications with the Internet through the control elements of traditional and emerging networks, specifically the gatekeepers of VoIP and the SCPs of PSTN     

Pseudomembranous colitis caused by antibiotics

To study the effectiveness of a trend at the Mayo Clinic toward modifying the standard radical mastectomy, the 5-year survival of 873 women treated surgically for breast cancer from 1965 through 1968 was evaluated. The observed survival of 534 patients treated by the standard radical mastectomy was 85% when nodes were negative and 56% when nodes were positive. For 339 patients treated by the modified radical mastectomy, the observed survival was 80% and 48% when axillary nodes were negative and positive, respectively. In order to accomplish a more significant analysis of cancer risk and results of the two operative procedures, a relatively homogeneous group of 541 patients was established from the total group. In this homogeneous group, the observed survival of 336 patients treated by the standard radical mastectomy was 86% when nodes were negative and 66% when nodes were positive. For 205 patients treated by the modified radical mastectomy, the observed survival was 84% and 66% when axillary nodes were negative and positive, respectively. When patients were further analyzed and compared according to the extent of axillary-node involvement, age at the time of treatment, grade, size, location, and histopathologic type of tumor, and the use of postoperative irradiation, survival was essentially the same, irrespective of the type of mastectomy performed.     

Tetraspanin CD9 Expression Predicts Sentinel Node Status in Patients with Cutaneous Melanoma

The tetraspanin CD9 is considered a metastasis suppressor in many cancers, however its role is highly debated. Currently, little is known about CD9 prognostic value in cutaneous melanoma. Our aim was to analyse CD9 expression in melanocytic nevi and primary cutaneous melanomas through immunohistochemistry and immunofluorescence approaches to determine its correlation with invasiveness and metastatic potential. CD9 displayed homogeneous staining in all melanocytic nevi. In contrast, it showed a complete loss of reactivity in all thin melanomas. Interestingly, CD9 was re-expressed in 46% of intermediate and thick melanomas in small tumor clusters predominantly located at sites of invasion near or inside the blood or lymphatic vessels. The most notable finding is that all CD9 stained melanomas presented sentinel node positivity. Additionally, a direct association between CD9 expression and presence of distant metastasis was reported. Finally, we confirm that CD9 expression is consistent with an early protective role against tumorigenesis, however, our data endorse in melanoma a specific function of CD9 in vascular dissemination during late tumor progression. The presence of CD9 hotspots could be essential for melanoma cell invasion in lymphatic and endothelial vessels. CD9 could be a valid prognostic factor for lymph node metastasis risk.     

Efficacy of lamivudine re-treatment in a patient with hepatitis B virus (HBV) recurrence after liver transplantation and HBV-DNA breakthrough during the first treatment

BACKGROUND: Transplantation for terminal hepatitis B virus (HBV) disease is aggravated by a high rate of reinfection and disease recurrence. Lamivudine, a new nucleoside analog, is a potent inhibitor of HBV synthesis, but its use may lead to the emergence of HBV-DNA polymerase mutants resistant to the drug. METHODS AND RESULTS: We describe the case of a patient who developed an HBV recurrence after liver transplantation and was treated with lamivudine. An HBV-DNA breakthrough occurred 7 months after the start of therapy, and the drug was stopped after 9 months. The molecular state of HBV-DNA was analyzed, and a mutation in the YMDD (tyrosine, methionine, aspartate, aspartate) locus of HBV-DNA polymerase was identified. Nine months after the suspension of lamivudine the patient experienced a new hepatic attack accompanied by high HBV-DNA levels. Lamivudine was given again. Serum HBV-DNA levels normalized after 45 days of re-treatment, but lamivudine-resistant mutants were again the prevalent viral population after 3 months. CONCLUSIONS: The case described suggests that retherapy with lamivudine after a first emergence of YMDD mutants is temporarily effective in recontrolling HBV synthesis but ultimately induces the accelerated reemergence of a prevalently mutant population of HBV. This emphasizes the need for combined antiviral therapy.     

Assessment of station cable condition using wireless telemetry and diagnostic tests

Following the premature in-service failure of a 15 kV, XLPE insulated cable in a hydraulic generating station, a program was devised to: determine the root cause of failure; assess the condition of the remaining cables in the station; and ensure that the field modifications proposed to rectify the problem were effective. The underlying mechanism driving the failure was found to be overheating of the cable sheath as a result of the inadvertent formation of ground loops in the cable support structure, and hence circulating currents. Physicochemical tests of cable sections recovered from the failed circuit showed that the cable had experienced temperatures in excess of 115 /spl deg/C. Electrical diagnostic testing of the affected cable circuits indicated that the majority of the cable length was unaffected by the overheating. However, the portion of the cable within the switchgear cubicle may have undergone some ageing as evidenced by higher dielectric loss values. On-line temperature measurements, including those on the current-carrying components using wireless telemetry, confirmed that one of the sources of the high temperatures was the ground structure in the cubicle.