Results of Hepatitis C Virus Treatment in Patients on Hemodialysis: Data From Published Meta-analyses in 2008

Reports on the outcome of treatment for hepatitis C virus (HCV) infection in dialysis patients are limited by small patient series, nonrandomized study designs, and few case-control studies. We reviewed 2 meta-analyses (Meta-1 and Meta-2) published in 2008, which analyzed sustained viral responses (SVR), adverse effects, and reasons for discontinuing treatment. Meta-1 analyzed the results obtained in 645 patients and Meta-2 the results in 459 patients (19 studies were duplicated). The overall SVR was 40%; the SVR in genotype 1 was 33%, with pegylated interferon providing few additional benefits over conventional interferon. Adverse events were reported in <50% of cases compiled in the meta-analyses. A high percentage of anemia was documented, although the use of erythropoietin, intravenous iron administration, or transfusions was not generally reported. A typical flu-like syndrome occurred in 41% of patients, requiring withdrawal of antiviral treatment in 11%. Severe adverse events were divided into the following groups: hormonal (thyroid): bone pain; cytopenia; gastrointestinal; immunological (prior graft rejection); central nervous system; cardiovascular; and infectious problems. The authors of the meta-analyses pointed out bias in the selection of candidates for treatment, limitations related to the number and type of adverse effects and their clinical evaluation, and in the cases of discontinuation of treatment or loss to follow-up. Additional studies reporting individual patient data are needed because the paucity of controlled studies limits generalization of the results to the population of dialysis patients.     

Calcitonin gene-related peptide in rat spinal cord motoneurons: subcellular distribution and changes induced by axotomy.

Using light and electron microscopy, a study has been made of the changes of calcitonin gene-related peptide-like immunoreactivity in rat lumbar spinal cord motoneurons during cell body response to sciatic nerve injury. At light microscopy level, calcitonin gene-related peptide-like immunoreactivity was evaluated using an indirect immunofluorescence technique combined with Fast Blue retrograde tracing and a peroxidase-antiperoxidase procedure. The calcitonin gene-related peptide changes to sciatic nerve transection and crushing were compared. Calcitonin gene-related peptide-like immunoreactivity was transiently increased after the peripheral nerve lesion, but the response was sustained for a longer period when the peripheral nerve was transected and nerve regeneration prevented. The first changes in calcitonin gene-related peptide-like immunoreactivity were detected four days after nerve crush or transection. In animal spinal cords to which nerve crush had been applied, the maximal enhancement of immunoreactivity was found 11 days after lesion. This was followed by a gradual decline, normal levels being attained 45 days after nerve crushing. When the nerve was transected, the response was similar, but the maximal calcitonin gene-related peptide-like immunoreactivity was maintained over a period of between 11 and 30 days. As with crushing, an important decrease was observed after 45 days. The ultrastructural compartmentation of calcitonin gene-related peptide-like immunoreactivity was studied using either peroxidase-antiperoxidase method or immunogold labelling. Calcitonin gene-related peptide-like immuno-reactivity was located in restricted sacs of the Golgi complex, multivesicular bodies, small vesicles and tubulo-vesicular structures. Large, strongly labelled vesicles resembling secretory granules were also observed in neuronal bodies. Our results reveal that the increase of calcitonin gene-related peptide in motoneurons is a relevant change the cell body undergoes in response to peripheral injury. The ultrastructural location of the peptide distribution suggests specific compartmentation on tubulo-vesicular structures connected with the Golgi complex which form a network in the neuronal cytoplasm. The distribution pattern observed may be related to the sorting and delivery of calcitonin gene-related peptide to secretory vesicles.     

Competition between ABO and Le Gene Specified Enzymes

Radioimmunoassays were prepared using two anti-A and one anti-B reagents. The specificity of the procedures was assessed with 13 artificial antigens. The amounts of A and B natural antigens in saliva of ABH secretors of known Lewis phenotype were measured with these assays. The results confirmed that the average amount of A antigen is lower in Lewis-positive (Leb) than in Lewis-negative (Led) donors and in A2 than in A1 donors. However, the differences among the four combined A and Lewis phenotypes were only supported by significantly lower amounts of A antigenic determinants in A2Leb as compared to the other three phenotypes (A1Leb, A1Led and A2Led) that had similar amounts of A antigenic determinants. No Lewis-related difference could be detected in the amounts of B antigens between BLeb and BLed donors. The results are discussed in terms of competition between A, B and Lewis-gene-specified enzymes for their common acceptors. The difference in the efficiency of the A2 enzyme as compared to that of the A1 enzyme is proposed as a possible explanation for the A1-A2 phenotypic difference.     

Immunohistological characterization of mucin epitopes by pre-treatment of gastro-intestinal sections with periodic acid.

Periodate pretreatment of paraffin sections of ethanol-fixed gastrointestinal mucosae was used to characterize the carbohydrate or peptidic nature of mucin epitopes by immunoperoxidase. Immunoreactivity of monoclonal antibodies (MAbs) against histo-blood group related carbohydrate epitopes such as A, Lea, Lec, Sialosyl Lea, H type 2, I, T, Tn and sialosyl Tn dramatically decreased or even disappeared after periodate pretreatment of deparaffinized sections. In contrast, the immunoreactivity of MAbs against peptide mucin epitopes such as the gastric M1 mucin epitopes was almost unaffected by this treatment. Moreover, periodate treatment revealed cryptic peptide M1 mucin epitopes and the peptide MUSE11 epitope associated with the 20 amino acid tandem repeat (PDTRPAPGSTAPPAHGVTSA). An increase of cross-reactions of anti-human M1 MAbs with gastric epithelium of different vertebrate species was detected with periodate treatment. Our results suggest that this method can be useful for preliminary characterization of the biochemical nature of mucin epitopes (peptidic or saccharidic) and for demasking peptidic tumour markers which are hidden by saccharide molecules in normal tissues.     

α galnac is essential for recognition of EXO-1 epithelial antigen by mouse monoclonal antibody Pa-G-14

Mouse monoclonal antibody Pa-G-14 detects Exo-1, an antigen whose expression is regulated in the processes of epithelial-cell differentiation and transformation. The epitope recognized by Pa-G-14 is present both in glycosphingolipids and in mucin glycoproteins. To characterize the specificity of Pa-G-14, immuno-thin-layer chromatography, biochemical, and enzymatic treatment of glycosphingolipid extracts from human pancreas were used. The antibody bound to all blood-group-A substances; αGaINAc, but not fucose, was essential for reactivity. In ELISA, Pa-G-14 also reacted with ovine and bovine submaxillary mucins but not with porcine submaxillary mucin. Binding to ovine submaxillary mucin was resistant to neuraminidase treatment. In solid-phase absorption assays on synthetic carbohydrate structures, Pa-G-14 recognized broadly blood group A, Tn and sialyl-Tn. Using immuno-electron-microscopic techniques, reactivity with all Golgi cisternae and mucin droplets of mucous cells in ovine submaxillary gland was demonstrated. All these assays indicate that Pa-G-14 shows a novel specificity, since it binds blood group A, Tn and sialyl-Tn, the common structural feature of these epitopes being the presence of a terminal αGalNAc sugar unit.     

Corticosteroid-sparing strategies in renal transplantation: are we still balancing rejection risk with improved tolerability?

Chronic allograft nephropathy and death with a functioning graft (mainly due to cardiovascular causes) are the most common causes of graft loss after the first year of renal transplantation. Immunosuppressants, and corticosteroids among them, contribute to an increase in cardiovascular risk because of their significant adverse effects, including hypertension, hyperlipidaemia and hyperglycaemia. Thus, corticosteroid discontinuation or avoidance has become a priority among the transplant community in order to enhance long-term graft and patient survival. Nevertheless, corticosteroid-sparing strategies may increase the risk of acute and chronic rejection and, thus, worsen the prognosis of transplant recipients. Initial attempts during the azathioprine epoch did not provide satisfactory results, as they were associated with high acute rejection rates, emphasising the risk of under-immunosuppression. The advent of new immunosuppressants, such as mycophenolate mofetil, mTOR inhibitors and anti-interleukin-2 receptor antibodies, have renewed the interest in corticosteroid-sparing protocols, and the results of new trials suggest that these corticosteroid-sparing strategies, even at an early stage after transplantation, are safe enough in view of the stable renal function and low rates of acute rejection reported. However, immunological risk factors, such as African American ethnicity, the presence of panel-reactive anti-HLA antibodies (even at low rates), and a history of previous acute rejection episodes should be taken into account and corticosteroid withdrawal strategies should be undertaken with caution. Long-term follow-up studies must be performed to confirm the encouraging short-term data.     

Cofactors associated with liver disease mortality in an HBsAg-positive Mediterranean cohort: 20 years of follow-up

The risk of developing liver cancer in hepatitis B virus (HBV) carriers differs across geographical areas, suggesting that exposure to other risk factors may contribute to HBV-linked cancer risk. Our study estimates the mortality due to liver disease and the role of other risk factors in a Spanish HBV cohort. 2,352 hepatitis B surface antigen (HBsAg)-positive and 15,504 HBsAg-negative subjects were identified among blood donors during 1972-1985 and were followed until December 2000 through the Mortality Registry. Clinical examination and an epidemiological questionnaire were performed on 1,000 HBsAg-positive survivors during 1994-1996. In subjects deceased from liver disease, medical records were revised and relatives were interviewed. A nested case-control analysis was conducted comparing both groups. In HBsAg-positive men, an excess mortality from liver cancer [standardized mortality ratio (SMR): 14.1; 7.7-23.6], cirrhosis (SMR: 10.5; 7.0-15.1), haematological neoplasms (SMR: 3.2; 1.2-6.9) and AIDS was detected (SMR: 5.5; 2.2-11.4). In women, an excess was found for cirrhosis (SMR: 7.2; 1.4-21.1). Progression factors to liver disease were alcohol intake [odds ratio (OR): 6.3; 3.1-12.8], diabetes (OR: 3.6; 1.3-9.6), HBV replication (OR: 50.0; 14.9-167.3) and hepatitis C virus (HCV) infection (OR: 27.4; 7.1-107.7). In conclusion, in Spain after 20 years of follow-up, chronic HBV exposure appears as a major risk factor for liver cancer among men and for cirrhosis in both sexes. The risk of death from liver disease among HBV carriers with the presence of HBV replication, HCV, alcohol consumption and diabetes was significantly increased and suggests synergism among these exposures and HBV. Mortality from haematological neoplasms was detected and could be associated to HIV coinfection. These results support screening and adequate follow-up among HBsAg-positive subjects at high risk to develop liver disease, particularly when these risk cofactors are present.