HCV carriers with normal alanine aminotransferase levels: Healthy persons or severely ill patients?: Dealing with an everyday clinical problem

Approximately 30% of patients with chronic HCV infection show persistently normal ALT levels. Although formerly referred to as ‘healthy’ or ‘asymptomatic’ HCV carriers, and thus historically excluded from antiviral treatment, it has now become clear that the majority of these patients have some degree of histological liver damage that may be significant in up to 20% of patients and might progress toward a more severe degree of liver fibrosis. A significant proportion of patients (≥ 20%) experience periods of increased serum ALT (flare) associated with enhanced disease progression. However, controversies still exist in clinical practice regarding the definition of ‘persistent’ ALT normality, the virological and histological features of these subjects, the need for liver biopsy, the role of non invasive tools for the assessment of liver fibrosis (transient hepatic elastography, fibroscan), and the natural history and optimal management of chronic hepatitis C with normal ALT. The advent of new therapeutic options (pegylated interferons plus ribavirin) has shifted treatment targets toward eradication of underlying infection, with therapy decision based on age, severity of disease and likelihood of response rather than on aminotransferase levels. This review does approach the main unresolved issues on this topic in the form of a dialog between a hepatologist and a patient with HCV infection but normal alanine aminotransferase levels, trying to give evidence-based answers to the more frequently asked questions from patients and their physicians.     

Comparison between VDR analogs and current immunosuppressive drugs in relation to CXCL10 secretion by human renal tubular cells

During kidney allograft rejection, CXC chemokine ligand 10 (CXCL10)–CXC chemokine receptor 3 (CXCR3) trafficking between peripheral blood and tissues initiates alloresponse and perpetuates a self‐inflammatory loop; thus, CXCL10–CXCR3 axis could represent a pharmacologic target. In this perspective, immunosuppressors targeting graft‐resident cells, beside immune cells, could be very advantageous. Vitamin D receptor (VDR) agonists exhibit considerable immunomodulatory properties. This study aimed to investigate whether elocalcitol and BXL‐01‐0029 could decrease the expression of CXCL10 in activated renal tubular cells in vitro and thus be useful in kidney allograft rejection treatment. Experiments were performed in human tubular renal cells stimulated with interferon‐γ + tumor necrosis factor‐α with and without VDR agonists, tacrolimus, sirolimus, hydrocortisone, methylprednisolone, cyclosporin A and mycophenolate mofetil. CXCL10 protein secretion and gene expression were measured by ELISA and by quantitative PCR. Specific inhibitors were used to investigate intracellular pathways involved in tubular cells activation. For IC₅₀ determination and comparison, dose‐response curves with VDR agonists, tacrolimus and mycophenolic acid were performed. Elocalcitol and BXL‐01‐0029 inhibited CXCL10 secretion by renal cells, without affecting cell viability, while almost all the immunosuppressors were found to be ineffective, except for tacrolimus and mycophenolate mofetil. BXL‐01‐0029 was the most potent drug and, notably, it was found to be capable of allowing reduction in tacrolimus‐inhibitory doses. Our data suggest that BXL‐01‐0029 could potentially be a dose‐reducing agent for conventional immunosuppressors in kidney rejection management.     

Evidence for the involvement of 5-HT2A receptors in mild mesenteric ischemia/reperfusion dysfunctions in mice

In this study, the involvement of 5-HT2A receptors on mesenteric ischemia-reperfusion injury was examined in mice. Intestinal ischemia produced by 45 min occlusion of superior mesenteric artery was followed by 24h reperfusion (I/R). The 5-HT2A selective antagonist, ketanserin (0.5 mgkg(-1)) or the 5-HT2A agonist DOI (0.25 mgkg(-1)) was intravenously administered before ischemia and 8h after the beginning of reperfusion. The effects were compared with those obtained in sham operated animals (S). Ketanserin prevented the upper gastrointestinal transit delay induced by I/R (P<0.01), protected intestine from leukocyte recruitment as indicated by jejunal myeloperoxidase activity (P<0.05) and reverted Evans Blue extravasation elicited by I/R in lung, colon and jejunum (P<0.05). On the other hand, 5-HT2A activation by DOI mimicked the effects of I/R in S mice prolonging small intestine transit (P<0.05) and enhancing neutrophil accumulation in jejunal tissues (P<0.05). Furthermore, the reduction of ADP-induced platelet aggregation in plasma of I/R mice was prevented by ketanserin treatment. All together, these findings support the critical involvement of 5-HT2A receptor subtype in mediating the damage induced by mesenteric I/R in mice.     

Lack of apoptosis in patients with progressive external ophthalmoplegia and mutated adenine nucleotide translocator-1 gene

Adenine nucleotide translocator-1 (ANT-1), encoded by chromosome 4 (4q34-35 locus), is a component of the mitochondrial permeability transition pores that are involved in apoptotic mechanisms. We studied muscle biopsies from seven individuals with autosomal dominant progressive external ophthalmoplegia caused by ANT-1 mutations. We found no instance of terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL) positivity nor significant expression of apoptosis-related proteins. Furthermore, there was no morphological evidence of apoptosis at the ultrastructural level. Thus, degeneration of muscle in this disorder is nonapoptotic.     

Protective effect of erythropoietin and its carbamylated derivative in experimental Cisplatin peripheral neurotoxicity.

PURPOSE: Antineoplastic drugs, such as cisplatin (CDDP), are severely neurotoxic, causing disabling peripheral neuropathies with clinical signs known as chemotherapy-induced peripheral neurotoxicity. Cotreatment with neuroprotective agents and CDDP has been proposed for preventing or reversing the neuropathy. Erythropoietin given systemically has a wide range of neuroprotective actions in animal models of central and peripheral nervous system damage. However, the erythropoietic action is a potential cause of side effects if erythropoietin is used for neuroprotection. We have successfully identified derivatives of erythropoietin, including carbamylated erythropoietin, which do not raise the hematocrit but retain the neuroprotective action exerted by erythropoietin. EXPERIMENTAL DESIGN: We have developed previously an experimental chemotherapy-induced peripheral neurotoxicity that closely resembles CDDP neurotoxicity in humans. The present study compared the effects of erythropoietin and carbamylated erythropoietin (50 microg/kg/d thrice weekly) on CDDP (2 mg/kg/d i.p. twice weekly for 4 weeks) neurotoxicity in vivo. RESULTS: CDDP given to Wistar rats significantly lowered their growth rate (P < 0.05), with slower sensory nerve conduction velocity (P < 0.001) and reduced intraepidermal nerve fibers density (P < 0.001 versus controls). Coadministration of CDDP and erythropoietin or carbamylated erythropoietin partially but significantly prevented the sensory nerve conduction velocity reduction. Both molecules preserved intraepidermal nerve fiber density, thus confirming their neuroprotective effect at the pathologic level. The protective effects were not associated with any difference in platinum concentration in dorsal root ganglia, sciatic nerve, or kidney specimens. CONCLUSIONS: These results widen the spectrum of possible use of erythropoietin and carbamylated erythropoietin as neuroprotectant drugs, strongly supporting their effectiveness.     

High-dose versus standard chemotherapy in metastatic breast cancer: comparison of Cancer and Leukemia Group B trials with data from the Autologous Blood and Marrow Transplant Registry.

PURPOSE: To assess survival of patients with metastatic breast cancer treated with high-dose chemotherapy (HDC) versus standard-dose chemotherapy (SDC). PATIENTS AND METHODS: SDC in four Cancer and Leukemia Group B (CALGB) trials was compared with hematopoietic stem-cell support in patients from the Autologous Blood and Marrow Transplant Registry. Cox proportional hazard regression incorporated potentially confounding effects. A total of 1,509 women were enrolled onto CALGB trials, and 1,188 women received HDC. No significant survival differences existed by CALGB trial or HDC regimen. Consideration was restricted to candidates for both SDC and HDC. The resulting sample included 635 SDC and 441 HDC patients. The outcome of interest was overall survival. RESULTS: The HDC group displayed better performance status. The SDC group had slightly better survival in first year after treatment. The HDC group had lower hazard of death from years 1 to 4 and had somewhat higher probability of 5-year survival (adjusted probabilities [95% confidence intervals], 23% [17% to 29%] v 15% [11% to 19%], P =.03). CONCLUSION: After controlling for known prognostic factors in this nonrandomized analysis of two large independent data sets, women receiving HDC versus SDC for metastatic breast cancer have a similar short-term probability of survival, and might have a modestly higher long-term probability of survival.     

An outcome study of the use of computed tomography for the diagnosis of appendicitis in a community-based emergency department

OBJECTIVES: Previous studies evaluating the use of CT in the diagnosis of appendicitis have taken place at university-based institutions where surgical bedside consultation seems prudent before radiological study. In the private hospital setting, the emergency department (ED) physician is responsible for diagnosis. We attempt to assess if this process is detrimental to patient care. METHODS: Retrospective review of 150 patient's records admitted through the ED was performed with the discharge diagnosis of appendicitis between March 1998 and May 2000. Data was stratified for analysis based on age (< 15, 15-50, > 50) and gender. Using Graph Pad Prism software the groups were compared for complications based on whether or not CT was obtained. Chi-square, number needed to treat (NNT), absolute risk reduction (ARR), relative risk reduction (RRR) and respective confidence intervals were calculated for each group. RESULTS: No significant differences overall were obtained between CT and no CT groups at P < 0.05. A significant benefit is demonstrated at P = 0.017 in females of childbearing age while a detrimental trend is found for those over the age of 50 years. CONCLUSIONS: Contrary to our initial hypothesis, no increased incidence of appendiceal perforation or abscess was demonstrated based on the ED physician's decision to perform CT without surgical consultation.     

Long-term cyclophosphamide treatments against primary mammary tumors in C3H/He mice

Tumor-free inbred female C3H/He mice were given weekly injections of cyclophosphamide to prevent or delay the expected occurrence of spontaneous mammary carcinomas. Chemotherapy was started at an age when the mice would already have developed preneoplastic hyperplastic alveolar nodules and tumors were likely to appear within a few weeks. Treatments were given for periods ranging from 10 to 50 weeks with various schedules and doses. The mice were observed for the development of tumors until they died or were killed. Tumors were excised as they appeared. Treatments were most effective in reduction of the number of primary tumors when started early and given continuously. Longer term, low-dose treatments gave better results than short-term, high-dose treatments, although the total dose given was the same. The prophylactic effect of the drug appeared to be by the destruction of occult, drug-sensitive tumors, rather than by delay of their appearance. The toxicity of moderate, continuous drug administration was well tolerated with no mortality and only minor transient weight loss.