Tumor necrosis factor alpha gene expression and the response to interferon in chronic hepatitis C

Tumor necrosis factor alpha (TNF-alpha) is a cytokine with pleiotropic properties that is induced in a variety of pathological situations including viral infections. In this work, we analyzed the expression of TNF-alpha gene in patients with chronic hepatitis C. Serum TNF-alpha levels were found to be elevated in all chronic hepatitis C patients including those cases presenting sustained biochemical remission of the disease after interferon therapy. Untreated patients with chronic hepatitis C showed increased TNF-alpha messenger RNA (mRNA) levels in the liver and mononuclear cells as compared with healthy controls. After completion of treatment with interferon, patients experiencing sustained complete response showed values of TNF-alpha mRNA, both in the liver and in peripheral mononuclear cells, within the normal range, significantly lower than patients who did not respond to interferon and than those with complete response who relapsed after interferon withdrawal. Pretreatment values of TNF-alpha mRNA were lower in long-term responders to interferon than in cases who failed to respond to the treatment. Values of TNF-alpha mRNA in the liver or in mononuclear cells were higher in specimens with positive hepatitis C virus (HCV) RNA than in those samples where the virus was undetectable. Neither the intensity of the liver damage nor the amount of HCV RNA in serum or in cells showed correlation with the levels of TNF-alpha transcripts in peripheral mononuclear cells but it was found that high TNF-alpha values were associated with genotype 1b. In conclusion, there is an enhanced expression of TNF-alpha in HCV infection. High levels of this cytokine may play a role in the resistance to interferon therapy

Ribavirin in the treatment of chronic hepatitis C unresponsive to alfa interferon

For the 30-50% of patients with chronic hepatitis C who do not respond to alpha-interferon therapy there is no alternative treatment. Some previously untreated patients have shown a biochemical response to ribavirin, but the antiviral effects of this substance on alpha-interferon-resistant cases is largely unknown. Twelve patients with chronic hepatitis C who had not responded to a 6-12 month course of alpha-interferon were included in this study. Oral ribavirin was administered at a dose of 16 mg/kg per day for 6 or 9 months. Aminotransferase levels had not significantly changed during interferon therapy but decreased significantly during ribavirin treatment (mean alanine aminotransferase at baseline, 102 +/- 18 IU/l vs. 55 +/- 14 IU/l at 6 months; P = 0.0001). Aminotransferase levels became normal in 6 cases (50%), significantly decreased in 3 patients (25%), and did not significantly change in the remaining 3 cases (25%). All patients with normalized aminotransferase values relapsed after ribavirin was discontinued and aminotransferase activity returned to pretreatment levels. Before therapy serum hepatitis C virus RNA was detected by polymerase chain reaction in 10 cases. None of them had cleared viral RNA when tested following 3, 6 and 9 months of ribavirin therapy. Side-effects were mild and reversible. In conclusion, about half of the patients with chronic hepatitis C who are unresponsive to alpha-interferon show a clear-cut biochemical response after 6-9 months of ribavirin administration. However, ribavirin does not clear circulating hepatitis C virus RNA and relapses occur after withdrawal.

Cellular immunity to hepatitis C virus core protein and the response to interferon in patients with chronic hepatitis C

To investigate the involvement of T-cell response against hepatitis C virus (HCV) antigens in viral clearance after interferon therapy, we measured interleukin-2 (IL-2) production by peripheral mononuclear cells in response to HCV core in patients with chronic hepatitis C. In a cohort of 43 patients, we investigated the frequency of circulating core-specific T-helper (Th) cell precursors by the limiting-dilution assay, and in a second cohort of 60 patients, we analyzed the response to specific core epitopes using 52 synthetic 15-mer overlapping peptides. We observed that the frequency of core-specific Th cell precursors was significantly higher in patients with sustained biochemical and virological response (SR) after interferon (IFN) therapy (median, 1/55,736) than in untreated patients (1/274,023) or that in patients who remained viremic after completion of the treatment-nonresponders (NR) plus transient responders (TR) (1/1,909,972). Patients who failed to respond to IFN (NR) and those who relapsed after IFN discontinuation (TR) had a similarly low number of precursors. The number of core peptides recognized by SR, TR, NR, UT, and healthy controls was 8.2 +/- 1.5, 6.5 +/- 1.2, 2.0 +/- 0.5, 2.7 +/- 0.9, and 0.3 +/- 0.2, respectively. In SR, the intensity of the proliferative response to core peptides as estimated by the summation of stimulation indexes (sigmaSI) was significantly higher than in NR and than in UT, but not different from that of TR. Our results indicate that both expansion of HCV-specific Th cell precursors and Th cell recognition of multiple core epitopes seem to be important in the elimination of HCV after IFN therapy

Inherited photoreceptor degeneration causes the death of melanopsin-positive retinal ganglion cells and increases their coexpression of brn3a

Purpose: To study the population of intrinsically photosensitive retinal ganglion cells (melanopsin-expressing RGCs, m+RGCs) in P23H-1 rats, a rat model of inherited photoreceptor degeneration. Methods: At postnatal (P) times P30, P365, and P540, retinas from P23H dystrophic rats (line 1, rapid degeneration; and line 3, slow degeneration) and Sprague Dawley (SD) rats (control) were dissected as whole-mounts and immunodetected for melanopsin and/or Brn3a. The dendritic arborization of m+RGCs and the numbers of Brn3a+RGCs and m+RGCs were quantified and their retinal distribution and coexpression analyzed. Results: In SD rats, aging did not affect the population of Brn3a+RGCs or m+RGCs or the percentage that showed coexpression (0.27%). Young P23H-1 rats had a significantly lower number of Brn3a+RGCs and showed a further decline with age. The population of m+RGCs in young P23H-1 rats was similar to that found in SD rats and decreased by 22.6% and 28.2% at P365 and P540, respectively, similarly to the decrease of the Brn3a+RGCs. At these ages the m+RGCs showed a decrease of their dendritic arborization parameters, which was similar in both the P23H-1 and P23H-3 lines. The percentage of coexpression of Brn3a was, however, already significantly higher at P30 (3.31%) and increased significantly with age (10.65% at P540). Conclusions: Inherited photoreceptor degeneration was followed by secondary loss of Brn3a+RGCs and m+RGCs. Surviving m+RGCs showed decreased dendritic arborization parameters and increased coexpression of Brn3a and melanopsin, phenotypic and molecular changes that may represent an effort to resist degeneration and/or preferential survival of m+RGCs capable of synthesizing Brn3a

Distortion product otoacoustic emissions in normally hearing subjects.

The finding of active function by the outer hair cells for sound processing prior to neural transduction in the inner hair cells represents the basic mechanism for the generation of Otoacoustic Emissions in the cochlea. Among them the so-called Distortion Product Otoacoustic Emissions represent a tool for an in depth knowledge of the Organ of Corti micromechanics, more advantageous than others, based on their properties, that makes possible an objective frequency-specific study: The response in a group of normally hearing subjects is presented and characterized to ascertain the basic features to be used in further testing of deaf people

Tratamiento de la hepatitis crónica por virus C

La hepatitis crónica por virus C es la principal causa de enfermedad crónica hepática en nuestro medio y la indicación más frecuente de trasplante hepático. Afecta a un millón de personas en España, cerca de 4 millones en los Estados Unidos, más de 5 millones en Europa y de 170 millones en todo el mundo. Estas cifras hablan de la necesidad de encontrar un tratamiento eficaz, capaz de eliminar la infección o, al menos, detener la progresión de la enfermedad hepática. El tratamiento de elección en la actualidad, la combinación de interferón alfa pegilado y ribavirina, ha duplicado las tasas de respuesta sostenida obtenidas hace tan sólo algunos años, pero dista aún de ser óptimo. El gran número de enfermos no respondedores al tratamiento, la mala respuesta de los enfermos cirróticos o en circunstancias especiales y la evidencia de la recurrencia universal de la enfermedad tras el trasplante exigen nuevas estrategias terapéuticas en el futuro inmediato.Chronic hepatitis C is the major cause of chronic liver disease in western countries and the leading indication for liver transplant. An estimated one million people are infected in Spain, four million in the US, five million in Europe and more than 170 million worldwide. An effective treatment, able to eradicate the virus or to stop the progression of liver disease is clearly needed. Current treatment of chronic hepatitis C, the combination of pegylated alpha interferon and ribavirin, has doubled the sustained response rate there was only a few years ago, but this treatment is far from ideal. The number of non-responders, the low response rates in cirrhotic patients or those with special situations, and the evidence of recurrence of liver disease after liver transplant call for new therapeutic strategies in the near future

Información de medicamentos a la población desde el Servicio de Farmacia a través de Internet

Objectives: To describe and discuss the work of a Pharmacy Department for the health-care portal www.viatusalud.com. Methods: Using a web portal, a Pharmacy Department develops and updates a vademecum on drugs, and answers enquiries by end-users. Results: On December 31, 2002 more than 750 records on drugs were available, and 3030 enquiries had been answered. Conclusions: With this drug information and online enquiry service, our Pharmacy Department helps meet the demand of health-care information posed by the community and by patients previously seen at Clínica Universitaria. In addition, it allows areas of improvement to be detected in the information to be offered to patients fron a Pharmacy Department, and represents a tertiary source of information for health-care professionals

Performance of SAPS II and SAPS 3 in Intermediate Care

Objective: The efficacy and reliability of prognostic scores has been described extensively for intensive care, but their role for predicting mortality in intermediate care patients is uncertain. To provide more information in this field, we have analyzed the performance of the Simplified Acute Physiology Score (SAPS) II and SAPS 3 in a single center intermediate care unit (ImCU). Materials and Methods: Cohort study with prospectively collected data from all patients admitted to a single center ImCU in Pamplona, Spain, from April 2006 to April 2012. The SAPS II and SAPS 3 scores with respective predicted mortality rates were calculated according to standard coefficients. Discrimination was evaluated by calculating the area under receiver operating characteristic curve (AUROC) and calibration with the Hosmer-Lemeshow goodness of fit test. Standardized mortality ratios (SMR) with 95% confidence interval (95% CI) were calculated for each model. Results: The study included 607 patients. The observed in-hospital mortality was 20.1% resulting in a SMR of 0.87 (95% CI 0.73-1.04) for SAPS II and 0.56 (95% CI 0.47-0.67) for SAPS 3. Both scores showed acceptable discrimination, with an AUROC of 0.76 (95% CI 0.71-0.80) for SAPS II and 0.75 (95% CI 0.71- 0.80) for SAPS 3. Calibration curves showed similar performance based on Hosmer-Lemeshow goodness of fit C-test: (X2=12.9, p=0.113) for SAPS II and (X2=4.07, p=0.851) for SAPS 3. Conclusions: Although both scores overpredicted mortality, SAPS II showed better discrimination for patients admitted to ImCU in terms of SMR