Identifying content to improve risk assessment communications within the Risk Profile: Literature reviews and focus groups with expert and non-expert stakeholders.

OBJECTIVE: To improve consumer decision making, the results of risk assessments on food, feed, consumer products or chemicals need to be communicated not only to experts but also to non-expert audiences. The present study draws on evidence from literature reviews and focus groups with diverse stakeholders to identify content to integrate into an existing risk assessment communication (Risk Profile). METHODS: A combination of rapid literature reviews and focus groups with experts (risk assessors (n = 15), risk managers (n = 8)), and non-experts (general public (n = 18)) were used to identify content and strategies for including information about risk assessment results in the "Risk Profile" from the German Federal Institute for Risk Assessment. Feedback from initial focus groups was used to develop communication prototypes that informed subsequent feedback rounds in an iterative process. A final prototype was validated in usability tests with experts. RESULTS: Focus group feedback and suggestions from risk assessors were largely in line with findings from the literature. Risk managers and lay persons offered similar suggestions on how to improve the existing communication of risk assessment results (e.g., including more explanatory detail, reporting probabilities for individual health impairments, and specifying risks for subgroups in additional sections). Risk managers found information about quality of evidence important to communicate, whereas people from the general public found this information less relevant. Participants from lower educational backgrounds had difficulties understanding the purpose of risk assessments. User tests found that the final prototype was appropriate and feasible to implement by risk assessors. CONCLUSION: An iterative and evidence-based process was used to develop content to improve the communication of risk assessments to the general public while being feasible to use by risk assessors. Remaining challenges include how to communicate dose-response relationships and standardise quality of evidence ratings across disciplines.

Interstitial nephritis and high titers of PR3-ANCA: an unusual manifestation of ANCA-associated disease.

We present the case of a 75-year-old female with weight loss, anemia, systemic signs of inflammation, mild renal insufficiency, microscopic hematuria, mixed glomerular and tubular proteinuria, and high titers of PR3-ANCA. Renal biopsy demonstrated interstitial nephritis with some sclerosed but otherwise normal glomeruli. Extensive work-up showed no signs of granulomatous inflammation or other vasculitic organ involvement. We presumed this to be a rare renal manifestation of ANCA-associated disease with the presence of sclerosed glomeruli suggesting a previous history of glomerular involvement. In view of the absence of active vasculitic or granulomatous disease, treatment was limited to low-dose corticosteroids with good response.

History of the term 'andrology'.

The article is a report about the history of the origin and usage of the term 'andrology' in the last 150 years. It is demonstrated that this term was used at different times by different authorities without any knowledge of the foregoing publications.

Minimal T-cell-stimulatory sequences and spectrum of HLA restriction of immunodominant CD4+ T-cell epitopes within hepatitis C virus NS3 and NS4 proteins.

The hepatitis C virus (HCV)-specific CD4+ T-cell response against nonstructural proteins is strongly associated with successful viral clearance during acute hepatitis C. To further develop these observations into peptide-based vaccines and clinical immunomonitoring tools like HLA class II tetramers, a detailed characterization of immunodominant CD4+ T-cell epitopes is required. We studied peripheral blood mononuclear cells from 20 patients with acute hepatitis C using 83 overlapping 20-mer peptides covering the NS3 helicase and NS4. Eight peptides were recognized by > or = 40% of patients, and specific CD4+ T-cell clones were obtained for seven of these and three additional, subdominant epitopes. Mapping of minimal stimulatory sequences defined epitopes of 8 to 13 amino acids in length, but optimal T-cell stimulation was observed with 10- to 15-mers. While some epitopes were presented by different HLA molecules, others were presented by only a single HLA class II molecule, which has implications for patient selection in clinical trials of peptide-based immunotherapies. In conclusion, using two different approaches we identified and characterized a set of CD4+ T-cell epitopes in the HCV NS3-NS4 region which are immunodominant in patients achieving transient or persistent viral control. This information allows the construction of a valuable panel of HCV-specific HLA class II tetramers for further study of CD4+ T-cell responses in chronic hepatitis C. The finding of immunodominant epitopes with very constrained HLA restriction has implications for patient selection in clinical trials of peptide-based immunotherapies.

Acute hepatitis C: high rate of both spontaneous and treatment-induced viral clearance.

BACKGROUND & AIMS: Acute hepatitis C virus infection accounts for approximately 20% of cases of acute hepatitis today. The aim of this study was to define the natural course of the disease and to contribute to the development of treatment strategies for acute hepatitis C virus. METHODS: The diagnosis of acute hepatitis C virus in 60 patients was based on seroconversion to anti-hepatitis C virus antibodies or clinical and biochemical criteria and on the presence of hepatitis C virus RNA in the first serum sample. RESULTS: Fifty-one of 60 (85%) patients presented with symptomatic acute hepatitis C virus. In the natural (untreated) course of acute symptomatic hepatitis C (n = 46), spontaneous clearance was observed in 24 patients (52%), usually within 12 weeks after the onset of symptoms, whereas all asymptomatic patients (n = 9) developed chronic hepatitis C. The start of antiviral therapy (interferon-alpha with or without ribavirin) beyond 3 months after the onset of acute hepatitis induced sustained viral clearance in 80% of treated patients. CONCLUSIONS: The management of acute hepatitis C has to take into account the high rate of spontaneous viral clearance within 12 weeks after the onset of symptomatic disease. Treatment of only those patients who remain hepatitis C virus RNA positive for more than 3 months after the onset of disease led to an overall viral clearance (self-limited and treatment induced) in 91% of patients, and unnecessary treatment was avoided in those with spontaneous viral clearance. Patients with asymptomatic acute hepatitis C virus infection are unlikely to clear the infection spontaneously and should be treated as early as possible.

[Acute liver failure in nefazodone therapy? A case report]. / Akutes Leberversagen unter Nefazodon-Therapie? Ein Fallbericht.

Antidepressant-induced hepatotoxicity is generally considered of minimal clinical importance and is not well recognized. We report on a patient with recurrent major depression who was treated with nefazodone. Six weeks after initiation of therapy with nefazodone, he developed fatal liver failure. After cessation of the drug, the patient did not recover. He underwent liver transplantation but unfortunately died.

[Human experimentation in dermatology 100 years ago and today]. / Versuche am Menschen in der Dermatologie vor 100 Jahren und heute.

The problem of ethics in dermatology is explored using selected examples from the literature. The classic case of Neisser as well as Eduard Arning's experiments on a Hawaiian with leprosy convicted to death are discussed. In addition, inoculation studies with syphilis 100 years ago and the author's own experiences are cited. The differences in the approaches to medical ethics 100 years ago and today lead to the conclusion that ethics change to fit the needs of the society and do not have a permanent fixed status.

Hepatitis C virus-specific CD4+ T cell response after liver transplantation occurs early, is multispecific, compartmentalizes to the liver, and does not correlate with recurrent disease.

The role of hepatitis C virus (HCV)-specific CD4+ T cells in recurrent HCV infection after orthotopic liver transplantation (OLTx) is unclear. In parallel, 73 intrahepatic and 73 blood-derived T cell lines were established from 34 patients. At a single cell level, virus-specific interferon (IFN)-gamma production to various HCV proteins was determined by ELISPOT assay: 45 (62%) of 73 liver- or blood-derived T cell lines produced IFN-gamma in response to one of the HCV antigens. HCV specificity was detected mainly in the liver (47% vs. 23% in the blood; P<.05, chi(2) test) and was detectable earlier (< or =6 months) significantly more often than later (>6 months) after OLTx (78% vs 49%; P<.05, chi(2) test). Histology, histologic activity index, liver enzymes, and virus load did not correlate with the occurrence of HCV-specific CD4+ T cells. Despite strong immunosuppressive treatment, OLTx recipients can develop an early, multispecific, preferentially intrahepatic CD4+ T cell response that decreases over time, making it a potential candidate target for novel therapeutic approaches in the transplant setting.

Liver-derived hepatitis C virus (HCV)-specific CD4(+) T cells recognize multiple HCV epitopes and produce interferon gamma.

Virus-specific CD4(+) T-cell response at the site of inflammation is believed to play a decisive role for the course of viral disease. In hepatitis C virus (HCV) infection, the majority of studies focused on the peripheral blood T-cell response. In this study we analyzed intrahepatic virus-specific CD4(+) T-cell response and compared this with that in the peripheral blood. Liver and blood-derived T-cell lines were studied in 36 patients (18 with chronic hepatitis C and 18 with HCV-associated cirrhosis). Virus-specific interferon gamma (IFN-gamma) production at a single cell level to various HCV-proteins (core, nonstructural [NS] 3/4, NS5) were determined by enzyme-linked immunospot (ELIspot). Phenotyping was done by fluorescent-activated cell sorter analysis. In approximately half (16 of 36 [44%]) of intrahepatic T-cell lines a significant number of IFN-gamma spots were observed, whereas this was the case in only 19% (7 of 36 T-cell lines) in the blood. In relative terms, core and nonstructural proteins were recognized with the same frequency in both compartments, but HCV-specificity was significantly more often detected in liver tissue compared with the blood. Hepatitis activity index, viral load, and alanine transaminase levels did not correlate with the detection of HCV-specific CD4(+) T cells. All T-cell lines were dominated by CD4(+) T cells. In conclusion, HCV-specific CD4(+) T cells are multispecific, compartmentalize to the liver, and produce IFN-gamma. We speculate that our data would support the concept of compartmentalization of specific T cells at the site of inflammation and that a low frequency of specific T cells is associated with failure to clear the virus and a chronic course of disease.

Association of hepatitis C virus-specific CD8+ T cells with viral clearance in acute hepatitis C.

CD8+ T lymphocytes play a major role in antiviral immune defense. Their significance for acute hepatitis C is unclear. Our aim was to correlate the CD8+ T cell response with the outcome of infection. Eighteen patients with acute hepatitis C and 19 normal donors were studied. Hepatitis C virus (HCV)-specific CD8+ T cells were identified in the enzyme-linked immunospot assay by their interferon-gamma (IFN-gamma) production after specific stimulation. The highest numbers of IFN-gamma-producing HCV-specific CD8+ T cells were found in patients with acute hepatitis C and a self-limited course of disease during the first 6 months after onset of disease, but these numbers dropped thereafter to undetectable levels. The differences in responsiveness between patients with self-limited disease versus patients with a chronic course were statistically significant (P<.001). Our data show that the number of IFN-gamma-producing HCV-specific CD8+ T cells during the first 6 months after onset of disease is associated with eradication of the HCV infection.

Cytokine profile of liver- and blood-derived nonspecific T cells after liver transplantation: T helper cells type 1/0 lymphokines dominate in recurrent hepatitis C virus infection and rejection.

Orthotopic liver transplantation (OLT) is a successful treatment in patients with hepatitis C virus (HCV)-associated end-stage liver disease worldwide. T lymphocytes and their cytokines are believed to have a pivotal role in the defense against HCV and in allograft rejection. An immunosuppressive drug regimen may cause a cytokine imbalance toward a T helper (TH) cell type 2 profile that is associated with the persistence of infection and acceptance of the graft. The aim of this study is to assess whether cytokine imbalances toward a TH1- or TH2-type response may have a role in recurrent HCV infection and rejection after OLT. Twenty-one intrahepatic T-cell lines of 15 patients with recurrent HCV infection after OLT (group A) and 15 lines of 11 patients with rejection (group B) were studied. Both patient groups had received liver allografts because of HCV-associated end-stage liver disease. Patients with HCV-induced liver disease who did not undergo OLT served as controls: 17 patients with chronic hepatitis C (CH-C) and 8 patients with cirrhosis. At the time of liver biopsy, 14 blood-derived T-cell lines of 12 patients with recurrent HCV infection, 7 of 10 patients with rejection, and 18 of 18 control patients were also investigated. Regardless of the underlying disease (recurrent HCV infection, rejection, HCV-induced hepatitis, and cirrhosis), all liver tissue-derived T-cell lines produced interferon-gamma; some additionally produced interleukin-4 (IL-4), but none produced IL-10, indicating that the TH0/1 cytokine profile dominates. T-cell lines showing a TH1 cytokine profile derived from intrahepatic T cells could be established significantly more often in recurrent HCV infection and rejection than in controls with CH-C (Fisher's exact test, P <.05). The cytokine profile of intrahepatic T cells did not differ from that obtained in peripheral blood. TH0/1 cytokine profile dominates the intrahepatic and blood-derived immune response in recurrent HCV infection and rejection after OLT regardless of the mode of immunosuppression. The lymphokine profile of immunocompromised patients with recurrent HCV infection or rejection does not differ principally from that of patients with HCV-induced hepatitis and cirrhosis, but seems to show a TH1 profile significantly more often.

Recurrence of hepatitis C virus after loss of virus-specific CD4(+) T-cell response in acute hepatitis C.

BACKGROUND & AIMS: The prospective comparison of patients with acute hepatitis C virus (HCV) who spontaneously clear the virus with those who cannot achieve viral elimination and progress to chronic hepatitis offers the unique opportunity to analyze natural mechanisms of viral elimination. METHODS: We studied the HCV-specific CD4(+) T-cell response in 38 patients with acute HCV and correlated the clinical course with the antiviral immune response. The individual HCV-specific T-cell response was assessed in a proliferation assay ((3)H-thymidine uptake) and an enzyme-linked immunospot assay. RESULTS: Patients were classified according to their clinical course and pattern of CD4(+) T-cell responses in 3 categories: first, patients mounting a strong and sustained antiviral CD4(+)/Th1(+) T-cell response who cleared the virus (HCV RNA-negative; n = 20); second, patients who were unable to mount an HCV-specific CD4(+) T-cell response and developed chronic disease (n = 12); and third, patients who initially displayed a strong CD4(+) T-cell response and eliminated the virus (HCV PCR-negative) but subsequently lost this specific T-cell response (n = 6). The loss of the HCV-specific CD4(+) T-cell response was promptly followed by HCV recurrence. CONCLUSIONS: The results indicate that a virus-specific CD4(+)/Th1(+) T-cell response that eliminates the virus during the acute phase of disease has to be maintained permanently to achieve long-term control of the virus. The induction and/or maintenance of virus-specific CD4(+) T cells could represent a promising therapeutic approach in HCV infection.