[Cutaneous adverse events of telaprevir/peginterferon/ribavirin therapy for chronic hepatitis C: A multicenter prospective cohort study]. / Effets secondaires cutanés de l'association télaprévir/peg-interféron/ribavirine pour le traitement de l'hépatite C chronique : étude prospective d'une cohorte multicentrique.

BACKGROUND: Telaprevir, sale of which was suspended, has been approved in combination with pegylated interferon and ribavirin (triple therapy) in the treatment of chronic hepatitis C virus (HCV). Skin eruptions and isolated cases of severe cutaneous adverse reactions (SCAR) have been reported. AIMS: Our aim was to assess the incidence of skin eruption and the clinical characteristics of mucocutaneous adverse events (AE), and to identify potential risk factors for telaprevir-associated skin eruption. PATIENTS AND METHODS: A prospective observational multicenter follow-up cohort study with monthly controls by a dermatologist and additional examinations in case of any undercurrent AE. RESULTS: Among the 48 enrolled patients, the incidence of skin eruption was 58.4%, consisting mainly of maculopapular and eczematous lesions and only one case of SCAR. Telaprevir was discontinued in 6% of patients due to severe rash, whereas peginterferon and ribavirin were continued. The median time to onset of rash following telaprevir initiation was 25 days (range: 3-79 days). The rash was preceded by skin dryness and associated with pruritus in 100% and 90% of patients, respectively. Of those presenting with skin eruption, 37.5% also complained of conjunctival or oral lesions, or of anorectal symptoms. Neither a past history of dermatological conditions nor sociodemographic or viral status was predictive factor for skin rash. CONCLUSIONS: Telaprevir-related dermatitis has a high incidence but is mostly of mild intensity. In most cases, tri-therapy was continued under close dermatological follow-up allowing rapid detection of rare instances of severe drug eruptions. Ribavirin and Interferon were thus continued even in the event of diffuse eruptions, enabling confirmation of the causative role of telaprevir in these eruptions.

[In process]. / Insomnie, anxiété: faut-il réguler la prescription des benzodiazépines?

Benzodiazepine hypnotics bear a higher risk of high dose dependence than benzodiazepine anxiolytics, according to a recent study in Luxemburg. This article summarizes the main indications of these molecules and the current treatment recommendations. It provides an overview of public health actions of the past and the future to reduce their excessive consumption.

Sensorimotor effects of plasticity-inducing percutaneous peripheral nerve stimulation protocols: a blinded, randomized clinical trial.

BACKGROUND: Electrical stimulation of skin afferents can induce somatosensory plasticity in humans. Nevertheless, it is unknown if this is possible to do through percutaneous stimulation of a peripheral nerve, which will allow for regional anaesthesia interventions. Furthermore, potentiation protocols applied over mainly non-nociceptive fibres inhibit nociception in rodents, but this has not been tested in humans. OBJECTIVE: To determine whether a protocol aiming to depress the nociceptive circuit and another aiming to potentiate non-nociceptive circuits produce regional hypoalgesia and changes in motor function, applied through percutaneous peripheral nerve stimulation (pPNS), and to assess which of them is more promising for pain relief, immediately and 24 h after the intervention. METHODS: PT-cLF protocol aims to depress the nociceptive pathway through Pain Threshold, continuous Low Frequency stimulation and ST-bHF aims to produce potentiation of the non-nociceptive pathway, through Sensory Threshold burst stimulation at High Frequency. All subjects (n = 29) went through both protocols and a control condition in a randomized and blinded crossover design. RESULTS: Compared to control, ST-bHF induced distal hypoalgesia, towards electrical (p = 0.04) and mechanical stimuli (p = 0.02) and produced mechanical hypoesthesia (p = 0.02). Contrarily, hypoalgesia was not observed after PT-cLF (p > 0.05) but increased electrical motor threshold (p = 0.04), reduced motor recruitment (p = 0.03), and the subjects reported feeling reduced strength (p < 0.01). CONCLUSION: This works provides evidence that is possible to induce antinociceptive plasticity in a wide territory using pPNS. Moreover, it demonstrates for the first time in humans that a protocol aiming to produce long-term potentiation applied predominantly over non-nociceptive afferents induces hypoesthesia and hypoalgesia.

Linkage of death certification of AIDS and cancer registration in Vaud, Switzerland.

58 death certifications (40 males and 18 females) of residents of the Canton of Vaud (Switzerland) which reported AIDS as the cause of death in 1986-1989 were matched with the list of incident cancers available since 1974 from the Vaud Cancer Registry. Such linkage was successful for 20 individuals (age range 25-63, median 37), mostly males (18/20), homosexual or bisexual (11/18) and affected by Kaposi's sarcoma (14 males and 1 female). Other identified neoplasms included one Burkitt's lymphoma, one prostate adenocarcinoma and one multiple myeloma (whose histological picture included, however, lymphocytosis in addition to plasmocytosis). Three additional malignancies (one undifferentiated skin cancer, one carcinoma of the salivary glands and one in situ cervical carcinoma), and one myelodysplastic syndrome had also been diagnosed from 1 to 2 years before AIDS death. Cancer was mentioned on the death certificate, in addition to AIDS, in only 2 cases. Albeit of limited size, the present report confirms that a systematic integration of AIDS and cancer registration statistics provides additional information, of particular interest for histological classification, on the AIDS-cancer relationship.

Non-Hodgkin's lymphoma: time trends for incidence and survival in Côte-d'Or, France.

BACKGROUND: A generally reported increased incidence of non-Hodgkin's lymphomas (NHL) and a recent evolution in treatment strategies, as well as several clinical trials suggesting improved survival, have prompted this study to evaluate time trends in incidence and prognosis of NHL. METHOD: NHL recorded by the population-based Registry of Hematopoietic Malignancies in Côte-d'Or (France) were considered over three 4-year periods from 1980 to 1992. A multivariate survival analysis was carried out in terms of both crude and relative survivals. RESULTS: Overall incidence, increased over the 12 years considered, by an average of 6.8% per annum (P < 0.05). Only two cases of AIDS-related NHL were registered during this period. NHL incidence has increased slightly more for males than for females, further widening the gap in incidence between the sexes. In terms of histological grade the increase in incidence was more pronounced for low-grade and high-grade NHL than for intermediate-grade NHL. The overall 5-year relative survival rate was 69.3%. In multivariate relative survival analysis, neither sex, age, period of diagnosis nor place of hospitalization were significant prognostic factors. Only place of residence, with RR 2.2 (1.41-3.42) for people living in rural areas compared to urban areas and histological type, according to the working formulation with RR 3.8 (2.22-6.61) for high-grade tumours compared to low-grade tumours, remained informative for prognosis. CONCLUSIONS: Although incidence of NHL has increased in Côte-d'Or, this trend has remained independent of the AIDS epidemic. Contrary to the findings of clinical trials, the patients' survival in this population-based series has not been shown to have improved over the study period.

Optimized stepwise combination algorithms of non-invasive liver fibrosis scores including Hepascore in hepatitis C virus patients.

BACKGROUND: Non-invasive liver fibrosis scores such as Hepascore (HS) have been proposed as an alternative to liver biopsy in hepatitis C virus (HCV)-infected patients. AIM: To validate HS as an alternative to liver biopsy and Fibrotest (FT) and propose five optimized combination algorithms to improve diagnostic accuracy. METHODS: The cohort included 467 patients with HCV. There were 274/467 (59%) men, and mean age was 47 +/- 12 years. RESULTS: Hepascore area under ROC curves (AUC) for > or =F2, F3F4 and F4 diagnosis were 0.82, 0.84 and 0.90 respectively, in the same range as FT. HS and FT were concordant in 387/467 (82%) for fibrosis staging. Among these patients, 342/387 (88%) were concordant with liver biopsy. AUCs of aspartate aminotransferase (AST) to Platelets Ratio Index (APRI) and Forns for > or =F2 were 0.76 and 0.73 (0.65-0.79) respectively. The algorithm combining APRI and HS had the highest rate of avoided liver biopsies (45%) with a high diagnostic accuracy (91%). CONCLUSIONS: Hepascore is an accurate non-invasive marker for > or =F2 and F4 diagnosis in HCV patients. In a pragmatic approach, a stepwise optimized algorithm combining APRI and FT or HS considerably increases diagnostic accuracy and avoided liver biopsies.

Validation and comparison of indexes for fibrosis and cirrhosis prediction in chronic hepatitis C patients: proposal for a pragmatic approach classification without liver biopsies.

Noninvasive indexes have been developed to predict fibrosis staging. The aim of this study was to assess the diagnostic accuracy of these indexes in comparison with liver histology in hepatitis C virus (HCV)-infected patients. A total of 235 consecutive patients with HCV infection from the Fibropaca multicentre independent study were included in this paper. FibroTest (FT), aspartate aminotransferase to platelet ratio index (APRI) and Forns score were assessed in the cohort and compared with liver histology performed on the same day. The main end point was the area under characteristic curves (AUCs) for the diagnosis of significant fibrosis (F2-F4) and cirrhosis (F4) by the METAVIR classification. Mean age was 46 (+/-11) years, 55% were males, 42% (n = 99) had significant fibrosis (F2-F4) and 7% (n = 16) had cirrhosis (F4). For the diagnosis of significant fibrosis, respective AUCs of FT, APRI and Forns score were 0.81 (95% confidence interval: 0.76-0.86), 0.71 (0.67-0.79) and 0.76 (0.70-0.82); for cirrhosis prognosis, AUCs of FT and APRI were 0.82 (0.77-0.87) and 0.81 (0.76-0.86) (AUCs not significantly different). Using each index independently, all patients were classified by FT, 214 (91%) patients were classified by APRI and 129 (55%) by Forns score. There were significantly more cases of discordances between APRI and liver biopsy than between FT or Forns score and liver biopsy (P < 0.05). Performing all scores (FT, Forns and APRI) without liver biopsy allowed fibrosis to be well evaluated in 191 patients (81.3%), including patients with FT failure. Liver biopsy remained mandatory to evaluate fibrosis in 44 patients (18.7%). Our study shows that performing all the tests and liver biopsy improves the diagnostic accuracy for liver fibrosis in chronic hepatitis C patients without patent comorbidities. The combination of all tests with liver biopsy allowed 225/235 (96%) patients to be correctly classified. The combination of all tests without liver biopsy allowed 191/235 (81.3%) patients to be correctly classified; liver biopsy remained mandatory in some patients (18.7%).

Changing of hepatitis C virus genotype patterns in France at the beginning of the third millenium: The GEMHEP GenoCII Study.

This cross-sectional study aimed to investigate, during a short period between 2000 and 2001, in a large population of patients with chronic hepatitis C, the epidemiological characteristics of hepatitis C virus (HCV) genotypes in France. Data from 26 referral centres, corresponding to 1769 patients with chronic hepatitis C were collected consecutively during a 6-month period. HCV genotyping in the 5'-non-coding region (NCR) was performed in each center using the line probe assay (LiPA, in 63% of cases), sequencing (25%) or primer-specific polymerase chain reaction (PCR) (12%). HCV genotypes 1a, 1b, 2, 3, 4, 5, non-subtyped 1 and mixed infection were found in 18, 27, 9, 21, 9, 3, 11 and 1% of our population, respectively. HCV genotype distribution was associated with gender, age, source and duration of infection, alanine aminotransferase (ALT) levels, cirrhosis, alcohol consumption, hepatitis B virus (HBV) and human immunodeficiency virus (HIV) coinfection. In multivariate analysis, only the source of infection was the independent factor significantly associated with genotype (P = 0.0001). In conclusion, this study shows a changing pattern of HCV genotypes in France, with i.v. drug abuse as the major risk factor, an increase of genotype 4, and to a lesser extent 1a and 5, and a decrease of genotypes 1b and 2. The modification of the HCV genotype pattern in France in the next 10 years may require new therapeutic strategies, and further survey studies.

Endoscopic ultrasonographic diagnosis of pancreatic cancer complicating chronic pancreatitis.

BACKGROUND AND STUDY AIMS: Pancreatic cancer is a rare complication of chronic pancreatitis (CP), and its diagnosis remains difficult. The present study attempted to evaluate the ability of endoscopic ultrasonography (EUS) to diagnose pancreatic masses associated with CP and provide evidence of malignancy in patients with a pancreatic mass on EUS. PATIENTS AND METHODS: Between 1991 and 1994, EUS examinations yielded a diagnosis of CP in 85 patients at our institution. Forty patients had early CP, 18 had pancreatic pseudocysts complicating CP, and 27 had advanced chronic pancreatitis - five of whom were considered as presenting pancreatic cancer associated with CP. RESULTS: The five patients studied had jaundice, weight loss, and calcifications visible on plain abdominal films. Three of them had histological confirmation of pancreatic carcinoma. The pancreatic carcinomas were hypoechoic masses of 20-35 mm, with an irregular, rounded shape. Calcifications were limited to the periphery of the hypoechoic masses. Two patients had negative EUS-guided cytological punctures, and are still alive two years later. They were considered as false-positive cases. EUS showed a hypoechoic mass with peripheral calcifications in one of these false-positive patients, with a large central calcification in the other case. The overall sensitivity of EUS for the diagnosis of pancreatic carcinoma was 100%, but the positive predictive value was 60%. CONCLUSION: EUS is highly sensitive in detecting abnormal masses in cases of CP, but the positive predictive value of the diagnosis of pancreatic cancer seems to be weak.

Leishmania spp: temperature sensitivity of promastigotes in vitro as a model for tropism in vivo.

Since in humans, skin temperature is lower than internal temperature, the temperature sensitivity of Leishmania may influence the tropism of Leishmania in the human host; temperature-sensitive parasites may remain in the skin, temperature-resistant parasites may go to the viscera. In order to pursue the genetic factors controlling Leishmania tropism, we have developed an in vitro promastigote temperature model. Promastigote growth is measured at 30, 32, and 34 degrees C and compared with growth at the control temperature (25 degrees C). The results from tests of the promastigote temperature sensitivity of eight species (33 different strains) show that visceral species (L. donovani and L. chagasi) are more temperature resistant than cutaneous species (L. major, L. tropica, L. mexicana, L. braziliensis, L. panamensis, and L. amazonensis), that Old World species are more temperature-resistant than New World species, and that within the New World cutaneous species there are three distinct temperature sensitivity groupings (L. mexicana > L. braziliensis and L. panamensis > L. amazonensis). Interestingly, viscerotropic L. tropica from Operation Desert Storm and L. donovani complex strains isolated from cutaneous lesions are more and less temperature-sensitive, respectively, than strains of the same species with the expected tropism in vivo.

Field evaluation of a lethal ovitrap against dengue vectors in Brazil.

Field evaluation of a "lethal ovitrap" (LO) to control dengue vector Aedes mosquitoes (Diptera: Culicidae), was undertaken in two Brazilian municipalities, Areia Branca and Nilopolis, in the State of Rio de Janeiro. The LO is designed to kill Aedes via an insecticide-treated ovistrip (impregnated with deltamethrin). In each municipality, the intervention was applied to a group of 30 houses (10 LOs/house) and compared to 30 houses without LOs in the same neighbourhood. Five LOs were put outside and five LOs inside each treated house. Three methods of monitoring Aedes density were employed: (i) percentage of containers positive for larvae and/or pupae; (ii) total pupae/house; (iii) total adult females/house collected by aspirator indoors. Weekly mosquito surveys began during the month before LO placement, by sampling from different groups of 10 houses/week for 3 weeks pre-intervention (i.e. 30 houses/month) and for 3 months post-intervention in both treated and untreated areas. Prior to LO placement at the end of February 2001, Aedes aegypti (L) densities were similar among houses scheduled for LO treatment and comparison (untreated control) at each municipality. Very few Ae. albopictus (Skuse) were found and this species was excluded from the assessment. Post-intervention densities of Ae. aegypti were significantly reduced for most comparators (P < 0.01), as shown by fewer positive containers (4-5 vs. 10-18) and pupae/house (0.3-0.7 vs. 8-10) at LO-treated vs. untreated houses, 3 months post-treatment at both municipalities. Numbers of adult Ae. aegypti females indoors were consistently reduced in LO-treated houses at Areia Branca (3.6 vs. 6.8/house 3 months post-intervention) but not at Niloplis (approximately 3/house, attributed to immigration). These results demonstrate sustained impact of LOs on dengue vector population densities in housing conditions of Brazilian municipalities.

Covert transmission of hepatitis C virus during bloody fisticuffs.

Hepatitis C virus (HCV) is transmitted primarily through direct percutaneous exposure to infected blood. Sporadic HCV cases exist and may represent more than 10% of HCV transmission. We report the first case of documented transmission of HCV during a fight from a person who unknowingly had chronic HCV infection to a person who subsequently contracted acute hepatitis C. Patient-to-patient transmission was ascertained by sequence analysis of part of the NS5B genome and phylogenetic analysis. This case report suggests that sporadic HCV infection may be a result of blood exposure. This example of transmission could have a major impact in sports such as boxing or rugby. We suggest that in any fight, single use or nondisposable material should be used to dry blood to avoid such contamination.

Importance of high-density lipoprotein-phosphatidylcholine in secretion of phospholipid and cholesterol in bile.

The purpose of this work was to evaluate biliary phosphatidylcholine (PC) secretion after intravenous infusion of high density lipoprotein (HDL)-[3H]phosphatidylcholine (HDL-[3H]PC) in rats and to study the effect of infusion of dehydrocholic and cholic acids, which, respectively, inhibit and stimulate biliary secretion of PC. The data obtained in this study showed that, in the basal state, HDL-PC accounted for 38% of biliary PC. Dehydrocholic acid infusion caused only a "residual" secretion of HDL-PC in the bile; however, cholic acid infusion stimulated the secretion of HDL-PC as well as PC from intrahepatic microsomes. The low level of radioactivity of HDL-PC in intrahepatic compartments suggests that HDL-PC taken up by the liver is predestined for the bile secretion. The correlation between the kinetics of bile secretion of HDL-cholesterol and HDL-[3H]PC suggests the importance of HDL-PC in reverse transport of cholesterol to the liver and its transport to the bile. The differences between the effects of dehydrocholic acid and cholic acid infusions can be explained by the differences in bile salts binding to the surface of HDL.

Assessment of spontaneous fluctuations of viral load in untreated patients with chronic hepatitis C by two standardized quantitation methods: branched DNA and Amplicor Monitor.

Quantitation of hepatitis C virus (HCV) RNA in serum has been used to predict and monitor the efficacy of interferon therapy in chronic HCV infection. We prospectively studied the fluctuation of viremia by a longitudinal follow-up of HCV RNA levels for 2 months in six untreated patients. Spontaneous fluctuations of HCV RNA ranged from 2.8- to 5.7-fold with branched DNA assay and from 2.9- to 5.6-fold with Monitor. These large spontaneous fluctuations (up to 0.75 log), observed daily, weekly, and monthly, raise doubt about the clinical value of a single assessment of pretherapeutic viremia.

Epidemiological changes in hepatitis C virus genotypes in France: evidence in intravenous drug users.

Hepatitis C virus (HCV) genotypes are distributed differently depending on geography and route of infection. We characterized the distribution of genotypes in a large cohort of patients with chronic hepatitis C in the South-east of France and evaluated the relative prevalence according to time of acquisition. One thousand, one hundred-and-eighty-three patients who were anti-HCV-positive were studied. HCV genotype distribution has changed significantly from the 1960s to 2000. The prevalence of genotype 1b decreased from 47% before 1978 to 18.8% in the 1990s while the prevalence of genotype 1a and 3a increased during the same period from 18% and 15.3% to 28.8% and 26.3%, respectively. The logistic regression model showed that genotype 1a was significantly more common in patients infected through intravenous drug injection odds ratio ((OR): 2.08, P < 0.01) and after 1990 (OR: 1.98, P < 0.05). Genotype 1b was significantly less frequent in patients infected through intravenous drug injection (OR: 0.17, P < 0.001) and has decreased since 1978 (OR: 0.27, P < 0.001). Genotype 3a was independently associated with intravenous drug injection (OR: 6.1, P < 0.001) and tattooing (OR: 8.01, P < 0.001) and was more frequent in the 1979-90 period (OR: 2.05 and 1.74, P < 0.001 and P < 0.05). Our results show a modification of HCV genotypes distribution over the last four decades due to an increase of intravenous drug use (IVDU) contamination and an evolution of HCV genotypes distribution only in IVDU population characterized by a decrease of genotype 1b, an increase of genotype 3a from 1970 to 1990 and a higher increase of genotype 1a which is currently the predominant genotype in our population.

Multiple primary cancers in the Vaud Cancer Registry, Switzerland, 1974-89.

Data collected by the Cancer Registry of the Swiss Canton of Vaud (whose population in 1980 was about 530,000 inhabitants) were used to estimate the incidence of second metachronous primary cancers following any specific neoplasm. Among 34,615 cases of incident neoplasms registered between 1974 and 1989 and followed through integrated active follow-up to the end of 1989, for a total of 118,241 person-years at risk, there were 2,185 second primaries (1,280 males, 905 females). For both sexes, the standardised incidence ratios (SIR) were significantly elevated by about 20%. Overall significantly elevated ratios were registered for cancers of the oral cavity and pharynx (SIR = 1.6 for males, 2.0 for females), oesophagus in males (SIR = 1.5), lung in males (SIR = 1.4), skin melanoma (SIR = 1.7 for males, 1.5 for females), non-melanomatous skin cancers (SIR = 1.6 for males, 1.5 for females), female breast (SIR = 1.3), kidney (SIR = 1.5 for males, 1.9 for females), and thyroid in males (SIR = 2.4). When specific first cancer sites were considered, the SIR following a cancer of the oral cavity and pharynx was around 3 in both sexes, mainly on account of a substantial excess of second primaries of the oral cavity, oesophagus, larynx and lung. The overall SIR following laryngeal cancer was 3.0, and significant excesses were observed for oral cavity and pharynx, oesophagus and lung. After lung cancer, the overall SIR was 1.7 for males and 2.6 for females, and significantly elevated SIRs were observed for oral cavity, lung and oesophagus. Following non-melanomatous skin cancers, elevated SIRs were observed in both sexes for skin melanoma and non-melanomas. The incidence of any cancer after breast cancer was significantly elevated (SIR = 1.2), mainly on account of an elevated risk of subsequent breast cancer (SIR = 1.7). With reference to cervical cancer, there was a significant excess for any subsequent primary (SIR = 1.6), and for lung cancer (SIR = 7.8). Significantly elevated SIRs were observed for kidney following bladder cancer, and for bladder after kidney cancer. In both sexes, the incidence of cancers of any site was elevated following leukaemias (SIR = 1.7 for males, 2.5 for females), and a significant excess was registered for lung in males and non-melanomatous skin cancers in both sexes.(ABSTRACT TRUNCATED AT 400 WORDS)

Reinforced regimen of interferon alfa-2a reduces the incidence of cirrhosis in patients with chronic hepatitis C: a multicentre randomised trial. Multicentre GER-CYT-04 Group.

BACKGROUND/AIMS: Our aim was to assess and compare the long-term effect of interferon at standard (6 months) and reinforced dose and duration regimens in chronic hepatitis C. METHODS: A multicentre institutional trial included 244 previously untreated patients with chronic hepatitis C, without cirrhosis, who were randomly allocated to either standard (3 MU thrice a week for 24 weeks; n=120) or reinforced (6 MU daily for 12 days, 6 MU thrice a week for 22 weeks, 3 MU thrice a week for 24 weeks; n=124) regimens. The main endpoint was sustained ALT response at 72 weeks (18 months); secondary end-points were virological (branched DNA and PCR) and histological responses (incidence of cirrhosis) at month 18. RESULTS: Sustained ALT response was observed in five patients (4%, 95% confidence interval 0-8%) in the standard group and in 21 patients (18%, 95% confidence interval 11-25%), from the reinforced group (p=0.002), in agreement with virological response in 21 (81%) patients. Cirrhosis at month 18 was observed in ten (10%) patients in the standard group and one (1%) in the reinforced group (p=0.004). CONCLUSIONS: The standard regimen of interferon, in chronic hepatitis C, confers a minimal sustained response rate at 18 months and may not prevent the occurrence of cirrhosis. Reinforced regimens allow sustained response to be reached in a limited number of patients and reduce the risk of cirrhosis during 18 months of follow-up.