Etiological assessment of status epilepticus.

Status epilepticus (SE) is a potentially serious condition that can affect vital and functional prognosis and requires urgent treatment. Etiology is a determining factor in the patient's functional outcome and in almost half of all cases justifies specific treatment to stop progression. Therefore, identifying and addressing the cause of SE is a key priority in SE management. However, the etiology can be difficult to identify among acute and remote causes, which can also be multiple and interrelated. The most common etiologies are the discontinuation of antiepileptic medication in patients with a prior history of epilepsy, and acute brain aggression in cases of new onset SE (cerebrovascular pathologies are the most common). The list of remaining possible etiologies includes heterogeneous pathological contexts. Refractory SE and especially New-Onset Refractory Status Epilepticus (NORSE) lead to an extension of the etiological assessment in the search for encephalitis of autoimmune or infectious origin in adults and in children, as well as a genetic pathology in children in particular. This is an overview of current knowledge of SE etiologies and a pragmatic approach for carrying out an etiological assessment based on the following steps: - Which etiological orientation is identified according to the field and clinical presentation?; - Which etiologies to look for in an inaugural SE?; - Which first-line assessment should be carried out? The place of the biological, EEG and imaging assessment is discussed; - Which etiologies to look for in case of refractory SE?

Evaluation of the impact of urban pollution on the quality of skin: a multicentre study in Mexico.

OBJECTIVE: After pilot and preliminary studies aimed at identifying pertinent biochemical parameters, a multicenter clinical study was performed to evaluate the effect of pollution on human skin. METHODS: The clinical study was performed in collaboration with the 'Centre Régional de lutte contre le cancer de Montpellier' and the 'National Institute of Public Health of Mexico' on 96 subjects in Mexico City (exposed to pollution) and 93 subjects in Cuernavaca (less exposed to pollution). Both biochemical and clinical skin parameters were studied. RESULTS: The study demonstrated significant quantitative and qualitative modifications of parameters related to sebum excretion in Mexico City compared to Cuernavaca one: An increased level of sebum excretion rate, a lower level of vitamin E and squalene in sebum, an increase of lactic acid and a higher erythematous index on the face of the subjects. In the stratum corneum, a significant higher level of carbonylated proteins and a lower level of IL 1α were noticed, as well as a decrease of ATP concentration with a decrease of chymotrysin like activity, without modifications of corneodesmosin content and trypsin like activity. From a clinical point of view, a higher frequency of atopic and urticarial skins, a higher frequency of red dermographism, an important seborrheic status at the forehead level and a lower level of dandruffs were noted in Mexico City population. The analysis taking into account the sex does not modify the observed results. CONCLUSION: The study demonstrated an important impact of polluted environmental conditions on skin quality, evidencing important modifications of superficial biochemical parameters. The cause/effects relationships of these modifications remain, however, to be further assessed by a complementary in vitro/in vivo approaches.

Mupirocin/chlorexidine to prevent methicillin-resistant Staphylococcus aureus infections: post hoc analysis of a placebo-controlled, randomized trial using mupirocin/chlorhexidine and polymyxin/tobramycin for the prevention of acquired infections in intubated patients.

PURPOSE: The reduction in acquired infections (AI) due to methicillin-resistant Staphylococcus aureus (MRSA) with the mupirocin/chlorhexidine (M/C) decontamination regimen has not been well studied in intubated patients. We performed post hoc analysis of a prior trial to assess the impact of M/C on MRSA AI and colonization. METHODS: We conducted a multicenter, placebo-controlled, randomized, double-blind study with the primary aim to reduce all-cause AI. The two regimens used [topical polymyxin and tobramycin (P/T), nasal mupirocin with chlorhexidine body wash (M/C), or corresponding placebos for each regimen] were administered according to a 2 × 2 factorial design. Participants were intubated patients in the intensive care units of three French university hospitals. The patients enrolled in the study (n = 515) received either active P/T (n = 130), active M/C (n = 130), both active regimens (n = 129), or placebos only (n = 126) for the period of intubation and an additional 24 h. The incidence and incidence rates (per 1,000 study days) of MRSA AI were assessed. Due to the absence of a statistically significant interaction between the two regimens, analysis was performed at the margins by comparing all patient receiving M/C (n = 259) to all patients not receiving M/C (n = 256), and all patients receiving P/T (n = 259) to all patients not receiving P/T (n = 256). RESULTS: Incidence [odds ratio (OR) 0.39, 95 % confidence interval (CI) (0.16-0.96), P = 0.04] and incidence rates [incidence rate ratio (IRR) 0.41, 95 % CI 0.17-0.97, P = 0.05] of MRSA AI were significantly lower with the use of M/C. We also observed an increase in the incidence (OR 2.50, 95 % CI 1.01-6.15, P = 0.05) and the incidence rate (IRR 2.90, 95 % CI 1.20-8.03, P = 0.03) of MRSA AI with the use of P/T. CONCLUSION: Among our study cohort of intubated patients, the use of M/C significantly reduced MRSA AI.

Reduced-dose tacrolimus with mycophenolate mofetil vs. standard-dose tacrolimus in liver transplantation: a randomized study.

We conducted a multicenter randomized study in liver transplantation to compare standard-dose tacrolimus to reduced-dose tacrolimus with mycophenolate mofetil to reduce the occurrence of tacrolimus side effects. Two primary outcomes (censored criteria) were monitored during 48 weeks post-transplantation: occurrence of renal dysfunction or arterial hypertension or diabetes (evaluating benefit) and occurrence of acute graft rejection (evaluating risk). Interim analyses were performed every 40 patients to stop the study in the case of increased risk of graft rejection. One hundred and ninety-five patients (control: 100; experimental: 95) had been included when the study was stopped. Acute graft rejection occurred in 46 (46%) and 28 (30%) patients in control and experimental groups, respectively (HR = 0.59; 95% CI: [0.37-0.94]; p = 0.024). Renal dysfunction or arterial hypertension or diabetes occurred in 80 (80%) and 61 (64%) patients in control and experimental groups, respectively (HR = 0.68; 95% CI: [0.49-0.95]; p = 0.021). Renal dysfunction occurred in 42 (42%) and 23 (24%) patients in control and experimental groups, respectively (HR = 0.49; 95% CI: [0.29-0.81]; p = 0.004). Leucopoenia (p = 0.001), thrombocytopenia (p = 0.017) and diarrhea (p = 0.002) occurred more frequently in the experimental group. Reduced-dose tacrolimus with mycophenolate mofetil reduces the occurrence of renal dysfunction and the risk of graft rejection. This immunosuppressive regimen could replace full-dose tacrolimus in adult liver transplantation.

[The outcome of children presenting with a prenatally diagnosed arachnoid cyst]. / Devenir des enfants présentant un kyste arachnoïdien de diagnostic anténatal.

AIM: Evaluate the outcome of children with prenatally diagnosed arachnoid cysts. MATERIAL AND METHODS: Retrospective study of seventeen cases of children who were diagnosed with an arachnoid cyst during prenatal MRI between July 1994 and January 2007 and followed up for a mean 6 years and 6 months. Follow-up was based on evaluation of clinical files and contacts with the physicians who were following the children. The children were divided into three groups: group 1 normal development, group 2: minor clinical signs, normal schooling, group 3: major clinical symptoms, schooling disturbed. RESULTS: Eight of the 17 patients included in this study underwent derivation surgery for the cyst. Eight of the 17 children were in group 1, and 3 in group 2. Four of the 6 children in group 3 had associated symptoms. Two of the children in group 3 present with a supratentorial cyst, and 4 with a cyst of the posterior fossa. CONCLUSION: The prenatal diagnosis of a arachnoid cyst should be accompanied by a search for associated lesions. The risk of hydroencephalitis should be explained to the parents.

Management of liver failure in general intensive care unit.

OBJECTIVE: To produce French guidelines on Management of Liver failure in general Intensive Care Unit (ICU). DESIGN: A consensus committee of 23 experts from the French Society of Anesthesiology and Critical Care Medicine (Société française d'anesthésie et de réanimation, SFAR) and the French Association for the Study of the Liver (Association française pour l'étude du foie, AFEF) was convened. A formal conflict-of-interest (COI) policy was developed at the start of the process and enforced throughout. The entire guideline process was conducted independently of any industrial funding. The authors were advised to follow the principles of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system to guide their assessment of the quality of evidence. The potential drawbacks of making strong recommendations in the presence of low-quality evidence were emphasised. Some recommendations were ungraded. METHODS: Two fields were defined: acute liver failure (ALF) and cirrhotic patients in general ICU. The panel focused on three questions with respect to ALF: (1) Which etiological examinations should be performed to reduce morbidity and mortality? (2) Which specific treatments should be initiated rapidly to reduce morbidity and mortality? (3) Which symptomatic treatment should be initiated rapidly to reduce morbidity and mortality? Seven questions concerning cirrhotic patients were addressed: (1) Which criteria should be used to guide ICU admission of cirrhotic patients in order to improve their prognosis? (2) Which specific management of kidney injury should be implemented to reduce morbidity and mortality in cirrhotic ICU patients? (3) Which specific measures to manage sepsis in order to reduce morbidity and mortality in cirrhotic ICU patients? (4) In which circumstances, human serum albumin should be administered to reduce morbidity and mortality in cirrhotic ICU patients? (5) How should digestive haemorrhage be treated in order to reduce morbidity and mortality in cirrhotic ICU patients? (6) How should haemostasis be managed in order to reduce morbidity and mortality in cirrhotic ICU patients? And (7) When should advice be obtained from an expert centre in order to reduce morbidity and mortality in cirrhotic ICU patients? Population, intervention, comparison and outcome (PICO) issues were reviewed and updated as required, and evidence profiles were generated. An analysis of the literature and recommendations was then performed in accordance with the GRADE® methodology. RESULTS: The SFAR/AFEF Guidelines panel produced 18 statements on liver failure in general ICU. After two rounds of debate and various amendments, a strong agreement was reached on 100% of the recommendations: six had a high level of evidence (Grade 1 ±), seven had a low level of evidence (Grade 2 ±) and six were expert judgments. Finally, no recommendation was provided with respect to one question. CONCLUSIONS: Substantial agreement exists among experts regarding numerous strong recommendations on the optimum care of patients with liver failure in general ICU.

Metabolic disorders and chronic viral disease: the case of HIV and HCV.

The importance of metabolic disorders in the pathophysiology of human immunodeficiency virus (HIV) and hepatitis C virus (HCV) infections is becoming increasingly apparent. Metabolic anomalies, with their potential for multiple-organ involvement, are to be expected, given the chronic nature of these diseases, and the intracellular dysregulation associated with them. Not only have the endocrine and cytokine metabolic anomalies seen in HIV and HCV infections been linked with the metabolic syndrome, but they also appear to have some pathways in common. Studying the differences and similarities between these metabolic anomalies may add to our understanding of HIV and HCV infection, and provide guidance on how to treat these chronic diseases. This review highlights the principal underlying factors for metabolic disorders in these chronic viral diseases-namely insulin resistance and liver damage. Both the chronic viral state itself and the host immune response give rise to glucose and lipid metabolic disorders that, in turn, are risk factors for hepatic damage. The various interactions between HIV and/or HCV with insulin resistance, type 2 diabetes, steatosis and fibrogenesis should be considered when determining the treatment and long-term follow-up of patients. Recent data indicate that HCV clearance improves insulin resistance and hepatic function in HCV-infected patients treated with interferon with or without ribavirin.

[Pulmonary embolism by cyanoacrylate following embolisation of an arteriovenous malformation]. / Embolie pulmonaire de cyanoacrylate après embolisation d'une malformation artérioveineuse.

INTRODUCTION: Symptomatic complications can occur after intravascular injection of cyanoacrylate glue. We report a case of pulmonary embolism following embolisation of an arteriovenous malformation (AVM). CASE REPORT: A 46-year-old woman was found to have an internal iliac AVM which was obliterated using N-butyl-2 cyanoacrylate (NBCA) mixed with lipiodol. The early clinical course was uneventful. On the third post-operative day she complained of sudden, transient chest tightness. On admission one hour later the chest pain had disappeared. Physical examination was normal. A chest roentgenogram showed multiple, dense, branched opacities scattered throughout both lung fields which were confirmed on HRCT, suggesting diffuse scattered embolism of iodine- labelled NBCA. The radiological signs persisted 6 months later. CONCLUSION: Endovascular treatment of arteriovenous malformations with NBCA can be responsible for symptomatic pulmonary embolism. This is not detectable radiologically in the absence of contrast medium. Radiologists should be aware of these often asymptomatic, but sometimes fatal, embolic complications.

[Epidemiology of and risk factors for invasive aspergillosis in nonneutropenic patients]. / Epidémiologie et facteurs de risque de l'aspergillose invasive du sujet non neutropénique.

INTRODUCTION: Invasive aspergillosis is a major cause of mortality among patients with hematological malignancies and undergoing bone marrow transplantation. Whereas diagnosis and therapeutic strategies are evaluated for neutropenic patients, only limited data among nonneutropenic patients are available. STATE OF THE ART: Beside classical chronic pulmonary aspergillosis, an increased incidence of acute invasive aspergillosis is reported for nonneutropenic patients, such as patients suffering from chronic respiratory diseases or systemic diseases treated with corticosteroid therapy, and solid organ transplant recipients. PERSPECTIVES: A better knowledge of pathophysiology and epidemiology of invasive aspergillosis is needed to adapt the disease classification for nonneutropenic patients. Beside, the performance of diagnostic tools must be evaluated specifically in this population. CONCLUSIONS: Invasive aspergillosis is underdiagnosed in nonneutropenic patients which may simultaneously be colonized by Aspergillus and receive immunosuppressive therapy. It remains a life-threatening disease as severe as in neutropenic patients, at least partially related to a delayed diagnostic.

[Difficult weaning due to tracheal compression by an esophageal bezoar]. / Difficulté de sevrage par compression trachéale due à un bézoard.

INTRODUCTION: Bezoars result from the aggregation of ingested materials (food, drugs, hair) that accumulate at a certain anatomic level in the gastrointestinal tract. It is a rare condition, which is favoured by a reduction in intestinal motility, or by a primary abnormality reducing the patency of gastrointestinal tract. CASE REPORT: We present a case when acute respiratory symptoms revealed an oesophageal bezoar. The patient presented with compression of the posterior tracheal wall by an oesophageal bezoar. The diagnosis was confirmed by oesophageal endoscopy. Treatment consisted in endoscopy-guided fragmentation and removal of the bezoar followed by topical lavage. CONCLUSION: Oesophageal bezoars may account for compression of the posterior tracheal wall causing acute respiratory failure or difficult weaning from the ventilator. The close anatomic proximity between the gastrointestinal and respiratory tract may explain the impact of oesophageal bezoars on the respiratory tract.

Selective digestive and oropharyngeal decontamination in medical and surgical ICU patients: individual patient data meta-analysis.

OBJECTIVES: Selective digestive decontamination (SDD) and selective oropharyngeal decontamination (SOD) improved intensive care unit (ICU), hospital and 28-day survival in ICUs with low levels of antibiotic resistance. Yet it is unclear whether the effect differs between medical and surgical ICU patients. METHODS: In an individual patient data meta-analysis, we systematically searched PubMed and included all randomized controlled studies published since 2000. We performed a two-stage meta-analysis with separate logistic regression models per study and per outcome (hospital survival and ICU survival) and subsequent pooling of main and interaction effects. RESULTS: Six studies, all performed in countries with low levels of antibiotic resistance, yielded 16 528 hospital admissions and 17 884 ICU admissions for complete case analysis. Compared to standard care or placebo, the pooled adjusted odds ratios for hospital mortality was 0.82 (95% confidence interval (CI) 0.72-0.93) for SDD and 0.84 (95% CI 0.73-0.97) for SOD. Compared to SOD, the adjusted odds ratio for hospital mortality was 0.90 (95% CI 0.82-0.97) for SDD. The effects on hospital mortality were not modified by type of ICU admission (p values for interaction terms were 0.66 for SDD and control, 0.87 for SOD and control and 0.47 for SDD and SOD). Similar results were found for ICU mortality. CONCLUSIONS: In ICUs with low levels of antibiotic resistance, the effectiveness of SDD and SOD was not modified by type of ICU admission. SDD and SOD improved hospital and ICU survival compared to standard care in both patient populations, with SDD being more effective than SOD.

[Severe drug rash with eosinophilia and systemic symptoms after treatment with minocycline]. / Syndrome d'hypersensibilité médicamenteuse avec manifestations systémiques sévères après traitement par minocycline.

INTRODUCTION: Lung involvement is rarely observed in the DRESS syndrome (Drug rash with eosinophilia and systemic symptoms). We report here a severe minocycline induced hypersensitivity syndrome with initial respiratory distress. CASE REPORT: A 19 year old man was admitted to the intensive care unit for acute respiratory distress with fever (400C), lymph node enlargement, hepatomegaly, splenomegaly and eosinophilia (1640/mm3). Bilateral alveolar opacities were observed on the chest x-ray. Sedation and mechanical ventilation rapidly became necessary because of severe hypoxaemia (47 mm Hg) and the sudden onset of severe aggressive behaviour. The diagnosis of DRESS was immediately suspected as the patient had been treated for acne with minocycline for 28 days, and IV corticosteroids (2 mmg/kg/day) were initiated. Skin lesions were delayed and appeared 3 days later. The outcome was uncertain for the following 6 weeks with serious disturbance of hepatic and renal function. Serology for human herpes virus (HHV6) was initially negative but became positive. One year later, after progressive withdrawal of corticosteroid therapy, the patient had made a complete recovery with no sequelae. CONCLUSION: The DRESS syndrome can cause considerable morbidity with multiple, severe visceral functional disturbances. Respiratory physicians should be aware of this syndrome as lung involvement can be serious and may precede cutaneous symptoms.

[Plasmapheresis failure in the treatment of auto-immune pulmonary alveolar proteinosis]. / Échec de plasmaphérèse dans une protéinose alvéolaire pulmonaire auto-immune.

INTRODUCTION: Auto-immune pulmonary alveolar proteinosis is a rare disorder characterized by the accumulation of surfactant proteins in the alveoli. CASE REPORT: We report a case of a 41-year-old smoker, presenting initially with acute respiratory failure. Whole lung lavages were effective initially but only for a few weeks. GM-CSF subcutaneous injections were not effective, and then plasmapheresis were tried. CONCLUSION: This is the fifth report of the use of this treatment in auto-immune pulmonary alveolar proteinosis. Plasmapheresis was not effective in our patient.

Variability of sweat chloride concentration in subjects with cystic fibrosis and G551D mutations.

INTRODUCTION: Sweat chloride concentration, a biomarker of CFTR function, is an appropriate outcome parameter in clinical trials aimed at correcting the basic CF defect. Although there is consensus on a cut-off value to diagnose CF, we have only limited information on the within subject variability of sweat chloride over time. Such information would be useful for sample size calculations in clinical trials. Therefore, we retrospectively analyzed repeated sweat chloride values obtained in patients with G551D mutation(s) assigned to placebo in an ivacaftor interventional trial. METHODS: In subjects with G551D at least 12years of age, a pilocarpine sweat test using Macroduct collector was taken on both arms at 8 time points over 48weeks. We explored 1062 pilocarpine sweat test values obtained in 78 placebo patients of the VX08-770-102 trial. RESULTS: Mean overall sweat chloride value (all patients, all tests, n=1062) was 100.8mmol/L (SD 12.7mmol/L). Using a multilevel mixed model, the between-subject standard deviation (SD) for sweat chloride was 8.9mmol/L (95% CI 7.4-10.6) and within-subject SD was 8.1mmol/L (95% CI 7.5-8.7). Limits of repeatability for repeat measurements were -19.7 to +21.6mmol/L using values from one arm, and -13.3 to 11.8mmol/L using mean of values obtained at 4 test occasions. Sample size calculations showed that the minimal treatment effect on sweat chloride concentration that can be demonstrated for a group of 5 patients is around 15mmol/L, using a cross-over design and combinations of 4 tests for each phase of the trial. CONCLUSION: Although the sweat test is considered a robust measure, sweat chloride measurements in patients with CF and a G551D mutation had an inherent biological variability that is higher than commonly considered. Further analyses of placebo group data are crucial to learn more about the natural variability of this outcome parameter.

Comparison of epidemiological, clinical, and biological features of invasive aspergillosis in neutropenic and nonneutropenic patients: a 6-year survey.

BACKGROUND: Invasive aspergillosis is an opportunistic infection that occurs mainly among patients with prolonged neutropenia. Few data are available on invasive aspergillosis in nonneutropenic patients. METHODS: The aim of this survey was to compare neutropenic and nonneutropenic patients who had received a diagnosis of invasive aspergillosis at our institution during a 6-year period. RESULTS: Among the 88 cases of invasive aspergillosis analyzed here, 12 were histologically proven, 52 were probable, and 24 were possible. Forty-seven percent of cases were diagnosed in the intensive care unit, and 40% were diagnosed in hematology units. Neutropenia was a risk factor for 52 patients (59%), most of whom had hematological or solid malignancies. Among the 36 nonneutropenic patients (41%), the main underlying conditions were steroid-treated chronic obstructive pulmonary disease, asthma, rheumatoid arthritis, giant-cell arteritis, and microvascular disorders; 10 patients were recipients of solid-organ transplants, and 1 patient was seropositive for human immunodeficiency virus. The distribution of proven and probable invasive aspergillosis was similar for neutropenic and nonneutropenic patients. The mortality rate was 71.5% overall and was significantly higher among nonneutropenic patients than among neutropenic patients (89% vs. 60%; P<.05). Compared with neutropenic patients, nonneutropenic patients were significantly less likely to have symptoms of invasive aspergillosis and more likely to have frequent intercurrent pneumonia due to another microorganism. The sensitivity of mycological examination of bronchoalveolar lavage fluid specimens was higher for nonneutropenic patients than for neutropenic patients (85% vs. 58%; P<.05), whereas the sensitivity of antigenemia was the same for the 2 populations (65% vs. 64%). Findings on thoracic computed tomographs were similar, except that segmental areas of consolidation occurred more frequently among neutropenic patients. CONCLUSION: This survey at a whole institution underlines the high number of cases of invasive aspergillosis among nonneutropenic patients, with an overall mortality rate that was significantly higher than that for neutropenic patients.

C4d: a marker for hepatic transplant rejection.

BACKGROUND: Acute rejection is still a common complication of hepatic transplantation. The diagnosis, based on the histological examination of the graft, may be difficult to confirm in the setting of combined hepatitis C virus infection. The presence of C4d in the portal capillaries could facilitate differentiation between acute rejection and relapsed hepatitis C. The deposit of C4d provides evidence of activation of humoral immunity. To attempt to confirm this hypothesis, we searched for the presence of C4d in posttransplant hepatic biopsies. METHODS: Thirty-six biopsies from 34 patients were analyzed retrospectively. The samples had been requested for one of the following reasons: suspected rejection, relapsed hepatitis C infection, or systematic check-up 1 year after the transplant. RESULTS: C4d expression was common in biopsies classified as acute rejection (33%) and chronic rejection (100%). C4d was never detected in the event of recurrent hepatitis C infection without rejection. CONCLUSION: These results, which are comparable to recently published data, give credence to the theory that C4d could be used as a marker for rejection following hepatic transplantation.

[Adherence to antiretroviral therapy during HIV infection, a multidisciplinary approach]. / "L'observance thérapeutique au cours de l'infection VIH, une approche multidisciplinaire".

Since HIV infection has become a chronic disease, antiretroviral therapy is now used on a long-term basis. Response to treatment is conditioned by numerous inter-dependent factors, including non-compliance, which can result in failure of the therapeutic regimen. Although compliance is crucial for long-term efficacy of the treatment, it is a dynamic factor, and therefore difficult to evaluate. This literature review proposes a multidisciplinary approach to treatment adherence during HIV infection, and deals with the following questions: how should adherence and non-adherence be defined? How are they correlated to the treatment response? How is adherence measured in trials and cohorts, as well as in clinical practice? By what factors is it influenced? What tools can be implemented to improve adherence? The interaction between adherence and response to antiretroviral therapy requires communication between clinicians, healthcare providers, patients, virologists, pharmacologists, and the companies responsible for developing drugs. The pharmaceutical industry must sustain its efforts to ensure a balance between demands for efficacy and adherence when developing new drugs. And the methods implemented by numerous healthcare teams plead in favour of a dynamic approach to adherence, with the active participation of all.

Identification of guanine exchange factor key residues involved in exchange activity and Ras interaction.

We have carried out a functional analysis of the human HGRF55 exchange factor in the yeast Saccharomyces cerevisiae. Twelve residues conserved among most of all known guanine exchange factors (GEFs) have been independently changed to alanine. Taking advantage of the ability of Hgrf55p to replace the yeast Cdc25p exchange factor, and using the two-hybrid system with RAS2ala22 allele, we have identified key residues for the interaction with Ras and/or its activation. Substitution of arginine 392 to alanine leads to a complete loss of interaction with Ras, though the protein remains stable. Substitution of Asp266 or Arg359 to alanine results in inactive proteins at 39 degrees C, still able however to interact with Ras. The other charged-to-alanine substitutions led to no detectable phenotype when present alone but most of them dramatically increased the temperature sensitive phenotype observed with [Asp266Ala] substitution. Surprisingly, the cysteine to alanine substitution in the highly conserved PCVPF/Y motif proved to be without effect, suggesting that the sulfhydryl group is not essential for stability or interaction with Ras.

Improved liver function and decreased hepatitis C viral load after tacrolimus was replaced by cyclosporine.

Potential antiviral properties of cyclosporine against hepatitis C virus have been highlighted in several publications. Therefore, we investigated the effect of a switch from tacrolimus to cyclosporine in a liver transplant recipient with recurrent hepatitis C who did not respond to antiviral therapy. The patient received a liver transplant for hepatitis C cirrhosis. Initial immunosuppressive treatment was based on tacrolimus. Because of viral activity, a combined therapy was initiated 20 months later including interferon and ribavirine. Then, due to a lack of virological and biochemical response, tacrolimus was replaced by cyclosporine (Neoral), while maintaining the same antiviral therapy. Decreases in the viral load and transaminases levels were observed.

Persistence of both peripheral and non-peripheral corneodesmosomes in the upper stratum corneum of winter xerosis skin versus only peripheral in normal skin.

To understand the biochemical abnormalities that underlie the reduced desquamation observed in dry skin, we analyzed corneodesmosome degradation in normal and winter xerosis skin. Western blotting of total proteins from corneocytes obtained by varnish-strippings from the legs of 56 volunteers with normal (26) or xerotic (30) skin was performed using antibodies specific for (corneo)desmosome proteins. In the whole population, the amounts of desmoglein 1 and plakoglobin were found to be correlated, but were not related to the amounts of corneodesmosin. This suggests simultaneous proteolysis for the former proteins differing from that of corneodesmosin. Neither entire desmoplakins nor any proteolysis-derived fragments were detected. The amounts of corneodesmosin, desmoglein 1, and plakoglobin detected were found to be significantly higher in xerotic compared with normal skin extracts. Conventional and freeze-fracture electron microscopy showed the absence of nonperipheral corneodesmosomes in the upper stratum corneum of normal skin but the presence of a significant number of these structures in the same layer of winter xerosis skin. These results provide a more precise description of the proteolysis of corneodesmosome components in the upper cornified layer of the epidermis. They support previous studies demonstrating the importance of corneodesmosome degradation in desquamation and reveal that the nonperipheral corneodesmosomes, which are totally degraded during maturation of the stratum corneum in normal skin, persist in winter xerosis, probably leading to abnormal desquamation.