Definition of an 18-mer Synthetic Peptide Derived from the GB virus C E1 Protein as a New HIV-1 Entry Inhibitor.

BACKGROUND: A slower progression of AIDS and increased survival in GBV-C positive individuals, compared with GBV-C negative individuals has been demonstrated; while the loss of GBV-C viremia was closely associated with a rise in mortality and increased progression of AIDS. Following on from the previous reported studies that support the thesis that GBV-C E2 interferes with HIV-1 entry, in this work we try to determine the role of the GBV-C E1 protein in HIV-1 inhibition. METHODS: The present work involves the construction of several overlapping peptide libraries scanning the GBV-C E1 protein and the evaluation of their anti-HIV activity. RESULTS: Specifically, an 18-mer synthetic peptide from the GBV-C E1 protein, E1(139-156), showed similar antiviral activity against HIVs from viruses from clades A, B, C, D and AE. Competitive ELISA using specific gp41-targeting mAbs, fluorescence resonance energy transfer as well as haemolysis assays demonstrated that this E1 peptide sequence interacts with the highly conserved N-terminal region of the HIV-1 gp41 (the fusion peptide) which is essential for viral entry. CONCLUSIONS: We have defined a novel peptide lead compound and described the inhibitory role of a highly conserved fragment of the E1 protein. GENERAL SIGNIFICANCE: The results together allow us to consider the non-pathogenic E1 GBV-C protein as an attractive source of peptides for the development of novel anti-HIV therapies.

rFVIIa administered by continuous infusion during surgery in patients with severe congenital FVII deficiency.

The use of recombinant FVIIa (rFVIIa) to control bleed in individuals with FVII deficiency has been proven to be effective. The main problems associated with its use are that it requires frequent bolus injections to counteract its short half-life and high cost. Our study aimed to evaluate whether any advantage could be gained by providing rFVIIa by continuous infusion during surgery with regard to haemostatic efficacy, safety and cost. The prospective study included 10 patients with severe FVII deficiency, who underwent 25 surgical procedures (13 major and 12 minor procedures) and were treated with rFVIIa administered by continuous infusion. Tranexamic acid was given concomitantly every 8 h. Prothrombin time, FVII:C assay and thrombin generation assay were used to monitor the treatment. The mean total dose given was 10 mg during a major surgery and 4.4 mg during a minor surgery for a mean treatment duration of 7.5 and 4.0 days respectively. This corresponds to a reduction of 70-90% in drug usage and medication cost compared with bolus injections. Except for one major perioperative bleeding, excellent haemostasis was achieved in all procedures. One patient developed a transient inhibitory activity. None of these events affected the postoperative course or prolonged the hospital stay. Our study demonstrated that continuous infusion of rFVIIa during surgery is safe, effective and highly cost effective.

[Links between stress factors, mental health and initial consumption of tobacco and alcohol during pre-adolescence]. / Liens entre stresseurs, santé psychique et premières consommations de tabac et d'alcool à la préadolescence.

BACKGROUND: We know the effects of stress hassles and life events on mental health at pre-adolescence and the impact of the first experiences with alcoholic beverages and tobacco, where the precocity of the initiation tends to encourage abuse and later dependence on these substances. The goal of this study was to look into the related effect of environmental factors (daily hassles, life events, and social support) on perceived mental health and on the initiation and consumption of tobacco and alcohol by preadolescents. POPULATION: The study was carried out in 12 institutions in a French department ("Indre-et-Loire") in the "Région Centre", including students from the last year of primary school (fifth grade) and the first two years of middle school (sixth and seventh grades): all nine elementary schools in Joué-lès-Tours, the second largest city of the department, and three middle schools in Tours and surrounding areas (urban, semi-rural and inner city). The sample was made up of 476 preadolescents attending school, 234 girls (49%) and 242 boys (51%), 267 primary school and 209 middle school students, with an average age of 11 years and 7 months. MATERIAL: Standardized questionnaires, specific to this population: with a scale of daily hassles, life events, mental health, and social support, were used. They proved to be adapted to each of them (Cronbach alpha coefficient>0.70) and the types of hassles and life events corresponded to the psycho developmental knowledge specific of this period. For the middle school students, dependence on tobacco was defined according to the "Hooked on nicotine checklist". PROCEDURE: In April 2004 in class (anonymity guaranteed). RESULTS: The results show that the hassles (considered in terms of occurrence or intensity, that is, the perceived stress) and life events (occurrence and negative perception) have a negative effect on mental health. In particular, pressure due to family problems has the greatest influence on mental health. For primary school students, this is followed by problems linked to self-perception; for middle school students, those linked to school. The consequences of hassles and life events on mental health allowed us to verify the solidity of the model used in previous studies [the Lausanne pediatric psychiatry team ], even with a younger preadolescent population. The effect of daily hassles is greater than that of life events, but they are not independent of one another (mediational model). Social support plays a modulating and protective role in mental health and the effects of daily hassles and life events. The prevalence of preadolescent smokers (simple experimentation or more or less regular use) is 5.7% (n=26). The prevalence of alcohol use is greater, encompassing more than one-third of subjects (33.4%; n=153). The influence of daily hassles can be seen both on the age of initiation to alcoholic beverages and to use of alcohol and intoxications. It is also observed on the age of initiation to tobacco and nicotine dependence (only taken into account for middle school students). That is to say that they promote precocity in the consumption of these products and increase their use. The absence of links with tobacco consumption may be due to the low number of preadolescent tobacco users. Life events also show an effect on tobacco and alcohol consumption, but it is lesser and should be moderated. Mental health is also correlated (but weakly) to the use of alcoholic beverages and intoxications. This applies more specifically to middle school students. Finally, the role of social support cannot be distinguished. CONCLUSIONS: This study shows the degree that daily hassles impact mental health and the recourse to psychoactive substances during preadolescence. Precocious use of tobacco and alcohol, the abuse of these substances and occasionally the beginning of dependence should be considered, at the very least, as warning signs for states of tension on individual, familial and environmental levels, or even as signs of established problems which could be revealed through a thorough clinical.

Orthopaedic surgery in severe bleeding disorders: a low-volume, high-cost procedure.

As more and more nations are scrutinizing their health care costs, attention has been focused on high-cost low-density disease. Assessment of actual total cost of care for haemophilia and its positive outcome becomes essential to justify support for these patients. In this study, we assessed hospital cost and diagnosis-related group (DRG) reimbursement for patients undergoing elective orthopaedic surgical procedures from May 1999 to December 1999. Hospital cost was assessed by a prospective microcost-analysis method. To identify real hospital costs, we performed registration of preoperative phase, operative phase and 1-year follow-up costs. Hospital cost included personnel costs and costs for clinical and laboratory procedures, blood products, prosthetic implants, coagulation factor concentrates and drugs. These data were compared with hospital DRG reimbursement. We included nine consecutive patients, with a mean age 38 years (19-54 years) who had had 10 major orthopaedic surgical procedures performed during the study period. Six patients had haemophilia A, two had haemophilia B and one had factor VII deficiency. Data analysis showed a mean cost of US$ 54,201 (range US$ 25,795-105,479; 1US$ = 8.5 NOK). The average actual hospital revenue (50% DRG reimbursement + income related to length of stay) was $4,730 (range $ 1,308-13,601). Our study confirms that orthopaedic surgery in patients with severe bleeding disorders puts the hospital to a considerable expense. Activity-based financing, as used in Norway, does not provide a proper reimbursement for this part of the haemophilia care.

Dynamic MR-imaging in the diagnosis of pigmented villonodular synovitis of the knee.

The aim of this report was to study the rate of contrast enhancement at MRI in pigmented villonodular synovitis (PVNS). Dynamic MRI was performed in a patient with PVNS just before and 1 week and 3 years following synovectomy of the knee. As opposed to patients with rheumatic disease the patient with PVNS showed a slower enhancement rate before synovectomy than 1 week after. At 3 years follow-up the patient with PVNS showed an enhancement rate just above that of the normal controls. The results indicate that PVNS has features more common to hyperplastic or neoplastic lesions than to inflammatory ones. The results at 3 years follow-up also suggest that dynamic MRI may indicate the efficacy of arthroscopic synovectomy.

A new role for neurotrophins: involvement of brain-derived neurotrophic factor and neurotrophin-4 in hair cycle control.

Neurotrophins exert many biological effects not directly targeted at neurons, including modulation of keratinocyte proliferation and apoptosis in vitro. Here we exploit the cyclic growth and regression activity of the murine hair follicle to explore potential nonneuronal functions of neurotrophins in the skin, and analyze the follicular expression and hair growth-modulatory function of BDNF, NT-4, and their high-affinity receptor, TrkB. The cutaneous expression of BDNF and NT-4 mRNA was strikingly hair cycle dependent and peaked during the spontaneous, apoptosis-driven hair follicle regression (catagen). During catagen, BDNF mRNA and immunoreactivity, as well as NT-4-immunoreactivity, were expressed in the regressing hair follicle compartments, whereas TrkB mRNA and immunoreactivity were seen in dermal papilla fibroblasts, epithelial strand, and hair germ. BDNF or NT-4 knockout mice showed significant catagen retardation, whereas BDNF-overexpressing mice displayed acceleration of catagen and significant shortening of hair length. Finally, BDNF and NT-4 accelerated catagen development in murine skin organ culture. Together, our data suggest that BDNF and NT-4 play a previously unrecognized role in skin physiology as agents of hair growth control. Thus, TrkB agonists and antagonists deserve exploration as novel hair growth-modulatory drugs for the management of common hair growth disorders.

Arthroscopic synovectomy. When, which diseases and which joints.

The success of arthroscopic synovectomy depends both on surgical skill and patient selection. Close cooperation between rheumatologist and rheumasurgeon is advocated. Alternative local joint treatments are discussed, with particular respect to radiation synovectomy. Patients with chronic inflammatory joint disease comprise the major group of patients. However, other diseases like haemophilia, pigmented villonodular synovitis, synovial chondromatosis, posttraumatic synovitis and septic arthritis are also discussed. A discussion of open versus arthroscopic synovectomy for each joint is presented. Arthroscopic synovectomy is preferred when arthroscopic access allows radical synovectomy. Treating concomitant tenosynovitis is underlined.

[Physicians as leaders. Evaluation of a leadership training program for physicians (Medled)]. / Leger i ledelse. Evaluering av et lederutviklingsprogram for leger (Medled).

In September 1990, 40 doctors started a two year management training programme consisting of six one week courses organised by the Norwegian Medical Association. The programme was evaluated, and this article presents the results of two of the methods, used for evaluation: the first an interview with 12 participants, and the second a questionnaire answered by participants, colleagues at the same department and colleagues at other hospitals (a control group) before and after the course. Compared with colleagues from the same department and from the control group the participants had changed their attitude towards important questions of management. They had become more concerned about the importance of motivating the staff, that the department should give priority to the hospital's objectives in preference to own interests, and that the ultimate responsibility for the department should reside in one person and this person should be a doctor with a relevant specialty. The results of the questionnaire survey are confirmed by the results of the interviews. In addition the results of the interviews suggest that, during the management training programme, the participants had changed from an individual-oriented to a more group-oriented style of management.

Arthroscopic and radiographic examination of patients with juvenile rheumatoid arthritis before and after open synovectomy of the knee joint. A prospective study with a 5-year follow-up.

In a 5-year follow-up after open knee joint synovectomy in 18 patients with juvenile rheumatoid arthritis (JRA) there was no radiographic progression of the juvenile rheumatoid arthritic changes. Radiographic evidence indicative of osteoarthrosis and of the soft tissue swelling were scored separately. Radiographic changes consistent with osteoarthrosis increased significantly during the observation period (P < 0.001). Arthroscopic evaluation of cartilage changes and radiographic evaluation of osteoarthrosis correlated significantly (P = 0.004). These were the only parameters found predicting the development of further cartilage destruction (P = 0.001). Clinically, the patients had significant improvement five years following synovectomy (P = 0.018), even though three patients required resynovectomy (one successfully after four years, and two patients are waiting for resynovectomy). At the 5-year follow-up both radiographic and clinical data indicate that juvenile rheumatoid arthritic activity of the knee joint was reduced following open synovectomy while osteoarthrosis developed. A new system of scoring radiographic JRA changes of the knee joint was found useful.

A prospective clinical five year follow up study after open synovectomy of the knee joint in patients with chronic inflammatory joint disease. The prognostic power of clinical, arthroscopic, histologic and immunohistologic variables.

Arthroscopy and clinical examination was performed on the knee joint of 26 patients with chronic inflammatory joint disease, before and at 6 and 12 months after open synovectomy. Biopsies were examined by histologic and immunohistologic methods. Clinically the patients improved until 6 months after synovectomy, and the improvement was maintained for 5 years. Patients with the best clinical function prior to synovectomy also had the best long term results (p = 0.024). The state of the cartilage was the best predicting variable with a significant prognostic power (p = 0.01). Thus patients with normal cartilage at the time of synovectomy had the best clinical score five years later. The patients with most resynovitis 12 months after surgery did less well at five year clinical follow up (p = 0.032) than those with little or no resynovitis. Absence or low number of IgA-positive plasma cells in the cellular infiltrate at 12 months after surgery correlated with a good clinical score five years after surgery (p = 0.036). This suggests that a high number of IgA-positive plasma cells may be indicative of a more aggressive, destructive disease.

Evaluation of knee joint cartilages and menisci in patients with chronic inflammatory joint diseases. A prospective arthroscopic study before, six and twelve months after open synovectomy.

Destruction of joint cartilage is an important feature in chronic inflammatory joint diseases. This article considers the areas of the cartilages of the knee joint prone to destructive changes, pannus growth and marginal erosions, and the changes of pattern after open synovectomy. Twenty-eight patients with chronic inflammatory joint disease which gave indication for synovectomy of the knee joint had arthroscopy immediately before, 6 and 12 months after open synovectomy. A method of grading the changes of the cartilage, pannus growth, menisci and marginal erosions is described. There was an increase in cartilage pathology 12 months after synovectomy (p less than 0.001), particularly on the weight bearing areas of the femur and on the tibial condyles. No significant deterioration in areas with pathology at the time of synovectomy was found in the follow up. Pannus growth was particularly located to areas 2 and 4 on the femoral condyles. We conclude that cartilage destruction after synovectomy is more likely to be a result of osteoarthrosis than arthritic changes.

Arthroscopic evaluation of the synovial lining before and after open synovectomy of the knee joint in patients with chronic inflammatory joint diseases.

Twenty-eight patients with chronic inflammatory joint diseases had arthroscopy immediately before synovectomy of the knee joint and 6 and 12 months postoperatively. In patients with moderate and/or severe synovitis of the knee joint all of the synovial membrane is involved in the disease process. Resynovitis (synovitis of the regenerated synovial membrane after synovectomy), however, is patchy and if biopsy should be indicated, arthroscopic guidance is advocated. Following synovectomy there is a recurrence of mild synovitis of varying degree in some cases with an increase in resynovitis between 6 and 12 months. The level of synovitis at 12 months was, however, markedly less than at synovectomy (p less than 0.01). Similar development was found both in histopathology and immunohistopathology after synovectomy. Arthroscopic examination of the synovial membrane in chronic inflammatory disease of the knee joints gives valuable information of the severity and the longitudinal changes of synovitis. A simple method of scoring is described and is imperative when comparing patients or groups of patients and when doing longitudinal arthroscopic studies. The method was used both at arthroscopy and at subsequent synovectomy giving a highly significant correlation (p less than 0.001).

Histopathologic changes in arthroscopic synovial biopsies before and after open synovectomy in patients with chronic inflammatory joint diseases.

Synovial biopsies were taken from five preselected areas of knee joints in patients with chronic inflammatory joint diseases immediately prior to synovectomy as well as 6 and 12 months later. The histologic changes were assessed by evaluating 16 different parameters in each individual biopsy. When the 16 parameters were treated as a group there was a significant reduction (p less than 0.001) in inflammatory changes at 6 months, but a slight increase again after 12 months. This was expressed by a significant reduction in lymphocytes (p less than 0.025) and plasma cells (p less than 0.01). The reduction seen in macrophages was not significant (p greater than 0.05). The cellular infiltrates in the interstitial stroma were dominated by lymphocytes, plasma cells and macrophages preoperatively and by lymphocytes and macrophages following synovectomy. Fibrosis was a dominating feature before synovectomy, and it increased (p less than 0.025) following the operation, probably due to the surgical intervention. Before synovectomy the severity of inflammatory changes within each single joint varied, but none of the preselected areas was more prone to these changes than any other. Postoperatively at both 6 and 12 months the inflammatory parameters were more pronounced in the intercondylar area (p less than 0.025).

Immunohistopathologic findings in synovial biopsies before and after synovectomy in patients with chronic inflammatory joint diseases and their relation to clinical evaluation. A prospective study of biopsies taken from areas selected by arthroscopy.

Synovial biopsies were obtained from 28 patients with various kinds of chronic arthritis, at synovectomy and 6 and 12 months later. The tissues were examined by immunofluorescence technique, recording the quantities of cells and extracellular deposits staining with polyclonal antisera to IgG, IgA, IgM, C3c, fibrinogen, and chi and lambda light chains, and monoclonal antibodies to CD3, CD5, CD11b, HLA DR, and TCC (Terminal Complement Complex). These parameters were compared with scores obtained by arthroscopy and clinical evaluation (Colorado Knee Score) performed at the same time. Taken as a group, the immunological parameters showed reduction in activity 6 months after synovectomy (p less than 0.01), and a tendency to revert to base-line values after 12 months. A similar reduction in activity after 6 months was also found by arthroscopic and clinical evaluation. Thus, this longitudinal study demonstrated a relationship between changes in immunologic activity, arthroscopic findings and clinical activity after synovectomy in patients with chronic arthritis. This is consistent with an immunological pathogenesis for the inflammation in these joints.

Complement activation in synovial fluid and tissue from patients with juvenile rheumatoid arthritis.

Synovial fluid (SF) and synovial tissue from 10 patients with juvenile rheumatoid arthritis were examined. The SFs were heterogeneous with respect to the degree of complement activation. Quantification of C3dg and the terminal complement complex revealed a positive correlation between activation of the early and the late parts of the cascade in all patients. The amount of C-reactive protein and the number of white blood cells in the SF correlated significantly with the degree of complement activation. Weak deposits of C3, C3dg, or terminal complement complex were observed in a few vessels in the synovial tissue from 5 of the patients. There was no correlation between complement activity in SF and in the corresponding tissue. Furthermore, there was no correlation between clinical activity in the joints and the degree of complement activation. It is concluded that there is a discrepancy between synovial tissue and synovial fluid with respect to complement activation. C-reactive protein may, to some extent, be responsible for activation in SF, and the accumulation of white blood cells may be due to complement activation products.

The value of arthroscopy in the diagnosis and treatment of patients with juvenile rheumatoid arthritis.

Arthroscopy of 49 knee joints in patients with juvenile rheumatoid arthritis (JRA) or suspected JRA is described. A large number of patients had a monoarticular involvement with a difficult differential diagnostic problem. Arthroscopy gave important additional diagnostic information. Arthroscopy gives accurate information regarding cartilage destruction and severity of synovitis. In some patients with JRA arthroscopy was a final tool in deciding whether or not to do a synovectomy. Arthroscopy is a safe examination which gives important additional diagnostic information in patients with JRA.