Prevention of bone marrow graft failure by an anti LFA-1 monoclonal antibody

Graft rejection is the major cause of failure of HLA mismatched bone marrow transplantation because of residual host immunity. we have proposed to use a monoclonal murine antibody specific for the LFA-1 molecule (25-3) to prevent graft failure in HLA mismatched bone marrow transplantation (BMT). The rationale for this approach is three fold: LFA-1 deficient patients (3/3) do not reject HLA mismatched BMT; anti LFA-1 blocka in vitro the induction of T cell responses and T/ non T cytotoxic functions; LFA-1 is not expressed by other cells than leucocytes. We have accordingly treated twenty two patients with inherited diseases and 8 with leikemia. The bone marrow was T cells depled by E rosetting of Campath antibody. The antibody was given at days -3, -1, +1, +3, +5 at dose of .1 mg/kg/d for the first 9 and then .2mg/kg/d from day -3 to +6. Engraftment occured in 23/30 patients as shown by at least HLA typing. Hematological recovery was rapid, GVH was limited. Side effects of antibody infusion included fever and possibly an increased incidence of early bacteral infection (sepsis, 1 death). Immunological reconstitution occured slowly leading in six cases to EBV-induced B cell poliferation (1 death and in two others to transient auto immune hemolytic anemia. There has been only one secondary graft rejection. Sisteen patients are alive 3 to 26 months post transplant with functional grafts. Although the number of patients treated is still low the absence of late rejection so far, gives hope for long term maintenance of the graft using anti LFA-1. Since the antibody is an IgG 1 unable to bind human complement, and since it is known to inhibit phagocytosis, there is a good suggestion that 25-3 act through functional blocking of host T and non T luymphocytes at both induction and effector levels.

Differential effect of long versus short wavelength light exposure on pupillary re-dilation in patients with outer retinal disease.

BACKGROUND: In patients with outer retinal degeneration, a differential pupil response to long wavelength (red) versus short wavelength (blue) light stimulation has been previously observed. The goal of this study was to quantify differences in the pupillary re-dilation following exposure to red versus blue light in patients with outer retinal disease and compare them with patients with optic neuropathy and with healthy subjects. DESIGN: Prospective comparative cohort study. PARTICIPANTS: Twenty-three patients with outer retinal disease, 13 patients with optic neuropathy and 14 normal subjects. METHODS: Subjects were tested using continuous red and blue light stimulation at three intensities (1, 10 and 100 cd/m2) for 13 s per intensity. Pupillary re-dilation dynamics following the brightest intensity was analysed and compared between the three groups. MAIN OUTCOME MEASURES: The parameters of pupil re-dilation used in this study were: time to recover 90% of baseline size; mean pupil size at early and late phases of re-dilation; and differential re-dilation time for blue versus red light. RESULTS: Patients with outer retinal disease showed a pupil that tended to stay smaller after light termination and thus had a longer time to recovery. The differential re-dilation time was significantly greater in patients with outer retinal disease (median = 28.0 s, P < 0.0001) compared with controls and patients with optic neuropathy. CONCLUSIONS: A differential response of pupil re-dilation following red versus blue light stimulation is present in patients with outer retinal disease but is not found in normal eyes or among patients with visual loss from optic neuropathy.

Microbiota abnormalities in inflammatory airway diseases - Potential for therapy.

Increasingly the development of novel therapeutic strategies is taking into consideration the contribution of the intestinal microbiota to health and disease. Dysbiosis of the microbial communities colonizing the human intestinal tract has been described for a variety of chronic diseases, such as inflammatory bowel disease, obesity and asthma. In particular, reduction of several so-called probiotic species including Lactobacilli and Bifidobacteria that are generally considered to be beneficial, as well as an outgrowth of potentially pathogenic bacteria is often reported. Thus a tempting therapeutic approach is to shape the constituents of the microbiota in an attempt to restore the microbial balance towards the growth of 'health-promoting' bacterial species. A twist to this scenario is the recent discovery that the respiratory tract also harbors a microbiota under steady-state conditions. Investigators have shown that the microbial composition of the airway flora is different between healthy lungs and those with chronic lung diseases, such as asthma, chronic obstructive pulmonary disease as well as cystic fibrosis. This is an emerging field, and thus far there is very limited data showing a direct contribution of the airway microbiota to the onset and progression of disease. However, should future studies provide such evidence, the airway microbiota might soon join the intestinal microbiota as a target for therapeutic intervention. In this review, we highlight the major advances that have been made describing the microbiota in chronic lung disease and discuss current and future approaches concerning manipulation of the microbiota for the treatment and prevention of disease.

ESCMID* guideline for the diagnosis and management of Candida diseases 2012: developing European guidelines in clinical microbiology and infectious diseases.

The process to develop a guideline in a European setting remains a challenge. The ESCMID Fungal Infection Study Group (EFISG) successfully achieved this endeavour. After two face-to-face meetings, numerous telephone conferences, and email correspondence, an ESCMID task force (basically composed of members of the Society's Fungal Infection Study Group, EFISG) finalized the ESCMID diagnostic and management/therapeutic guideline for Candida diseases. By appreciating various patient populations at risk for Candida diseases, four subgroups were predefined, mainly ICU patients, paediatric, HIV/AIDS and patients with malignancies including haematopoietic stem cell transplantation. Besides treatment recommendations, the ESCMID guidelines provide guidance for diagnostic procedures. For the guidelines, questions were formulated to phrase the intention of a given recommendation, for example, outcome. The recommendation was the clinical intervention, which was graded by a score of A-D for the 'Strength of a recommendation'. The 'level of evidence' received a score of I-III. The author panel was approved by ESCMID, European Organisation for Research and Treatment of Cancer, European Group for Blood and Marrow Transplantation, European Society of Intensive Care Medicine and the European Confederation of Medical Mycology. The guidelines followed the framework of GRADE and Appraisal of Guidelines, Research, and Evaluation. The drafted guideline was presented at ECCMID 2011 and points of discussion occurring during that meeting were incorporated into the manuscripts. These ESCMID guidelines for the diagnosis and management of Candida diseases provide guidance for clinicians in their daily decision-making process.

Modern British Retailing in the Late 20th Century: Increasing Value?

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Host-microorganism interactions in lung diseases.

Until recently, the airways were thought to be sterile unless infected; however, a shift towards molecular methods for the quantification and sequencing of bacterial DNA has revealed that the airways harbour a unique steady-state microbiota. This paradigm shift is changing the way that respiratory research is approached, with a clear need now to consider the effects of host-microorganism interactions in both healthy and diseased lungs. We propose that akin to recent discoveries in intestinal research, dysbiosis of the airway microbiota could underlie susceptibility to, and progression and chronicity of lung disease. In this Opinion article, we summarize current knowledge of the airway microbiota and outline how host-microorganism interactions in the lungs and other tissues might influence respiratory health and disease.

Oral valganciclovir prophylaxis in kidney transplant recipients

Background: Immunosuppressive and antivira[ prophy[ actic drugs are needed to prevent acute rejection and infection after organ transplantation. We assessed the effectiveness of a new combined regimen introduced at our transplantation center. Methods: We reviewed at[ consecutive patients who underwent kidney transplantation at our institution over a 5.5-year period, with a follow-up of at [east 6 months. Patients transplanted from 1/2000 to 3/2003 (Period 1) were compared to patients transplanted from 4/2003 to 7/2005 (Period 2). In period 1, patients were treated with Basi[iximab, Cic[osporin, steroids and Mycophenotate or Azathioprine. Prophylaxis with Va[acic[ ovir was prescribed in CMV D+/R- patients; otherwise, a preemptive antivira[ approach was used. In period 2, immunosuppressive drugs were Basi[- iximab, Tacro[imus, steroids and Mycopheno[ate. A 3-month CMV prophylaxis with Va[gancic[ovir was used, except in D-/R- patients. Results: Sixty-three patients were transplanted in period 1 and 70 patients in period 2. Baseline characteristics of both groups were comparable; in particular 17% of patients were CMV D+/R- in period 1 compared to 23% in period 2 (p=0.67). Acute rejection was more frequent in period 1 than in period 2 (40% of patients vs 7%, respectively p<0.001). Nineteen patients (30%) in period 1 were diagnosed with CMV infection/disease that required treatment, compared with 8 patients (11.4%) in period 2 (p = 0.003). Of these 8 patients, at[ had CMV infection/disease after discontinuation of Va[gancic[ovir prophylaxis, 6 were D+/R- (75%), and at[ were treated with oral Va[gancic[ovir. There was no difference between periods in terms of incidence of BK nephropathy, post-transplant [ymphopro[ iferative disease, graft toss, and mortality. Conclusions: These results indicate that a 3-month course of oral Va[gancic[ovir is very effective to prevent CMV infection/disease in kidney transplantation. Late-onset CMV disease is a residual problem in D+/R- patients receiving VGC prophylaxis.

Please die during office hours : periodicity of cardiovascular events in switzerland between 1969 and 2007

Purpose: to evaluate and compare the periodical patterns of death from cardiovascular disease (CVD), including acute myocardial infarction (AMI) and stroke in the Swiss population between the years 1969 and 2007.¦Methods: Swiss mortality database for the period of 1969- 2007 (2'362'430 deaths overall). The number of deaths due to CVD, AMI and stroke according to the time of day, day of the week and month were assessed, overall and after dividing the events according to gender and age (< 65 or ≥65 years old).¦Results: In general and for all four subgroups according to age and sex, there is a daily variation in the number of deaths with a first peak in the morning (8h00 -12h00) and a smaller second peak in the late afternoon (14h - 18h). Both males and females have similar hourly patterns, although the magnitude of the difference diminishes in older patients particularly for people who die from stroke. For the weekly variation, there seems to be a significant trend only in the younger population with the lowest mortality rates on Sunday and the highest on Mondays for all diseases. When it comes to seasonal variation according to month, the trend is more significant in the elder patients with the highest death rates during the winter months (+31%) and the lowest in the summer (July/August).¦Conclusion: There is a timely pattern for CVD, AMI and stroke deaths in Switzerland. This pattern changes according to the age and sex of the patients. Knowing this trend, its triggering factors and consequences, perhaps there could be measures put in place to prevent, diagnose and treat the population which is the most vulnerable at certain times.

Cardiopathies congénitales de l'âge adulte: nouvelle population de patients, prise en charge multidisciplinaire [Adults with congenital heart diseases: a growing population, a multidisciplinary approach].

Untill recently, congenital heart disease was considered as a childhood's disease. With improvement in pediatric survival, adults with a congenital heart disease (ACHD) represent an emerging group of patients who need specialized medical care. In 2010, the ESC published newguidelines on global and specific management of adults with congenital heart disease. ACHD centers organize appropriate medical care for these patients, promote specialist training and national scientific research in collaboration with other national ACHD centers.

Radiolarian biostratigraphic evidence for a Late Jurassic age of the El Tambor group ophiolites (Guatemala)

We present a radiolarian biostratigraphic study of the metacherts of the El Tambor Group ophiolites (South Motagua Unit), Guatemala. The ophiolite sequence comprises MOR pillow metabasalts, massive metabasalts, metacherts and micaschists. The age of the studied metacherts is referable to the Late Jurassic (Oxfordian-Kimmeridgian). The radiolarian assemblage described in this paper is the first Jurassic finding in the ophiolitic MOR succession of the Motagua zone and represents a valuable tool to constrain the geodynamic evolution of the Caribbean area. A review of the ages of Jurassic rocks associated with the ophiolites from the Caribbean area is also reported.

Proteomic analysis of cytokine induced proteins in human intestinal epithelial cells: implications for inflammatory bowel diseases.

A role for cytokine regulated proteins in epithelial cells has been suggested in the pathogenesis of inflammatory bowel diseases (IBD). The aim of this study was to identify such cytokine regulated targets using a proteomic functional approach. Protein patterns from (35)S-radiolabeled homogenates of cultured colon epithelial cells were compared before and after exposure to interferon-gamma, interleukin-1beta and interleukin-6. Proteins were separated by two-dimensional polyacrylamide gel electrophoresis. Both autoradiographies and silver stained gels were analyzed. Proteins showing differential expression were identified by tryptic in-gel digestion and mass spectrometry. Metabolism related proteins were also investigated by Western blot analysis. Tryptophanyl-tRNA synthetase, indoleamine-2,3-dioxygenase, heterogeneous nuclear ribonucleoprotein JKTBP, interferon-induced 35kDa protein, proteasome subunit LMP2 and arginosuccinate synthetase were identified as cytokine modulated proteins in vitro. Using purified epithelial cells from patients, overexpression of indoleamine-2,3-dioxygenase, an enzyme involved in tryptophan metabolism, was confirmed in Crohn's disease as well as in ulcerative colitis, as compared to normal mucosa. No such difference was found in diverticulitis. Potentially, this observation opens new avenues in the treatment of IBD.

Mass spectrometry for the evaluation of cardiovascular diseases based on proteomics and lipidomics.

The identification and quantification of proteins and lipids is of major importance for the diagnosis, prognosis and understanding of the molecular mechanisms involved in disease development. Owing to its selectivity and sensitivity, mass spectrometry has become a key technique in analytical platforms for proteomic and lipidomic investigations. Using this technique, many strategies have been developed based on unbiased or targeted approaches to highlight or monitor molecules of interest from biomatrices. Although these approaches have largely been employed in cancer research, this type of investigation has been met by a growing interest in the field of cardiovascular disorders, potentially leading to the discovery of novel biomarkers and the development of new therapies. In this paper, we will review the different mass spectrometry-based proteomic and lipidomic strategies applied in cardiovascular diseases, especially atherosclerosis. Particular attention will be given to recent developments and the role of bioinformatics in data treatment. This review will be of broad interest to the medical community by providing a tutorial of how mass spectrometric strategies can support clinical trials.