Showing papers by "Charité published in 2004"

Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock

Abstract: To develop management guidelines for severe sepsis and septic shock that would be of practical use for the bedside clinician, under the auspices of the Surviving Sepsis Campaign, an international effort to increase awareness and improve outcome in severe sepsis. The process included a modified Delphi method, a consensus conference, several subsequent smaller meetings of subgroups and key individuals, teleconferences, and electronic-based discussion among subgroups and among the entire committee. The modified Delphi methodology used for grading recommendations built upon a 2001 publication sponsored by the International Sepsis Forum. We undertook a systematic review of the literature graded along 5 levels to create recommendation grades from A–E, with A being the highest grade. Pediatric considerations were provided to contrast adult and pediatric management. Participants included 44 critical care and infectious disease experts representing 11 international organizations. A total of 46 recommendations plus pediatric management considerations. Evidence-based recommendations can be made regarding many aspects of the acute management of sepsis and septic shock that will hopefully translate into improved outcomes for the critically ill patient. The impact of these guidelines will be formally tested and guidelines updated annually, and even more rapidly when some important new knowledge becomes available.

Myostatin Mutation Associated with Gross Muscle Hypertrophy in a Child

Abstract: Both acquired and inherited disorders of muscle are common; thus, greater understanding of muscle growth and maintenance is important for future therapies. Myostatin down-regulates muscle growth. These investigators describe a mutation in the gene for myostatin in a child with muscle hypertrophy and unusual strength.

The Collaborative Cross, a community resource for the genetic analysis of complex traits

Abstract: The goal of the Complex Trait Consortium is to promote the development of resources that can be used to understand, treat and ultimately prevent pervasive human diseases. Existing and proposed mouse resources that are optimized to study the actions of isolated genetic loci on a fixed background are less effective for studying intact polygenic networks and interactions among genes, environments, pathogens and other factors. The Collaborative Cross will provide a common reference panel specifically designed for the integrative analysis of complex systems and will change the way we approach human health and disease.

Angiotensin Type 1 Receptor Blockers Induce Peroxisome Proliferator–Activated Receptor-γ Activity

Abstract: Background— Angiotensin type 1 receptor (AT1R) blockers (ARB) have been shown to reduce the incidence of type 2 diabetes mellitus by an unknown molecular mechanism. The peroxisome proliferator–activated receptor-γ (PPARγ) is the central regulator of insulin and glucose metabolism improving insulin sensitivity. We investigated the regulation of PPARγ function by ARBs. Methods and Results— The ARBs irbesartan and telmisartan (10 μmol/L) potently enhanced PPARγ-dependent 3T3-L1 adipocyte differentiation associated with a significant increase in mRNA expression of the adipogenic marker gene adipose protein 2 (aP2), as measured by quantitative real-time polymerase chain reaction (irbesartan: 3.3±0.1-fold induction; telmisartan: 3.1±0.3-fold induction; both P<0.01). Telmisartan showed a more pronounced induction of aP2 expression in lower, pharmacologically relevant concentrations compared with the other ARBs. The ARB losartan enhanced aP2 expression only at high concentrations (losartan 100 μmol/L: 3.6±0.3-fol...

The natural course of atopic dermatitis from birth to age 7 years and the association with asthma.

Abstract: Background Atopic dermatitis (AD) is considered to be one of the first manifestations in the atopic march. However, few prospective studies on AD and its association with childhood asthma exist. Objective The aim of this study was to prospectively investigate the natural course of AD to determine factors influencing its prognosis and to analyze the relationship of AD with childhood asthma. Methods The Multicenter Allergy Study, a German birth cohort, followed 1314 children from birth to age 7 years. Physical examinations, parental interviews on atopic symptoms and diagnoses, and determination of specific IgE levels were performed regularly. Results The cumulative prevalence of AD in the first 2 years of life was 21.5%. Of these children with early AD, 43.2% were in complete remission by age 3 years, 38.3% had an intermittent pattern of disease, and 18.7% had symptoms of AD every year. Severity (adjusted cumulative odds ratio, 5.86; 95% CI, 3.04-11.29) and atopic sensitization (adjusted cumulative odds ratio, 2.76; 95% CI, 1.29-5.91) were major determinants of prognosis. Early wheeze and a specific sensitization pattern were significant predictors for wheezing at school age, irrespective of AD. Early AD without these cofactors constituted no increased risk of subsequent wheeze (adjusted odds ratio, 1.11; 95% CI, 0.56-2.20) or bronchial hyperreactivity. Conclusion AD is a common condition in infancy but disappears around age 3 years in a significant proportion of children. The prognosis is mostly determined by the severity and the presence of atopic sensitization. Early AD is associated with asthma at school age, but in many of these asthmatic children, wheezing manifests before or with the onset of AD. Children with AD and wheeze have a marked loss in lung function, suggesting a distinct phenotype rather than a progressive development from AD to asthma.

Pharmacogenetics of antidepressants and antipsychotics: the contribution of allelic variations to the phenotype of drug response

Abstract: Genetic factors contribute to the phenotype of drug response. We systematically analyzed all available pharmacogenetic data from Medline databases (1970-2003) on the impact that genetic polymorphisms have on positive and adverse reactions to antidepressants and antipsychotics. Additionally, dose adjustments that would compensate for genetically caused differences in blood concentrations were calculated. To study pharmacokinetic effects, data for 36 antidepressants were screened. We found that for 20 of those, data on polymorphic CYP2D6 or CYP2C19 were found and that in 14 drugs such genetic variation would require at least doubling of the dose in extensive metabolizers in comparison to poor metabolizers. Data for 38 antipsychotics were examined: for 13 of those CYP2D6 and CYP2C19 genotype was of relevance. To study the effects of genetic variability on pharmacodynamic pathways, we reviewed 80 clinical studies on polymorphisms in candidate genes, but those did not for the most part reveal significant associations between neurotransmitter receptor and transporter genotypes and therapy response or adverse drug reactions. In addition associations found in one study could not be replicated in other studies. For this reason, it is not yet possible to translate pharmacogenetic parameters fully into therapeutic recommendations. At present, antidepressant and antipsychotic drug responses can best be explained as the combinatorial outcome of complex systems that interact at multiple levels. In spite of these limitations, combinations of polymorphisms in pharmacokinetic and pharmacodynamic pathways of relevance might contribute to identify genotypes associated with best and worst responders and they may also identify susceptibility to adverse drug reactions.

HDL induces NO-dependent vasorelaxation via the lysophospholipid receptor S1P3

Abstract: HDL is a major atheroprotective factor, but the mechanisms underlying this effect are still obscure. HDL binding to scavenger receptor-BI has been shown to activate eNOS, although the responsible HDL entities and signaling pathways have remained enigmatic. Here we show that HDL stimulates NO release in human endothelial cells and induces vasodilation in isolated aortae via intracellular Ca2+ mobilization and Akt-mediated eNOS phosphorylation. The vasoactive effects of HDL could be mimicked by three lysophospholipids present in HDL: sphingosylphosphorylcholine (SPC), sphingosine-1-phosphate (S1P), and lysosulfatide (LSF). All three elevated intracellular Ca2+ concentration and activated Akt and eNOS, which resulted in NO release and vasodilation. Deficiency of the lysophospholipid receptor S1P3 (also known as LPB3 and EDG3) abolished the vasodilatory effects of SPC, S1P, and LSF and reduced the effect of HDL by approximately 60%. In endothelial cells from S1P3-deficient mice, Akt phosphorylation and Ca2+ increase in response to HDL and lysophospholipids were severely reduced. In vivo, intra-arterial administration of HDL or lysophospholipids lowered mean arterial blood pressure in rats. In conclusion, we identify HDL as a carrier of bioactive lysophospholipids that regulate vascular tone via S1P3-mediated NO release. This mechanism may contribute to the vasoactive effect of HDL and represent a novel aspect of its antiatherogenic function.

The BCI competition 2003: progress and perspectives in detection and discrimination of EEG single trials

Abstract: Interest in developing a new method of man-to-machine communication-a brain-computer interface (BCI)-has grown steadily over the past few decades. BCIs create a new communication channel between the brain and an output device by bypassing conventional motor output pathways of nerves and muscles. These systems use signals recorded from the scalp, the surface of the cortex, or from inside the brain to enable users to control a variety of applications including simple word-processing software and orthotics. BCI technology could therefore provide a new communication and control option for individuals who cannot otherwise express their wishes to the outside world. Signal processing and classification methods are essential tools in the development of improved BCI technology. We organized the BCI Competition 2003 to evaluate the current state of the art of these tools. Four laboratories well versed in EEG-based BCI research provided six data sets in a documented format. We made these data sets (i.e., labeled training sets and unlabeled test sets) and their descriptions available on the Internet. The goal in the competition was to maximize the performance measure for the test labels. Researchers worldwide tested their algorithms and competed for the best classification results. This paper describes the six data sets and the results and function of the most successful algorithms.

Developmental stage, phenotype, and migration distinguish naive- and effector/memory-like CD4+ regulatory T cells

Abstract: Regulatory T cells (Tregs) fulfill a central role in immune regulation. We reported previously that the integrin αEβ7 discriminates distinct subsets of murine CD4+ regulatory T cells. Use of this marker has now helped to unravel a fundamental dichotomy among regulatory T cells. αE−CD25+ cells expressed L-selectin and CCR7, enabling recirculation through lymphoid tissues. In contrast, αE-positive subsets (CD25+ and CD25−) displayed an effector/memory phenotype expressing high levels of E/P-selectin–binding ligands, multiple adhesion molecules as well as receptors for inflammatory chemokines, allowing efficient migration into inflamed sites. Accordingly, αE-expressing cells were found to be the most potent suppressors of inflammatory processes in disease models such as antigen-induced arthritis.

Boosting bit rates in noninvasive EEG single-trial classifications by feature combination and multiclass paradigms

Abstract: Noninvasive electroencephalogram (EEG) recordings provide for easy and safe access to human neocortical processes which can be exploited for a brain-computer interface (BCI). At present, however, the use of BCIs is severely limited by low bit-transfer rates. We systematically analyze and develop two recent concepts, both capable of enhancing the information gain from multichannel scalp EEG recordings: 1) the combination of classifiers, each specifically tailored for different physiological phenomena, e.g., slow cortical potential shifts, such as the premovement Bereitschaftspotential or differences in spatio-spectral distributions of brain activity (i.e., focal event-related desynchronizations) and 2) behavioral paradigms inducing the subjects to generate one out of several brain states (multiclass approach) which all bare a distinctive spatio-temporal signature well discriminable in the standard scalp EEG. We derive information-theoretic predictions and demonstrate their relevance in experimental data. We will show that a suitably arranged interaction between these concepts can significantly boost BCI performances.

How to diagnose axial spondyloarthritis early

Abstract: Background: Chronic low back pain (LBP), the leading symptom of ankylosing spondylitis (AS) and undifferentiated axial spondyloarthritis (SpA), precedes the development of radiographic sacroiliitis, sometimes by many years. Objective: To assign disease probabilities and to develop an algorithm to help in the early diagnosis of axial SpA. Methods: Axial SpA comprises AS and undifferentiated SpA with predominant axial involvement. Clinical features include inflammatory back pain (IBP), alternating buttock pain, enthesitis, arthritis, dactylitis, acute anterior uveitis, a positive family history, psoriasis, inflammatory bowel disease, and good response to NSAIDs. Associated laboratory findings include raised acute phase reactions, HLA-B27 association, and abnormalities on skeletal imaging. Sensitivities, specificities, and likelihood ratios (LRs) of these parameters were determined from published studies. A 5% prevalence of axial SpA among patients with chronic LBP was used. The probability of the presence of axial SpA, depending on the presence or absence of the above clinical features of SpA, was determined. A probability of ⩾90% was used to make a diagnosis of axial SpA. Results: The presence of inflammatory back pain features increased the probability of axial SpA from the background 5% prevalence to 14%. The presence of 2–3 SpA features was necessary to increase the probability of axial SpA to 90%. The highest LRs were obtained for HLA-B27 and MRI. Diagnostic algorithms to be used in daily practice were suggested. Conclusions: This approach can help clinicians to diagnose with a high degree of confidence axial SpA at an early stage in patients with IBP who lack radiographic sacroiliitis.

Correlation between dopamine D(2) receptors in the ventral striatum and central processing of alcohol cues and craving.

Abstract: OBJECTIVE: Alcohol and other drugs of abuse stimulate dopamine release in the ventral striatum, which includes the nucleus accumbens, a core region of the brain reward system, and reinforce substance intake. Chronic alcohol intake is associated with down-regulation of central dopamine D2 receptors, and delayed recovery of D2 receptor sensitivity after detoxification is positively correlated with high risk for relapse. Prolonged D2 receptor dysfunction in the ventral striatum may interfere with a dopamine-dependent error detection signal and bias the brain reward system toward excessive attribution of incentive salience to alcohol-associated stimuli. METHOD: Multimodal imaging, with the radioligand [18F]desmethoxyfallypride and positron emission tomography as well as functional magnetic resonance imaging (fMRI), was used to compare 11 detoxified male alcoholics with 13 healthy men. The authors measured the association of D2-like dopamine receptors in the ventral striatum with alcohol craving and central pr...

Cue-induced activation of the striatum and medial prefrontal cortex is associated with subsequent relapse in abstinent alcoholics

Abstract: Animal experiments have provided evidence that the striatum and medial prefrontal cortex play a predominant role in the acquisition and maintenance of drug-seeking behavior. Alcohol-associated stimuli that were regularly paired with alcohol intake may become conditioned cues and elicit a motivational response that triggers relapse in alcohol-dependent patients. We used functional magnetic resonance imaging and visual alcohol-associated and control cues to assess brain activation in ten abstinent alcoholics and control subjects. Patients were followed for 3 months, and alcohol intake was recorded. Alcohol-related versus neutral visual stimuli activated the putamen, anterior cingulate and adjacent medial prefrontal cortex in alcoholics compared with healthy controls. Cue-induced activation of these brain areas was pronounced in the five alcoholics who subsequently relapsed during the observation period. A multiple regression analysis showed that, in alcoholics, the amount of subsequent alcohol intake was associated with the intensity of cue-induced brain activation but not the severity of alcohol craving, amount of previous alcohol intake or duration of abstinence before scanning. This pilot study showed that cue-induced activation of the anterior cingulate, medial prefrontal cortex and striatum may play a role in the attribution of incentive salience to alcohol-associated stimuli, thus increasing the motivational value and attentional processing of alcohol cues. Functional brain imaging may help to identify a group of alcoholics with an otherwise undetected high risk of relapse.

Lasting Blood-Brain Barrier Disruption Induces Epileptic Focus in the Rat Somatosensory Cortex

Abstract: Perturbations in the integrity of the blood-brain barrier have been reported in both humans and animals under numerous pathological conditions. Although the blood-brain barrier prevents the penetration of many blood constituents into the brain extracellular space, the effect of such perturbations on the brain function and their roles in the pathogenesis of cortical diseases are unknown. In this study we established a model for focal disruption of the blood-brain barrier in the rat cortex by direct application of bile salts. Exposure of the cerebral cortex in vivo to bile salts resulted in long-lasting extravasation of serum albumin to the brain extracellular space and was associated with a prominent activation of astrocytes with no inflammatory response or marked cell loss. Using electrophysiological recordings in brain slices we found that a focus of epileptiform discharges developed within 4-7 d after treatment and could be recorded up to 49 d postoperatively in >60% of slices from treated animals but only rarely (10%) in sham-operated controls. Epileptiform activity involved both glutamatergic and GABAergic neurotransmission. Epileptiform activity was also induced by direct cortical application of native serum, denatured serum, or albumin-containing solution. In contrast, perfusion with serum-adapted electrolyte solution did not induce abnormal activity, thereby suggesting that the exposure of the serum-devoid brain environment to serum proteins underlies epileptogenesis in the blood-brain barrier-disrupted cortex. Although many neuropathologies entail a compromised blood-brain barrier, this is the first direct evidence that it may have a role in the pathogenesis of focal cortical epilepsy, a common neurological disease.

Guidelines for the diagnosis and treatment of neuroendocrine gastrointestinal tumours. A consensus statement on behalf of the European Neuroendocrine Tumour Society (ENETS).

Abstract: Guidelines for the diagnosis and treatment of neuroendocrine gastrointestinal tumours. A consensus statement on behalf of the European Neuroendocrine Tumour Society (ENETS).

Short-lived Plasmablasts and Long-lived Plasma Cells Contribute to Chronic Humoral Autoimmunity in NZB/W Mice

Abstract: The current view holds that chronic autoimmune diseases are driven by the continuous activation of autoreactive B and T lymphocytes. However, despite the use of potent immunosuppressive drugs designed to interfere with this activation the production of autoantibodies often persists and contributes to progression of the immunopathology. In the present study, we analyzed the life span of (auto)antibody-secreting cells in the spleens of NZB × NZW F1 (NZB/W) mice, a murine model of systemic lupus erythematosus. The number of splenic ASCs increased in mice aged 1–5 mo and became stable thereafter. Less than 60% of the splenic (auto)antibody-secreting cells were short-lived plasmablasts, whereas 40% were nondividing, long-lived plasma cells with a half-life of >6 mo. In NZB/W mice and D42 Ig heavy chain knock-in mice, a fraction of DNA-specific plasma cells were also long-lived. Although antiproliferative immunosuppressive therapy depleted short-lived plasmablasts, long-lived plasma cells survived and continued to produce (auto)antibodies. Thus, long-lived, autoreactive plasma cells are a relevant target for researchers aiming to develop curative therapies for autoimmune diseases.

Prediction of a major clinical response (BASDAI 50) to tumour necrosis factor α blockers in ankylosing spondylitis

Abstract: Background: TNFα blockers have been shown to be highly efficacious in patients with active ankylosing spondylitis (AS). Objective: To identify parameters predicting the clinical response to TNF blockers in AS. Methods: Patients with active AS participated in two placebo controlled, randomised trials conducted in Germany with infliximab (n = 69) and etanercept (n = 30), respectively. For inclusion in either trial patients had to have high disease activity (BASDAI ⩾4) and a spinal pain score (numerical rating scale 0–10) ⩾4 despite treatment with NSAIDs. A major clinical response was defined as a 50% improvement of the initial BASDAI (BASDAI 50) after 12 weeks’ treatment with active drug. Logistic regression likelihood ratio tests (univariate and multivariate), Student’s t test, and χ 2 tests were performed. Results: Univariate analysis showed the following to be predictors of a major response (BASDAI 50) to treatment: shorter disease duration (p = 0.003); lower BASFI (p = 0.007); younger age (p = 0.009); raised ESR (p = 0.033); raised CRP (p = 0.035). After adjustment for disease duration, BASFI, ESR, and CRP, but not age, remained significantly associated. After adjustment for disease duration and for BASFI, ESR, CRP, and in addition, a higher BASDAI were significantly associated with response. The best multivariate model built by stepwise regression contained the covariables disease duration, BASFI, BASDAI, and CRP. Conclusion: A shorter disease duration, younger age, and a lower BASFI are predictors of a major clinical response to TNF blockers in active AS. Raised CRP and a higher BASDAI may also be valuable predictors. These data need to be confirmed in further studies.

Developmental Exposure to Low-Dose PBDE-99: Effects on Male Fertility and Neurobehavior in Rat Offspring

Abstract: In utero exposure to a single low dose of 2,2′,4,4′,5-pentabromodiphenyl ether (PBDE-99) disrupts neurobehavioral development and causes permanent effects on the rat male reproductive system apparent in adulthood. PBDEs, a class of flame retardants, are widely used in every sector of modern life to prevent fire. They are persistent in the environment, and increasing levels of PBDEs have been found in biota and human breast milk. In the present study we assessed the effects of developmental exposure to one of the most persistent PBDE congeners (PBDE-99) on juvenile basal motor activity levels and adult male reproductive health. Wistar rat dams were treated by gavage on gestation day 6 with a single low dose of 60 or 300 μg PBDE-99/kg body weight (bw). In offspring, basal locomotor activity was evaluated on postnatal days 36 and 71, and reproductive performance was assessed in males at adulthood. The exposure to low-dose PBDE-99 during development caused hyperactivity in the offspring at both time points and permanently impaired spermatogenesis by the means of reduced sperm and spermatid counts. The doses used in this study (60 and 300 μg/kg bw) are relevant to human exposure levels, being approximately 6 and 29 times, respectively, higher than the highest level reported in human breast adipose tissue. This is the lowest dose of PBDE reported to date to have an in vivo toxic effect in rodents and supports the premise that low-dose studies should be encouraged for hazard identification of persistent environmental pollutants.

Microarray immunoassay : association of clinical history, in vitro IgE function, and heterogeneity of allergenic peanut epitopes

Abstract: Background IgE epitope mapping of food allergens is a prerequisite for engineering hypoallergenic immunotherapeutic agents and might reveal basic information regarding a patient's immune response. Mapping of large numbers of epitopes by using individual patient sera has been impractical with current techniques. Objective We sought to develop a peptide microarray-based immunoassay to map peanut epitopes by using microliter quantities of serum. Methods A set of 213 overlapping 20-residue peptides was synthesized corresponding to the primary sequences of Ara h 1, Ara h 2, and Ara h 3. These were arrayed in triplicate along with the corresponding recombinant proteins onto glass slides and used for immunolabeling. Results Seventy-seven patient and 15 control sera were analyzed. The majority of patients (97%) had specific IgE to at least one of the recombinant allergens, and 87% had detectable IgE to sequential epitopes. Microarray mapping correlated well with previous studies. However, the analysis of individual patients revealed remarkable heterogeneity in the number and patterns of epitope recognition. High epitope diversity was found in patients with a history of more severe allergic reactions. Also, sensitization of effector cells with more diverse IgE antibodies conferred greater reactivity to specific allergen. Conclusions The protein microarray immunoassay confirmed that Ara h 1, Ara h 2, and Ara h 3 are major peanut allergens and allows for parallel epitope analysis. This has led to the discovery of an additional important epitope of Ara h 1 and the recognition of a high degree of patient heterogeneity. This qualitative difference in epitope diversity might provide prognostic information about the patient.