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Treatment of Enterohemorrhagic E. coli (EHEC) infection and Hemolytic Uremic Syndrome (HUS)
Verotoxigenic E. coli (VTEC) are a specialised group of E. coli, that cause severe colonic disease and renal failure. Their pathogenicity derives from virulence factors which enable the bacteria to colonise the colon and deliver extremely powerful toxins known as verotoxins (VT) or Shiga toxins (Stx) to the systemic circulation. The recent devastating E. coli O104:H4 epidemic in Europe has shown how helpless we are in terms of offering effective therapies. By examining the sources and distribution of these bacteria, and how they cause disease , we will be in better shape to prevent and treat the inevitable future cases of sporadic disease and victims of common-source outbreaks. Due to the complexity of pathogenesis, it is likely a multi-targeted approach is warranted. Developments in terms these treatments are discussed.See related article: http://www.biomedcentral.com/1741-7015/10/11
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Outbreaks of virulent diarrhoeagenic Escherichia coli - are we in control?
Shiga toxin-producing E. coli (STEC) are the most virulent diarrhoeagenic E. coli known to date. They can be spread with alarming ease via food as exemplified by a large sprout-borne outbreak of STEC O104:H4 in 2011 that was centered in northern Germany and affected several countries. Effective control of such outbreaks is an important public health task and necessitates early outbreak detection, fast identification of the outbreak vehicle and immediate removal of the suspected food from the market, flanked with consumer advice and measures to prevent secondary spread.In our view, opportunities to improve control of STEC outbreaks lie in early clinical suspicion for STEC infection, timely diagnosis of all STEC at the serotype-level and integrating molecular subtyping information into surveillance systems. Furthermore, conducting analytic studies that supplement patients' imperfect food history recall and performing, as an investigative element, product tracebacks, are pivotal but underutilised tools for successful epidemiologic identification of the suspected vehicle in food-borne outbreaks. As a corollary, these tools are amenable to tailor microbiological testing of suspected food.Please see related article: http://www.biomedcentral.com/1741-7015/10/12
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Cost -effectiveness analysis for clinicians.
In a climate of economic uncertainty, cost effectiveness analysis is a potentially important tool for making choices about health care interventions. Methods for such analyses are well established, but the results need to be interpreted carefully and are subject to bias. Making decisions based on results of cost-effectiveness analyses can involve setting thresholds, but for individual patients, there needs to be disaggregation of benefits and harms included in a quality adjusted life year to ensure appropriate consideration of benefits and harms as well as personal preferences and circumstances.
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Diindolylmethane suppresses ovarian cancer growth and potentiates the effect of cisplatin in tumor mouse model by targeting signal transducer and activator of transcription 3 (STAT3)
Background:
STAT-3 is activated in majority of ovarian tumors and confers resistance to cisplatin treatment in patients with ovarian cancer. We have reported previously that Diindolylmethane (DIM) inhibits the growth of ovarian cancer cells. However, the exact mechanism by which DIM induces growth suppressive effects was not yet understood and hence evaluated in this report.
Methods:
Six human ovarian cancer cells and ovarian tumor xenograft animal model were used to study the effect of diindolylmethane alone or in combination of cisplatin.
Results:
Diindolylmethane treatment induced apoptosis in all the six ovarian cancer cells. Phosphorylation of STAT3 at Tyr-705 and Ser-727 was reduced by DIM in a concentration-dependent manner. In addition, diindolylmethane treatment inhibited nuclear translocation, DNA binding, and transcriptional activity of STAT3. IL-6-induced phosphorylation of STAT3 at Tyr-705 was significantly blocked by DIM. Overexpression of STAT3 by gene transfection blocked DIM-induced apoptosis. In addition, diindolylmethane treatment reduced the levels of IL-6 in ovarian cancer cells and in the tumors. Diindolylmethane treatment also inhibited cell invasion and angiogenesis by suppressing HIF-1alpha and VEGF. Importantly, diindolylmethane treatment potentiated the effects of cisplatin in SKOV-3 cells by targeting STAT3. Oral administration of 3 mg diindolylmethane per day and subsequent administration of cisplatin substantially inhibited in vivo tumor growth. Western blotting analysis of tumor lysates indicated increased apoptosis and reduced STAT3 activation.
Conclusion:
These findings provide a rationale for further clinical investigation of diindolylmethane alone or in combination for chemoprevention and/or chemotherapy of ovarian cancer.
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Clinical evaluation of iron treatment efficiency among non-anemic but iron-deficient female blood donors:
a randomized controlled trial
Iron deficiency without anemia (IDWA) is related to adverse symptoms that can be relieved by supplementation. Since a blood donation can induce such an iron deficiency, we investigated the clinical impact of an iron treatment after blood donation.
Methods:
One week after donation, we randomly assigned 154 female donors with IDWA aged <50 years to a 4-week oral treatment of ferrous sulfate vs. placebo. The main outcome was the change in the level of fatigue before and after the intervention. Also evaluated were aerobic capacity, mood disorder, quality of life, compliance and adverse events. Biological markers were hemoglobin and ferritin.
Results:
Treatment effect from baseline to 4 weeks for hemoglobin and ferritin were 5.2 g/L (p < 0.01) and 14.8 ng/mL (p < 0.01) respectively. No significant clinical effect was observed for fatigue (-0.15 points, 95% confidence interval -0.9 to 0.6, p = 0.697) or for other outcomes. Compliance and interruption for side effects was similar in both groups. Additionally, blood donation did not induce overt symptoms of fatigue in spite of the significant biological changes it produces.
Conclusions:
These data are valuable as they enable us to conclude that donors with IDWA after a blood donation would not clinically benefit from iron supplementation.Trial registration: NCT00689793
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The role of copeptin as a diagnostic and prognostic biomarker for risk stratification in the emergency department
In response to stress, the hypothalamo-pituitary-adrenal axis is activated. One of the hypothalamic hormones that are activated by stress is Arginine vasopressin (AVP). Copeptin, the C-terminal part of the Arginine vasopressin precursor peptide, is a sensitive and stable surrogate marker for AVP release, a hormone involved in hemodynamics and osmoregulation. Measurement of Copeptin levels has been shown to be useful in a variety of clinical scenarios, particularly as a prognostic marker in patients with acute diseases such as lower respiratory tract infection, heart disease, and stroke. The measurement of copeptin levels may provide crucial information for risk stratification in a variety of clinical situations. As such, the emergency department appears to be the ideal setting for its potential use. This review summarizes the recent progress towards determining the prognostic and diagnostic value of copeptin in the emergency department.
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Systematic review and meta-analysis of the value of initial biomarkers in predicting adverse outcome in febrile neutropenic episodes in children and young people with cancer
Background:
Febrile neutropenia is a frequently occurring and occasionally life-threatening complication of treatment for childhood cancer. Many biomarkers have been proposed as predictors of adverse events. We aimed to undertake a systematic review and meta-analysis to summarise evidence on the discriminatory ability of initial serum biomarkers of febrile neutropenic episodes in children and young people.
Methods:
The review was conducted in accordance with Centre for Reviews and Dissemination methods, using three random effects models to undertake meta-analysis. It was registered with the HTA Registry of systematic reviews, CRD32009100485.
Results:
We found 25 studies exploring 14 different biomarkers assessed in 3585 episodes of FNP. CRP, PCT, and IL6 were subject to quantitative meta-analysis, and these revealed huge inconsistencies and heterogeneity in the studies included. Only CRP has been evaluated in assessing its' value over the predictive value of simple clinical decision rules.
Conclusions:
The limited data available describing the predictive value of biomarkers in the setting of paediatric febrile neutropenia mean firm conclusions can yet be reached, although the use of IL6, IL8 and procalcitonin warrant further study.
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Towards a genuinely medical model for psychiatric nosology
Psychiatric nosology is widely criticized, but solutions are proving elusive. Planned revisions of diagnostic criteria will not resolve heterogeneity, comorbidity, fuzzy boundaries between normal and pathological, and lack of specific biomarkers. Concern about these difficulties reflects a narrow model that assumes most mental disorders should be defined by their etiologies. A more genuinely medical model uses understanding of normal function to categorize pathologies. For instance, understanding the function of cough guides the search for problems arousing it, and decisions about when it is expressed abnormally. Understanding the functions of emotions is a foundation missing from decisions about emotional disorders. The broader medical model used by the rest of medicine also recognizes syndromes defined by failures of functional systems or failures of feedback control. Such medical syndromes are similar to many mental disorders in their multiple causes, blurry boundaries, and nonspecific biomarkers. Dissatisfaction with psychiatric nosology may best be alleviated not by new diagnostic criteria and categories, but by more realistic acknowledgment of the untidy landscape of mental and other medical disorders.
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Frailty in primary care: a review of its conceptualization and implications for practice
Frail, older patients pose a challenge to the primary care physician who may often feel overwhelmed by their complex presentation and tenuous health status. At the same time, family physicians are ideally suited to incorporate the concept of frailty into their practice. They have the propensity and skill set that lends itself to patient-centred care, taking into account the individual subtleties of the patient's health within their social context. Tools to identify frailty in the primary care setting are still in the preliminary stages of development. Even so, some practical measures can be taken to recognize frailty in clinical practice and begin to address how its recognition may impact clinical care. This review seeks to address how frailty is recognised and managed, especially in the realm of primary care.
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Reversal of type 1 diabetes via islet beta cell regeneration following immune modulation by cord blood-derived multipotent stem cells
Background:
Inability to control autoimmunity is the primary barrier to developing a cure for type 1 diabetes (T1D). Evidence that human cord blood-derived multipotent stem cells (CB-SCs) can control autoimmune responses by altering regulatory T cells (Tregs) and human islet beta cell-specific T cell clones offers promise for a new approach to overcome the autoimmunity underlying T1D.
Methods:
We developed a procedure for Stem Cell Educator therapy in which a patient's blood is circulated through a closed-loop system that separate lymphocytes from the whole blood and briefly co-cultures them with adherent CB-SCs before returning them to the patient's circulation. In an open-label, phase1/phase 2 study, patients (n = 15) with T1D received one treatment with the Stem Cell Educator. Median age was 29 years (range, 15 to 41), and median diabetic history was 8 years (range, 1 to 21).
Results:
Stem Cell Educator therapy was well tolerated in all participants with minimal pain from two venipunctures and no adverse events. Stem Cell Educator therapy can markedly improve C-peptide levels, reduce the median glycated hemoglobin A1C (HbA1C) values, and decrease the median daily dose of insulin in patients with some residual beta cell function (n = 6) and patients with no residual pancreatic islet beta cell function (n = 6). Treatment also produced an increase in basal and glucose-stimulated C-peptide levels through 40 weeks. However, participants in the Control Group (n = 3) did not exhibit significant change at any follow-up. Individuals who received Stem Cell Educator therapy exhibited increased expression of costimulating molecules (specifically, CD28 and ICOS), increases in the number of CD4+CD25+Foxp3+ Tregs, and restoration of Th1/Th2/Th3 cytokine balance.
Conclusions:
Stem Cell Educator therapy is safe, and in individuals with moderate or severe T1D, a single treatment produces lasting improvement in metabolic control. Initial results indicate Stem Cell Educator therapy reverses autoimmunity and promotes regeneration of islet beta cells. Successful immune modulation by CB-SCs and the resulting clinical improvement in patient status may have important implications for other autoimmune and inflammation-related diseases without the safety and ethical concerns associated with conventional stem cell-based approaches.Trial registration: ClinicalTrials.gov number, NCT01350219.
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