Both, toxin A and toxin B, are important in Clostridium difficile infection

The bacterium Clostridium difficile is the leading cause of healthcare associated diarrhoea in the developed world and thus presents a major financial burden. The main virulence factors of C. difficile are two large toxins, A and B. Over the years there has been some debate over the respective roles and importance of these two toxins. To address this, we recently constructed stable toxin mutants of C. difficile and found that they were virulent if either toxin A or toxin B was functional. This underlined the importance of each toxin and the necessity to consider both when developing countermeasures against Clostridium difficile infection (CDI). In this article we discuss our findings in the context of previous work and outline some of the challenges which face the field as a result.Key words: Clostridium difficile, toxin A, toxin B, Clostridium difficile infection (CDI)     

Flow‐sensitive four‐dimensional cine magnetic resonance imaging for offline blood flow quantification in multiple vessels: A validation study

Purpose:

To further validate the quantitative use of flow‐sensitive four‐dimensional velocity encoded cine magnetic resonance imaging (4D VEC MRI) for simultaneously acquired venous and arterial blood flow in healthy volunteers and for abnormal flow in patients with congenital heart disease.

Materials and Methods:

Stroke volumes (SV) obtained in arterial and venous thoracic vessels were compared between standard two‐dimensional (2D), 4D VEC MRI with and without respiratory navigator gating (gated/nongated) in volunteers (n = 7). In addition, SV and regurgitation fractions (RF) measured in aorta or pulmonary trunk of patients with malformed and/or insufficient valves (n = 10) were compared between 2D and nongated 4D VEC MRI methods.

Results:

In volunteers and patients, Bland–Altman tests showed excellent agreement between 2D, gated, and nongated 4D VEC MRI obtained quantitative blood flow measurements. The bias between 2D and gated 4D VEC MRI was <0.5 mL for SV; between 2D and nongated 4D VEC MRI the bias was <0.7 mL for SV and <1% for RF.

Conclusion:

Blood flow can be quantified accurately in arterial, venous, and pathological flow conditions using 4D VEC MRI. Nongated 4D VEC MRI has the potential to be suited for clinical use in patients with congenital heart disease who require flow acquisitions in multiple vessels. J. Magn. Reson. Imaging 2010;32:677–683. © 2010 Wiley‐Liss, Inc.     

Pattern response of dendritic cells in the tumor microenvironment and breast cancer

Breast cancer (BC) is the most common malignant neoplasm and the cause of death by cancer among women worldwide. Its development, including malignancy grade and patient prognosis, is influenced by various mutations that occur in the tumor cell and by the immune system’s status, which has a direct influence on the tumor microenvironment and, consequently, on interactions with non-tumor cells involved in the immunological response. Among the immune response cells, dendritic cells (DCs) play a key role in the induction and maintenance of anti-tumor responses owing to their unique abilities for antigen cross-presentation and promotion of the activation of specific lymphocytes that target neoplasic cells. However, the tumor microenvironment can polarize DCs, transforming them into immunosuppressive regulatory DCs, a tolerogenic phenotype which limits the activity of effector T cells and supports tumor growth and progression. Various factors and signaling pathways have been implicated in the immunosuppressive functioning of DCs in cancer, and researchers are working on resolving processes that can circumvent tumor escape and developing viable therapeutic interventions to prevent or reverse the expression of immunosuppressive DCs in the tumor microenvironment. A better understanding of the pattern of DC response in patients with BC is fundamental to the development of specific therapeutic approaches to enable DCs to function properly. Various studies examining DCs immunotherapy have demonstrated its great potential for inducing immune responses to specific antigens and thereby reversing immunosuppression and related to clinical response in patients with BC. DC-based immunotherapy research has led to immense scientific advances, both in our understanding of the anti-tumor immune response and for the treatment of these patients.     

Four‐dimensional velocity‐encoded magnetic resonance imaging improves blood flow quantification in patients with complex accelerated flow

Purpose:

To evaluate the use of four‐dimensional (4D) velocity‐encoded magnetic resonance imaging (VEC MRI) for blood flow quantification in patients with semilunar valve stenosis and complex accelerated flow.

Materials and Methods:

Peak velocities (Vmax) and stroke volumes (SV) were quantified by 2D and 4D VEC MRI in volunteers (n = 7) and patients with semilunar valve stenosis (n = 18). Measurements were performed above the aortic and pulmonary valve with both techniques and, additionally, at multiple predefined planes in the ascending aorta and in the pulmonary trunk within the 4D dataset. In patients, 4D VEC MRI streamline analysis identified flow patterns and regions of highest flow velocity (4D_{max‐targeted}) for further measurements and Vmax was also measured by Doppler‐echocardiography.

Results:

In patients, 4D VEC MRI showed higher Vmax than 2D VEC MRI (2.7 ± 0.6 m/s vs. 2.4 ± 0.5 m/s, P < 0.03) and was more comparable to Doppler‐echocardiography (2.8 ± 0.7 m/s). 4D_{max‐targeted} revealed highest Vmax values (3.1 ± 0.6 m/s). SV measurements showed significant differences between different anatomical levels in the ascending aorta in patients with complex accelerated flow, whereas differences in volunteers with laminar flow patterns were negligible (P = 0.004).

Conclusion:

4D VEC MRI improves MRI‐derived blood flow quantification in patients with semilunar valve stenosis and complex accelerated flow. J. Magn. Reson. Imaging 2013;37:208–216. © 2012 Wiley Periodicals, Inc.     

Steroidogenesis in the adrenal dysfunction of critical illness: impact of etomidate

ABSTRACT: INTRODUCTION: This study was aimed at characterizing basal and adrenocorticotropic hormone (ACTH)-induced steroidogenesis in sepsis and nonsepsis patients with a suspicion of critical illness-related corticosteroid insufficiency (CIRCI), taking the use of etomidate-inhibiting 11β-hydroxylase into account. METHOD: This was a prospective study in a mixed surgical/medical intensive care unit (ICU) of a university hospital. The patients were 62 critically ill patients with a clinical suspicion of CIRCI. The patients underwent a 250-μg ACTH test (n = 67). ACTH, adrenal steroids, substrates, and precursors (modified tandem mass spectrometry) also were measured. Clinical characteristics including use of etomidate to facilitate intubation (n = 14 within 72 hours of ACTH testing) were recorded. RESULTS: At the time of ACTH testing, patients had septic (n = 43) or nonseptic critical illness (n = 24). Baseline cortisol directly related to sepsis and endogenous ACTH, independent of etomidate use. Etomidate was associated with a lower baseline cortisol and cortisol/11β-deoxycortisol ratio as well as higher 11β-deoxycortisol, reflecting greater 11β-hydroxylase inhibition in nonsepsis than in sepsis. Cortisol increases < 250 mM in exogenous ACTH were associated with relatively low baseline (HDL-) cholesterol, and high endogenous ACTH with low cortisol/ACTH ratio, independent of etomidate. Although cortisol increases with exogenous ACTH, levels were lower in sepsis than in nonsepsis patients, and etomidate was associated with diminished increases in cortisol with exogenous ACTH, so that its use increased, albeit nonsignificantly, low cortisol increases to exogenous ACTH from 38% to 57%, in both conditions. CONCLUSIONS: A single dose of etomidate may attenuate stimulated more than basal cortisol synthesis. However, it may only partly contribute, particularly in the stressed sepsis patient, to the adrenal dysfunction of CIRCI, in addition to substrate deficiency.     

010 中年男性广泛性缺血性心脏病的自然病程

从英国24家综合医疗机构随机抽取年龄为40～59岁的7 735例病人(均为男性),依据调查表和心电图结果分为以下7个病组：Ⅰ组：已确诊的心肌梗死病人;Ⅱ组：隐匿性心肌梗死病人;Ⅲ组：已确诊的心绞痛病人;Ⅳ组：有心绞痛症侯群的病人;V组：有可疑心肌梗死症侯群的病人;Ⅵ组：心电图示心肌缺血或可能心肌梗死的病人,Ⅶ组：无缺血性心脏病(IHD)证据的病人。对以上各组病人进行15年随访,将这期间调查对象发生的一系列致命及非致命的并发症分别与相应病组加以联系评估。     

Targeted gene disruption reveals a leptin-independent role for the mouse beta3-adrenoceptor in the regulation of body composition.

Recombinant adenoviruses (Ads) efficiently transfer foreign genes into hepatocytes in vivo, but the duration of transgene expression is limited by the host immune response which precludes gene expression upon readministration of the virus. To test if this immune response can be abrogated by oral tolerization, we instilled protein extracts of a recombinant adenovirus type-5 via gastroduodenostomy tubes into bilirubin-UDP-glucuronosyltransferase-1 (BUGT1)-deficient jaundiced Gunn rats. Control rats received BSA. Subsequent intravenous injection 5 x 10(9) pfu of a recombinant adenovirus-expressing human BUGT1 (Ad-hBUGT1) resulted in hepatic expression of human BUGT1 (hBUGT1) with reduction of serum bilirubin levels by 70%. After 2 mo serum bilirubin increased gradually. In orally tolerized rats, but not in controls, a second dose of the virus on day 98 markedly reduced serum bilirubin again. In the tolerized rats, the development of antiadenoviral neutralizing antibodies and cytotoxic lymphocytes were markedly inhibited, and transplantation of their splenocytes into naive Gunn rats adoptively transferred the tolerance, indicating a role for regulatory cells. Lymphocytes from the tolerized rats hyperexpressed TGFbeta1, IL2, and IL4 upon exposure to viral antigens, whereas IFNgamma expression became undetectable. Thus, oral tolerization with adenoviral antigens permits long-term gene expression by repeated injections of recombinant adenoviruses.