A NOD2-NALP1 complex mediates caspase-1-dependent IL-1beta secretion in response to Bacillus anthracis infection and muramyl dipeptide

NOD2, a NOD-like receptor (NLR), is an intracellular sensor of bacterial muramyl dipeptide (MDP) that was suggested to promote secretion of the proinflammatory cytokine IL-1beta. Yet, the molecular mechanism by which NOD2 can stimulate IL-1beta secretion, and its biological significance were heretofore unknown. We found that NOD2 through its N-terminal caspase recruitment domain directly binds and activates caspase-1 to trigger IL-1beta processing and secretion in MDP-stimulated macrophages, whereas the C-terminal leucine-rich repeats of NOD2 prevent caspase-1 activation in nonstimulated cells. MDP challenge induces the association of NOD2 with another NLR protein, NALP1, and gel filtration analysis revealed the formation of a complex consisting of NOD2, NALP1, and caspase-1. Importantly, Bacillus anthracis infection induces IL-1beta secretion in a manner that depended on caspase-1 and NOD2. In vitro, Anthrax lethal toxin strongly potentiated IL-1beta secretion, and that response was NOD2 and caspase-1-dependent. Thus, NOD2 plays a key role in the B. anthracis-induced inflammatory response by being a critical mediator of IL-1beta secretion.     

Upper extremity deep venous thrombosis

PURPOSE: To determine the prevalence of symptomatic upper extremity deep venous thrombosis (DVT) and its association with symptomatic acute pulmonary embolism (PE) in a community teaching hospital. METHODS: The prevalence of symptomatic upper extremity DVT was evaluated retrospectively at a community teaching hospital during the 2-year period between July 1, 1998, and June 30, 2000. Patients were identified by International Classification of Disease, ninth revision, clinical modification, discharge codes and a review of the records of all compression Doppler ultrasonograms, venograms of the upper extremities, and magnetic resonance angiograms of the upper extremities. RESULTS: Symptomatic upper extremity DVT was diagnosed in 65 of 44,136 patients of all ages (0.15%) [or 64 of 34,567 adult patients >or= 20 years of age; 0.19%]. In seven patients, the upper extremity DVT was shown by venography to extend proximally to the brachiocephalic vein. Among these, the DVT extended to the superior vena cava in two. All of the patients received anticoagulant therapy for upper extremity DVT. No patients developed symptomatic PE. Central lines at the site of the upper extremity DVT were inserted in 39 of 65 patients (60%). Cancer was diagnosed in 30 of 65 patients (46%), 23 cancer patients also had central lines, and 19 patients (29%) had upper extremity DVT with no apparent cause. All patients had swelling of the upper extremities. Erythema over the affected site was present in four patients (6%). Pain was present in 26 patients (40%), although some discomfort due to swelling was present in all patients. CONCLUSION: Symptomatic upper extremity DVT is not uncommon in hospitalized patients. Symptomatic PE resulting from upper extremity DVT was not observed in these patients, all of whom were treated with anticoagulants.     

Endogenous selective inhibitors of 11beta-hydroxysteroid dehydrogenase isoforms 1 and 2 of adrenal origin

In earlier studies [Latif, S.A., Sheff, M.F., Ribeiro, C.E., Morris, D.J., 1997. Selective inhibition of sheep kidney 11beta-hydroxysteroid-dehydrogenase isoform 2 activity by 5alpha-reduced (but not 5beta) derivatives of adrenocorticosteroids. Steroids 62, 230-237], only derivatives of steroid hormones possessing the 5alpha-Ring A-reduced configuration selectively inhibited 11beta-HSD2-dehydrogenase, whereas their 5beta-derivatives were inactive. This present study focuses on an expanded group of endogenous 11-oxygenated, 5alpha and 5beta-Ring A-reduced metabolites of adrenocorticosteroids, and progestogen and androgen steroid hormones. These substances were tested for their inhibitory properties against 11beta-HSD2, 11beta-HSD1-dehydrogenase and 11beta-HSD1 reductase. The present studies showed that the following compounds stand out as potent inhibitors. These are 5alpha-DH-corticosterone, 3alpha,5alpha-TH-corticosterone, 11beta-OH-progesterone, 11beta-OH-allopregnanolone, 11beta-OH-testosterone, and 11beta-OH-androstanediol, inhibitors of 11beta-HSD1-dehydrogenase; 3alpha,5alpha-TH-11-dehydro-corticosterone, 11-keto-progesterone, 11-keto-allopregnanolone, and 11-keto-3beta,5alpha-TH-testosterone, inhibitors of 11beta-HSD1 reductase; 3alpha,5alpha-TH-aldosterone, 5alpha-DH-corticosterone, 3alpha,5alpha-TH-corticosterone,11-dehydro-corticosterone, 3alpha,5alpha-TH-11-dehydro-corticosterone, 11beta-OH-progesterone, 11-keto-progesterone, 11beta-OH-allopregnanolone, 11-keto-allopregnanolone, 11beta-OH-testosterone, and 11-keto-testosterone, inhibitors of 11beta-HSD2. All of these substances have the potential to be derived from adrenally synthesized corticosteroids. Substances with similar structures to those described may help in the design of exogenous agents for the management of a variety of disease states involving 11beta-HSD isoenzymes.     

Prognostic factors in allogeneic transplantation for patients with high-risk multiple myeloma after reduced intensity conditioning

OBJECTIVES: The aim of this study was to identify prognostic factors for outcome of high-risk patients with multiple myeloma after allogeneic transplantation prepared by reduced intensity conditioning (RIC). MATERIALS AND METHODS: Data from 45 consecutive patients (median age 52 years, range 38-68), who received grafts from a sibling (n = 34) or unrelated donor (n = 11) were analyzed. Fourteen patients received an RIC allotransplant while chemosensitive (>/=partial remission [PR]), whereas 31 chemoresistant patients (相似文献   

Treatment of osteoporosis: facing the challenges in the Asia‐Pacific

The prevalence of osteoporosis and fractures is projected to increase rapidly in the Asia‐Pacific region in coming decades. At the societal level, healthcare providers will face the challenges of paucity of information, lack of awareness among physicians, resource constraints, lack of organization, absence of policies of cost reimbursement, insufficient representation of the problem in curricula and lack of effective, inexpensive and convenient therapy. Poverty, illiteracy, lack of awareness and interest in future quality of life, and co‐morbidities with seemingly greater importance, will all act as challenges at the level of individual patients. Lack of compliance is a function of lack of awareness and motivation, cost, complexity of administration, side‐effects and absence of immediately perceivable benefit. The challenges may be overcome through systematic collection of data, formation or activation of national osteoporosis planning and coordinating groups, development of national guidelines, programs of education of healthcare providers, patients and the general public, adoption of a population‐based prevention strategy, cost‐effective opportunistic screening using clinical decision rules like the osteoporosis self‐assessment tool for Asians, use of the fracture risk assessment tool for therapeutic decision‐making, giving due emphasis to the problem in curricula and development of mechanisms for cost reimbursement. The Asia‐Pacific League of Associations for Rheumatology may take a lead in stimulating, organizing and coordinating these activities.     

VE1 immunohistochemistry is an adjunct tool for detection of BRAF V600E mutation: Validation in thyroid cancer patients

Papillary thyroid carcinoma (PTC) is the most common endocrine malignancy among other endocrine tumors, and BRAF ^V600E is a frequent genetic mutation occurring in the disease. Although different molecular techniques, most importantly sequencing has been widely recognized as a gold standard but molecular diagnosis remains an expensive, laborious, and time‐intensive process. Recently, immunohistochemistry (IHC) with anti‐BRAF V600E (VE1) antibody has increased practical utility and implemented clinically for the detection of BRAF ^V600E mutation. Therefore, the study aimed to evaluate diagnostic accuracy of VE1 IHC for detecting the BRAF ^V600E mutation frequency and clinical implementation in diagnostic laboratories. In this study, 72 formalin fixed paraffin‐embedded tissues (FFPE) were used to determine the BRAF ^V600E mutation status using IHC and Sanger sequencing. The mutation was found in 29% and 28% cases using IHC and Sanger sequencing, respectively. Furthermore, the results showed 100% sensitivity, 98.07% specificity, 95.2% positive predictive value, and 100% negative predictive value. Notably, significant associations were found between BRAF ^V600E status and tumor stage, tumor focality, and extrathyroidal extensions, respectively. VE1 IHC was found to be a highly sensitive, specific, and diagnostically accurate method in this cohort. Therefore, BRAF ^V600E detection through IHC has been considered as the best tailored technique for routine pathology laboratories.     

Radiographic clues to the unstable knee: are findings of trochlear dysplasia on lateral knee radiographs reliable and predictive of patellar dislocation?

Emergency Radiology - Trochlear dysplasia (TD) is a key predisposing risk factor for patellar instability (PI) and lateral patellar dislocation (LPD) injuries. It is useful to understand the...     

Diagnosis and surgical treatment of non-lesional temporal lobe epilepsy with unilateral amygdala enlargement

Neurological Sciences - Exploring the role of amygdala enlargement (AE) in temporal lobe epilepsy (TLE) without ipsilateral mesial temporal sclerosis (MTS) using comprehensive presurgical workup...