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...     

Aberrant retropharyngeal (submucosal) internal carotid artery: an under-recognized, clinically significant variant

We present a case of a 71-year-old woman who was incidentally found to have aberrant retropharyngeal internal carotid artery, lying very close to the pharyngeal mucosa, on imaging. Radiologists, otolaryngologists and anaesthetists should be aware of this clinically significant variant which can result in life-threatening bleeding during procedures in the oral cavity or oropharynx.     

Joint ESCMID,FEMS, IDSA,ISID and SSI position paper on the fair handling of career breaks among physicians and scientists when assessing eligibility for early-career awards

BackgroundThough women increasingly make up the majority of medical-school and other science graduates, they remain a minority in academic biomedical settings, where they are less likely to hold leadership positions or be awarded research funding. A major factor is the career breaks that women disproportionately take to see to familial duties. They experience a related, but overlooked, hurdle upon their return: they are often too old to be eligible for ‘early-career researcher’ grants and ‘career-development’ awards, which are stepping stones to leadership positions in many institutions and which determine the demographics of their hierarchies for decades to come. Though age limits are imposed to protect young applicants from more experienced seniors, they have an unintended side effect of excluding returning workers, still disproportionately women, from the running.MethodsIn this joint effort by the European Society of Clinical Microbiology and Infectious Diseases, the Federation of European Microbiological Societies, the Infectious Disease Society of America, the International Society for Infectious Diseases and the Swiss Society for Infectious Diseases, we invited all European Congress of Clinical Microbiology and Infectious Diseases-affiliated medical societies and funding bodies to participate in a survey on current ‘early-career’ application restrictions and measures taken to provide protections for career breaks.RecommendationsThe following simple consensus recommendations are geared to funding bodies, academic societies and other organizations for the fair handling of eligibility for early-career awards: 1. Apply a professional, not physiological, age limit to applicants. 2. State clearly in the award announcement that career breaks will be factored into applicants' evaluations such that: ? Time absent is time extended: for every full-time equivalent of career break taken, the same full-time equivalent will be extended to the professional age limit. ? Opportunity costs will also be taken into account: people who take career breaks risk additional opportunity costs, with work that they did before the career break often being forgotten or poorly documented, particularly in bibliometric accounting. Although there is no standardized metric to measure additional opportunity costs, organizations should (a) keep in mind their existence when judging applicants' submissions, and (b) note clearly in the award announcement that opportunity costs of career breaks are also taken into account. 3. State clearly that further considerations can be undertaken, using more individualized criteria that are specific to the applicant population and the award in question.The working group welcomes feedback so that these recommendations can be improved and updated as needed.