Pediatric Cushing disease: disparities in disease severity and outcomes in the Hispanic and African-American populations.

BackgroundLittle is known about the contribution of racial and socioeconomic disparities to severity and outcomes in children with Cushing disease (CD).MethodsA total of 129 children with CD, 45 Hispanic/Latino or African-American (HI/AA) and 84 non-Hispanic White (non-HW), were included in this study. A 10-point index for rating severity (CD severity) incorporated the degree of hypercortisolemia, glucose tolerance, hypertension, anthropomorphic measurements, disease duration, and tumor characteristics. Race, ethnicity, age, gender, local obesity prevalence, estimated median income, and access to care were assessed in regression analyses of CD severity.ResultsThe mean CD severity in the HI/AA group was worse than that in the non-HW group (4.9±2.0 vs. 4.1±1.9, P=0.023); driving factors included higher cortisol levels and larger tumor size. Multiple regression models confirmed that race (P=0.027) and older age (P=0.014) were the most important predictors of worse CD severity. When followed up a median of 2.3 years after surgery, the relative risk for persistent CD combined with recurrence was 2.8 times higher in the HI/AA group compared with that in the non-HW group (95% confidence interval: 1.2-6.5).ConclusionOur data show that the driving forces for the discrepancy in severity of CD are older age and race/ethnicity. Importantly, the risk for persistent and recurrent CD was higher in minority children

Characterisation of feline renal cortical fibroblast cultures and their transcriptional response to transforming growth factor beta 1

Chronic kidney disease (CKD) is common in geriatric cats, and the most prevalent pathology is chronic tubulointerstitial inflammation and fibrosis. The cell type predominantly responsible for the production of extra-cellular matrix in renal fibrosis is the myofibroblast, and fibroblast to myofibroblast differentiation is probably a crucial event. The cytokine TGF-β1 is reportedly the most important regulator of myofibroblastic differentiation in other species. The aim of this study was to isolate and characterise renal fibroblasts from cadaverous kidney tissue of cats with and without CKD, and to investigate the transcriptional response to TGF-β1

A recurrent mosaic mutation of SMO, encoding the hedgehog signal transducer smoothened, is the major cause of Curry-Jones syndrome

Curry-Jones syndrome (CJS) is a multisystem disorder characterized by patchy skin lesions, polysyndactyly, diverse cerebral malformations, unicoronal craniosynostosis, iris colobomas, microphthalmia, and intestinal malrotation with myofibromas or hamartomas. Cerebellar medulloblastoma has been described in a single affected individual; in another, biopsy of skin lesions showed features of trichoblastoma. The combination of asymmetric clinical features, patchy skin manifestations, and neoplastic association previously led to the suggestion that this could be a mosaic condition, possibly involving hedgehog (Hh) signaling. Here, we show that CJS is caused by recurrent somatic mosaicism for a nonsynonymous variant in SMO (c.1234C>T [p.Leu412Phe]), encoding smoothened (SMO), a G-protein-coupled receptor that transduces Hh signaling. We identified eight mutation-positive individuals (two of whom had not been reported previously) with highly similar phenotypes and demonstrated varying amounts of the mutant allele in different tissues. We present detailed findings from brain MRI in three mutation-positive individuals. Somatic SMO mutations that result in constitutive activation have been described in several tumors, including medulloblastoma, ameloblastoma, and basal cell carcinoma. Strikingly, the most common of these mutations is the identical nonsynonymous variant encoding p.Leu412Phe. Furthermore, this substitution has been shown to activate SMO in the absence of Hh signaling, providing an explanation for tumor development in CJS. This raises therapeutic possibilities for using recently generated Hh-pathway inhibitors. In summary, our work uncovers the major genetic cause of CJS and illustrates strategies for gene discovery in the context of low-level tissue-specific somatic mosaicism

Adjuvant trastuzumab in the treatment of her-2-positive early breast cancer: a meta-analysis of published randomized trials

<p>Abstract</p> <p>Background</p> <p>Breast cancer is the most common cancer in women in the U.S. and Western Europe. Amplification of the her-2/neu gene occurs in approximately 25% of invasive ductal carcinomas of the breast. The first HER-2/neu-targeted approach to reach the clinic was trastuzumab, a humanized monoclonal antibody directed against the extracellular domain of the HER-2/neu protein. Trastuzumab therapy prolongs the survival of patients with metastático HER-2/neu-overexpressing breast cancer when combined with chemotherapy and has recently been demonstrated to lead to dramatic improvements in disease-free survival when used in the adjuvant therapy setting in combination with or following chemotherapy. Here, we performed a meta-analysis of completed clinical trials of adjuvant trastuzumab in the adjuvant setting. Survival, recurrence, brain metastases, cardiotoxicity and directions for future research are discussed.</p> <p>Methods</p> <p>A meta-analysis of randomized controlled trials (RCT) was performed comparing adjuvant trastuzumab treatment for HER2-positive early breast cancer (EBC) to observation. The MEDLINE, EMBASE, CANCERLIT and Cochrane Library databases, and abstracts published in the annual proceedings were systematically searched for evidence. Relevant reports were reviewed by two reviewers independently and the references from these reports were searched for additional trials, using guidelines set by QUOROM statement criteria.</p> <p>Results</p> <p>Pooled results from that five randomized trials of adjuvant Trastuzumab showed a significant reduction of mortality (p < 0.00001), recurrence (p < 0.00001), metastases rates (p < 0.00001) and second tumors other than breast cancer (p = 0.007) as compared to no adjuvant Trastuzumab patients. There were more grade III or IV cardiac toxicity after trastuzumab (203/4555 = 4.5%) versus no trastuzumab (86/4562 = 1.8%). The likelihood of cardiac toxicity was 2.45-fold higher (95% CI 1.89 – 3.16) in trastuzumab arms, however that result was associated with heterogeneity. The likelihood of brain metastases was 1.82-fold higher (95% CI 1.16 – 2.85) in patients who received trastuzumab.</p> <p>Conclusion</p> <p>The results from this meta-analysis are sufficiently compelling to consider 1 year of adjuvant trastuzumab treatment for women with HER-2-positive EBC based on the risk: benefit ratio demonstrated in these studies. Adequate assessment of HER-2/neu status is critical, and careful cardiac monitoring is warranted because of cardiac toxicity. Clinical trials should be designed to answer unsolved questions.</p

The time course of exogenous and endogenous control of covert attention

Studies of eye-movements and manual response have established that rapid overt selection is largely exogenously driven toward salient stimuli, whereas slower selection is largely endogenously driven to relevant objects. We use the N2pc, an event-related potential index of covert attention, to demonstrate that this time course reflects an underlying pattern in the deployment of covert attention. We find that shifts of attention that occur soon after the onset of a visual search array are directed toward salient, task-irrelevant visual stimuli and are associated with slow responses to the target. In contrast, slower shifts are target-directed and are associated with fast responses. The time course of exogenous and endogenous control provides a framework in which some inconsistent results in the capture literature might be reconciled; capture may occur when attention is rapidly deployed

Dermatofibrosarcoma protuberans treated by micrographic surgery

Dermatofibrosarcoma protuberans is an uncommon cutaneous tumour which rarely metastasises. However, local recurrence following apparently adequate surgical excision is well recognised, presumably as a result of sub-clinical contiguous growth, for which micrographically controlled excision would be a logical treatment. A retrospective study of all patients treated by micrographic surgery, from April 1995–March 2000, at a tertiary skin oncology centre. Twenty-one patients (11 males), age 14 to 71 years with dermatofibrosarcoma protuberans on the trunk (10 patients), groin (four), head and neck (four), and limbs (three) were treated. In 15 patients one micrographic layer cleared the tumour, and four were cleared with two layers. For one patient the second stage was completed by conventional excision guided by positive margins. Another patient with a multiply recurrent perineal dermatofibrosarcoma protuberans, not cleared in one area after two layers, died from a pulmonary embolus before total clearance could be achieved. There was no correlation between tumour size and lateral excision margin. No recurrence was observed during the follow-up, from 21 to 80 months, median 47 months. The study provides further support for micrographic surgery as the treatment of choice for dermatofibrosarcoma protuberans

Functional Roles of the N- and C-Terminal Regions of the Human Mitochondrial Single-Stranded DNA-Binding Protein

Biochemical studies of the mitochondrial DNA (mtDNA) replisome demonstrate that the mtDNA polymerase and the mtDNA helicase are stimulated by the mitochondrial single-stranded DNA-binding protein (mtSSB). Unlike Escherichia coli SSB, bacteriophage T7 gp2.5 and bacteriophage T4 gp32, mtSSBs lack a long, negatively charged C-terminal tail. Furthermore, additional residues at the N-terminus (notwithstanding the mitochondrial presequence) are present in the sequence of species across the animal kingdom. We sought to analyze the functional importance of the N- and C-terminal regions of the human mtSSB in the context of mtDNA replication. We produced the mature wild-type human mtSSB and three terminal deletion variants, and examined their physical and biochemical properties. We demonstrate that the recombinant proteins adopt a tetrameric form, and bind single-stranded DNA with similar affinities. They also stimulate similarly the DNA unwinding activity of the human mtDNA helicase (up to 8-fold). Notably, we find that unlike the high level of stimulation that we observed previously in the Drosophila system, stimulation of DNA synthesis catalyzed by human mtDNA polymerase is only moderate, and occurs over a narrow range of salt concentrations. Interestingly, each of the deletion variants of human mtSSB stimulates DNA synthesis at a higher level than the wild-type protein, indicating that the termini modulate negatively functional interactions with the mitochondrial replicase. We discuss our findings in the context of species-specific components of the mtDNA replisome, and in comparison with various prokaryotic DNA replication machineries

The health impact of remarriage behavior on chronic obstructive pulmonary disease: findings from the US longitudinal survey

<p>Abstract</p> <p>Background</p> <p>Chronic obstructive pulmonary disease (COPD) is a major disease among adults, and its deterioration was reported to be associated with psychological imbalance. Meanwhile, bereavement and divorce have proven harmful to the health status of a surviving spouse. But few studies have been conducted to evaluate the remedial effect on survivors' health outcome by remarriage after bereavement. The present study thus examined the associations between remarriage and the onset of COPD.</p> <p>Methods</p> <p>Our cohort was drawn from Health and Retirement Study participants in the United States, and consisted of 2676 subjects who were divorced or bereaved from 1992 to 2002. We then followed them for up to 11 years and assessed the incidence rate of COPD using a Cox proportional hazard model after adjusting for marital status, age, gender, education and the number of cigarettes smoked.</p> <p>Results</p> <p>Among all subjects, 224 who remarried after bereavement or divorce tended to be younger and more male dominated. Remarriage after bereavement/divorce was associated with significantly decreased risk of COPD onset for overall subjects [hazard ratio (HR): 0.51, 95% confidence interval (95% CI): 0.28-0.94], female subjects [HR: 0.36, 95% CI: 0.13-0.98], and for those under 70 years old [HR: 0.36, 95% CI: 0.17-0.79].</p> <p>Conclusion</p> <p>This study investigates the impact of remarriage on health outcome based on a large-scale population survey and indicates that remarriage significantly correlates with reduced risk of COPD incidence, even after adjusting smoking habit.</p

Patients' experiences and perceived causes of persisting discomfort following day surgery

<p>Abstract</p> <p>Background</p> <p>The aim of this study was to describe patients' experiences and perceived causes of persisting discomfort following day surgery. Earlier research has mainly covered symptoms and signs during a recovery period of up to one month, and not dealt with patients' perceptions of what causes persisting, longer-term discomfort.</p> <p>Methods</p> <p>This study is a part from a study carried out during the period May 2006 to May 2007 with a total of 298 day surgery patients. Answers were completed by 118 patients at 48 hours, 110 at seven days and 46 at three months to one open-ended question related to discomfort after day surgery constructed as follows: <it>If you are still experiencing discomfort related to the surgery, what is the reason, in your opinion</it>? Data was processed, quantitatively and qualitatively. Descriptive, inferential, correlation and content analyses were performed.</p> <p>Results</p> <p>The results suggest that patients suffer from remaining discomfort e.g. pain and wound problem, with effects on daily life following day surgery up to three months. Among patients' perceptions of <it>factors leading to discomfort </it>may be <it>wrongful or suboptimal treatment</it>, <it>type of surgery </it>or <it>insufficient access to provider/information.</it></p> <p>Conclusions</p> <p>The results have important implications for preventing and managing discomfort at home following day surgery, and for nursing interventions to help patients handle the recovery period better.</p

Spatial variation and hot-spots of district level diarrhea incidences in Ghana: 2010–2014

Background: Diarrhea is a public health menace, especially in developing countries. Knowledge of the biological and anthropogenic characteristics is abundant. However, little is known about its spatial patterns especially in developing countries like Ghana. This study aims to map and explore the spatial variation and hot-spots of district level diarrhea incidences in Ghana. Methods: Data on district level incidences of diarrhea from 2010 to 2014 were compiled together with population data. We mapped the relative risks using empirical Bayesian smoothing. The spatial scan statistics was used to detect and map spatial and space-Time clusters. Logistic regression was used to explore the relationship between space-Time clustering and urbanization strata, i.e. rural, peri-urban, and urban districts. Results: We observed substantial variation in the spatial distribution of the relative risk. There was evidence of significant spatial clusters with most of the excess incidences being long-Term with only a few being emerging clusters. Space-Time clustering was found to be more likely to occur in peri-urban districts than in rural and urban districts. Conclusion: This study has revealed that the excess incidences of diarrhea is spatially clustered with peri-urban districts showing the greatest risk of space-Time clustering. More attention should therefore be paid to diarrhea in peri-urban districts. These findings also prompt public health officials to integrate disease mapping and cluster analyses in developing location specific interventions for reducing diarrhea