High PD-L1 expression indicates poor prognosis of HIV-infected patients with non-small cell lung cancer

Abstract

Background

The status of antitumor immunity represented by the expression of programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) and immune cell (IC) infiltration is unknown in HIV-infected patients with non-small cell lung cancer (NSCLC).

Methods

Fifteen HIV-infected patients with NSCLC were compared with 29 non-HIV-infected patients with NSCLC. Analysis of 13 propensity-score-matched patients in the two groups was also compared. The expression of PD-1/PD-L1 and tumor infiltration by CD4⁺, CD8⁺, and CD56⁺ immune cells were examined by immunohistochemistry; score of ≥ 2 was defined as positive.

Results

Although high PD-L1 expression in tumor cells was observed in HIV and non-HIV cohorts, the association of PD-1/PD-L1 was significant only in the HIV cohort. In overall as well as the propensity-matched analyses, HIV-infected patients with high PD-L1 expression showed shorter survival than HIV-infected patients with low PD-L1 expression; no significant difference was observed in this respect in the non-HIV cohort.

Conclusion

High PD-L1 expression in tumor tissue was associated with poor prognosis in HIV-infected NSCLC patients but not in non-HIV-infected NSCLC patients. These results suggest that antitumor immunity by PD-1/PD-L1 axis might be suppressed more in HIV-infected NSCLC patients as compared to their non-HIV-infected counterparts.

http://ift.tt/2C4ao1g

A New 3D Printing Strategy by Harnessing Deformation, Instability, and Fracture of Viscoelastic Inks

Abstract

Direct ink writing (DIW) has demonstrated great potential as a multimaterial multifunctional fabrication method in areas as diverse as electronics, structural materials, tissue engineering, and soft robotics. During DIW, viscoelastic inks are extruded out of a 3D printer's nozzle as printed fibers, which are deposited into patterns when the nozzle moves. Hence, the resolution of printed fibers is commonly limited by the nozzle's diameter, and the printed pattern is limited by the motion paths. These limits have severely hampered innovations and applications of DIW 3D printing. Here, a new strategy to exceed the limits of DIW 3D printing by harnessing deformation, instability, and fracture of viscoelastic inks is reported. It is shown that a single nozzle can print fibers with resolution much finer than the nozzle diameter by stretching the extruded ink, and print various thickened or curved patterns with straight nozzle motions by accumulating the ink. A quantitative phase diagram is constructed to rationally select parameters for the new strategy. Further, applications including structures with tunable stiffening, 3D structures with gradient and programmable swelling properties, all printed with a single nozzle are demonstrated. The current work demonstrates that the mechanics of inks plays a critical role in developing 3D printing technology.

A new 3D printing strategy is reported by harnessing deformation, instability, and fracture of viscoelastic inks. The new strategy allows a single nozzle printing of various fiber diameters and patterns for viscoelastic inks. Furthermore, selection parameters for the new 3D printing strategy can be rationally guided by a quantitative phase diagram.

http://ift.tt/2krQmGL

Comparison of infliximab with adalimumab in 827 biologic-naïve patients with Crohn's disease: a population-based Danish cohort study

Summary

Background

There are conflicting data on comparative effectiveness of adalimumab and infliximab in patients with Crohn's disease (CD).

Aims

To compare the effectiveness and safety of adalimumab and infliximab in biologic-naïve patients with CD, in a nationwide register-based propensity score-matched cohort study in Denmark.

Methods

A total of 2908 Danish adults with CD had been treated with adalimumab or infliximab as their first biologic agent between 2005-2014. By Cox regression, we compared rates of all-cause hospitalisation, CD-related hospitalisation, major abdominal surgery and serious infections after variable 2:1 propensity score matching, accounting for baseline disease characteristics, healthcare utilisation and use of CD-related medications.

Results

After propensity-score matching, we included 315 adalimumab- (34.9 ± 12.9 years, 41.9% males) and 512 infliximab-treated (33.6 ± 12.6 years, 40.8% males) patients, with median disease duration 4.0 years; 36.9% had prior abdominal surgery. Over a median follow-up 2.3 years after starting biological therapy, there were no significant differences in rate of CD-related hospitalisation (hazard ratio [HR], 0.81 [95% CI, 0.55-1.20]) or major abdominal surgery (HR, 1.24 [0.66-2.33]) between adalimumab- and infliximab-treated patients, though rate of all-cause hospitalisation was lower in adalimumab-treated patients (HR, 0.74 [0.56-0.97]). There was no significant difference in incidence of serious infections requiring hospitalisation (HR, 1.06 [0.26-4.21]). These results were stable in patients treated with biological monotherapy (all-cause hospitalisation: HR, 0.75 [0.53-1.05]; CD-related hospitalisation: HR, 0.82 [0.51-1.32], abdominal surgery: HR, 1.47 [0.63-3.47]) or in combination with immunomodulators (all-cause hospitalisation: HR, 0.70 [0.44-1.11]; CD-related hospitalisation: HR, 0.80 [0.42-1.52], abdominal surgery: HR, 1.02 [0.39-2.64]).

Conclusions

In this population-based, propensity score matched, real-life cohort study using administrative claims, there was no significant difference in effectiveness and safety of adalimumab and infliximab in biologic-naïve patients with CD.

http://ift.tt/2zb2DHW

Hereditary and familial thyroid tumours

The worldwide incidence of thyroid malignancies has been increasing rapidly. Sensitive imaging modalities and early detection of thyroid lesions have made thyroid cancers the most rapidly increasing cancers in the USA in 2017 (SEER Cancer Facts, 2017). Clinical awareness of potential risk factors, such as inherited thyroid cancers, has allowed earlier recognition of more vulnerable population clusters. Hereditary thyroid neoplasms arising from calcitonin-producing C cells are known as familial medullary thyroid carcinomas (FMTCs), and include well-documented syndromes such as multiple endocrine neoplasia IIA or IIB, and pure familial medullary thyroid carcinoma syndrome. Familial thyroid cancers arising from follicular cells are referred to as familial non-medullary thyroid carcinoma (FNMTC), or familial follicular cell-derived carcinoma. Clinicopathological correlations have resulted in the further subclassification of FNMTCs into two groups. Among the first group are found syndromes characterised by a predominance of non-thyroidal tumours, including familial adenomatous polyposis, Cowden syndrome, Werner syndrome, Carney complex, and Pendred syndrome. The second group encompasses a spectrum of familial syndromes characterised by a predominance of non-medullary thyroid tumours, such as pure familial papillary thyroid carcinoma with or without oxyphilia, familial papillary thyroid carcinoma with papillary renal cell carcinoma, and familial papillary carcinoma with multinodular goitre. Most familial thyroid cancers have been described as being more aggressive than sporadic thyroid cancers, with a predisposition for lymph node metastasis, extrathyroidal invasion, and a younger age of onset. The distinct thyroid pathology in some of these syndromes should alert the pathologist to a possible familial cancer syndrome.

http://ift.tt/2AFZv9G

Issue Information

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Special types of thyroid carcinoma

This article reviews the small percentage of thyroid tumours that are not classified as classic papillary thyroid carcinoma, follicular thyroid carcinoma, and medullary thyroid carcinoma. It includes subtypes of papillary thyroid carcinoma, including, tall-cell, hobnail/micropapillary, columnar cell, diffuse sclerosing and solid variants. Poorly differentiated carcinoma, high-grade carcinoma and anaplastic thyroid carcinoma are reviewed. Also discussed are entities that are unusual but need to be recognized as primary thyroid neoplasms, i.e. mucoepidermoid carcinoma, sclerosing mucoepidermoid carcinoma with eosinophilia, and mammary analogue secretory carcinoma/secretory carcinoma. The pathological features and prognostic factors are described; a brief review of molecular correlates of these neoplasms is included.

http://ift.tt/2ADRz8D

Heritable forms of primary hyperparathyroidism: a current perspective

Primary hyperparathyroidism (PHPT) is one of the most common of all endocrine disorders encountered by the practising histopathologist. The vast majority of lesions are sporadic in nature, approximately 85% of which are parathyroid adenomas, while hyperplasia and carcinoma account for 10–15% and fewer than 1%, of cases, respectively. Heritable forms of PHPT are much less common and present challenges both to clinicians and pathologists, particularly when they are the presenting feature of an endocrine syndrome. In such instances, pathologists play a key role in alerting physicians to the possibility of an underlying heritable endocrine syndrome and the potential for extra-endocrine manifestations. Therefore, a working knowledge of these disorders is essential for providing guidance to treating physicians. The aim of this update is to review the clinicopathological features, genetic bases and current management for patients with PHPT associated with multiple endocrine neoplasia (MEN) types 1, 2A and 4 and hyperparathyroidism-jaw tumour (HPT-JT) syndrome in the context of the 2017 World Health Organization (WHO) Classification of Tumours of the Endocrine Organs. Additionally, familial isolated hyperparathyroidism, familial hypocalciuric hypercalcaemia and neonatal severe hyperparathyroidism are discussed.

http://ift.tt/2AEygMK

Succinate dehydrogenase (SDH)-deficient neoplasia

The succinate dehydrogenase (SDH) complex is a key respiratory enzyme composed of four subunits: SDHA, SDHB, SDHC and SDHD. Remarkably, immunohistochemistry for SDHB becomes negative whenever there is bi-alleic inactivation of any component of SDH, which is very rare in the absence of syndromic disease. Therefore, loss of SDHB immunohistochemistry serves as a marker of syndromic disease, usually germline mutation of one of the SDH subunits. Tumours which show loss of SDHB expression are termed succinate dehydrogenase-deficient. In addition to loss of SDHB, tumours associated with SDHA mutation also show loss of SDHA expression. Fifteen per cent of pheochromocytoma and paraganglioma (PHEO/PGL) are associated with germline SDH mutation, and therefore SDH-deficient. We recommend screening SDHB immunohistochemistry for all PHEO/PGL. SDH-deficient gastrointestinal stromal tumours (GISTs) show distinctive features, including absent KIT proto-oncogene receptor tyrosine kinase/platelet-derived growth factor receptor A (KIT/PDGFRA) mutations [but positive staining for cKIT and DOG1], virtually exclusive gastric location, lobulated growth, multi-focality, a prognosis not predicted by size and mitotic rate, frequent metastasis to lymph nodes and primary resistance to imatinib therapy. Thirty per cent are associated with SDHA germline mutation and 50% are associated with SDHC epimutation (post-zygotic promoter hypermethylation) – the hallmark of the syndromic but non-hereditary Carney triad (SDH- deficient GIST, SDH-deficient paraganglioma and pulmonary chondroma). SDH-deficient renal carcinoma is newly recognized under the World Health Organization (WHO) 2016 classification and shows vacuolated eosinophilic cytoplasmic and cytoplasmic inclusions. It is particularly associated with SDHB mutation, although SDHC and SDHA mutation occur. SDH-deficient pituitary adenomas are recognized, but appear to be the least common SDH-deficient neoplasm.

http://ift.tt/2AEfIvU

What's new in pituitary pathology?

The increasing recognition of pituitary disorders and their impact on quality of life and longevity has made understanding of this small gland a subject of paramount importance. Pituitary pathology has seen many significant studies that indicate progress in identification and classification of pituitary lesions, as well as improved management strategies for patients. In this review, we outline six major areas of advances: (i) changes in terminology from 'adenoma' to 'pituitary neuroendocrine tumour'; (ii) reclassification of hormone-negative tumours based on transcription factor expression that defines lineage; (iii) updates in new pathogenetic mechanisms, including those that underlie rare lesions such as X-LAG and pituitary blastoma; (iv) clarification of hypophysitis due to immunotherapy, xanthomatous hypophysitis due to rupture of a Rathke's cleft cyst and IgG4 disease as the cause of inflammatory pseudotumour; (v) the consolidation of pituicytoma variants, including spindle cell oncocytoma and granular cell tumour based on thyroid transcription factor-1 (TTF-1) reactivity; and (vi) the pathogenetic mechanisms that distinguish papillary from adamantinomatous craniopharyngioma. The remaining challenge is clarification of the pathogenetic mechanisms underlying the development of many of these disorders.

http://ift.tt/2yqi7nW

Annual review issue

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Gastroenteropancreatic neuroendocrine neoplasms: selected pathology review and molecular updates

Gastroenteropancreatic (GEP) neuroendocrine neoplasms can be broadly separated into well- and poorly differentiated categories. Tumours within each category have similarities in morphology and immunophenotype, but vary in grade, behaviour, molecular signature and responses to therapy. The aetiology of these differences is multifactorial. Site of origin, mucosal milieu and hereditary influences are some of the currently known factors. Given these differences, staging and grading systems continue to evolve, and the most recent World Health Organization classification of pancreatic neuroendocrine neoplasms reflects this by introducing a grade 3 neuroendocrine tumour category for morphologically well-differentiated tumours with an elevated Ki-67 proliferation index and/or mitotic count. This review aims to highlight current classification guidelines with discussion of unique site-specific features of selected GEP neuroendocrine neoplasms and an emphasis on practical issues related to daily reporting.

http://ift.tt/2yqWDr1

Annual review issue: An overview of 50 years of progress in endocrine pathology

http://ift.tt/2AFZnac

Molecular pathology of thyroid tumours of follicular cells: a review of genetic alterations and their clinicopathological relevance

Thyroid cancer is the most common endocrine malignancy. Knowledge of the molecular pathology of thyroid tumours originating from follicular cells has greatly advanced in the past several years. Common molecular alterations, such as BRAF p.V600E, RAS point mutations, and fusion oncogenes (RET–PTC being the prototypical example), have been, respectively, associated with conventional papillary carcinoma, follicular-patterned tumours (follicular adenoma, follicular carcinoma, and the follicular variant of papillary carcinoma/non-invasive follicular thyroid neoplasm with papillary-like nuclear features), and with papillary carcinomas from young patients and arising after exposure to ionising radiation, respectively. The remarkable correlation between genotype and phenotype shows how specific, mutually exclusive molecular changes can promote tumour development and initiate a multistep tumorigenic process that is characterised by aberrant activation of mitogen-activated protein kinase and phosphoinositide 3-kinase–PTEN–AKT signalling. Molecular alterations are becoming useful biomarkers for diagnosis and risk stratification, and as potential treatment targets for aggressive forms of thyroid carcinoma. What follows is a review of the principal genetic alterations of thyroid tumours originating from follicular cells and of their clinicopathological relevance.

http://ift.tt/2yrlhI7

Pathology and genetics of phaeochromocytoma and paraganglioma

Phaeochromocytoma and paraganglioma (PHEO/PGL) are rare tumours with an estimated annual incidence of 3 per million. Advances in molecular understanding have led to the recognition that at least 30–40% arise in the setting of hereditary disease. Germline mutations in the succinate dehydrogenase genes SDHA, SDHB, SDHC, SDHD and SDHAF2 are the most prevalent of the more than 19 hereditary genetic abnormalities which have been reported. It is therefore recommended that, depending on local resources and availability, at least some degree of genetic testing should be offered to all PHEO/PGL patients, including those with clinically sporadic disease. It is now accepted that that all PHEO/PGL have some metastatic potential; therefore, concepts of benign and malignant PHEO/PGL have no meaning and have been replaced by a risk stratification approach. Although there is broad acceptance that certain features, including high proliferative activity, invasive growth, increased cellularity, large tumour nests and comedonecrosis, are associated with an increased risk of metastasis, it remains difficult to predict the clinical behaviour of individual tumours and no single risk stratification scheme is endorsed or in widespread use. In this review, we provide an update on advances in the pathology and genetics of PHEO/PGL with an emphasis on the changes introduced in the WHO 2017 classification of endocrine neoplasia relevant to practising surgical pathologists.

http://ift.tt/2yqe5w0

Challenges in surgical pathology of adrenocortical tumours

Adrenocortical carcinomas are rare tumours that can be diagnostically challenging. Numerous multiparametric scoring systems and diagnostic algorithms have been proposed to differentiate adrenocortical adenoma from adrenocortical carcinoma. Adrenocortical neoplasms must also be differentiated from other primary adrenal tumours, such as phaeochromocytoma and unusual primary adrenal tumours, as well as metastases to the adrenal gland. Myxoid, oncocytic and sarcomatoid variants of adrenocortical tumours must be recognized so that they are not confused with other tumours. The diagnostic criteria for oncocytic adrenocortical carcinoma are different from those for conventional adrenocortical carcinomas. Adrenocortical neoplasms in children are particularly challenging to diagnose, as histological features of malignancy in adrenocortical neoplasms in adults may not be associated with aggressive disease in the tumours of children. Recent histological and immunohistochemical studies and more comprehensive and integrated genomic characterizations continue to advance our understanding of the tumorigenesis of these aggressive neoplasms, and may provide additional diagnostic and prognostic utility and guide the development of therapeutic targets.

http://ift.tt/2AFueUj

Developmental and gut-related changes to microbiomes of the cultured juvenile spiny lobster Panulirus ornatus

Abstract

With recent technologies making it possible for commercial scale closed life-cycle aquaculture production of spiny lobster (Panulirus ornatus) comes a strong impetus to further understand aspects of lobster health. The gut microbiome plays a crucial role in host health, affecting growth, digestion, immune responses and pathogen resistance. Herein we characterise and compare gut microbiomes across different developmental stages (6–7 days post-emergence [dpe], 52 dpe and 13 months post-emergence [mpe]) and gut regions (foregut, midgut and hindgut) of cultured P. ornatus juveniles. Gut samples were analysed using 16S rRNA next-generation sequencing. Core gut microbiomes of P. ornatus comprised the phyla Tenericutes and Proteobacteria. Within class Gammaproteobacteria, families Pseudoalteromonadaceae and Vibrionaceae were dominant members across the majority of the gut microbiomes. Characterisation of bacterial communities from 13 mpe lobsters indicated that the hindgut microbiome was more diverse and compositionally dissimilar to the foregut and midgut. The bacterial composition of the hindgut was more similar among younger juveniles (6–7 dpe and 52 dpe) compared to 13 mpe lobsters. This is the first study to explore gut microbiomes of spiny lobster juveniles. We demonstrate that the composition of the gut microbiome was shaped by gut region, whereas the structure of the hindgut microbiome was influenced by developmental stage.

http://ift.tt/2zVNvQo

Bacteria associated with decomposing dead wood in a natural temperate forest

Abstract

Dead wood represents an important pool of organic matter in forests and is one of the sources of soil formation. It has been shown to harbour diverse communities of bacteria, but their roles in this habitat are still poorly understood. Here, we describe the bacterial communities in the dead wood of Abies alba, Picea abies and Fagus sylvatica in a temperate natural forest in Central Europe. An analysis of environmental factors showed that decomposing time along with pH and water content was the strongest drivers of community composition. Bacterial biomass positively correlated with N content and increased with decomposition along with the concurrent decrease in the fungal/bacterial biomass ratio. Rhizobiales and Acidobacteriales were abundant bacterial orders throughout the whole decay process, but many bacterial taxa were specific either for young (<15 years) or old dead wood. During early decomposition, bacterial genera able to fix N₂ and to use simple C1 compounds (e.g. Yersinia and Methylomonas) were frequent, while wood in advanced decay was rich in taxa typical of forest soils (e.g. Bradyrhizobium and Rhodoplanes). Although the bacterial contribution to dead wood turnover remains unclear, the community composition appears to reflect the changing conditions of the substrate and suggests broad metabolic capacities of its members.

http://ift.tt/2iDs5wg

Fecal bacterial communities of wild-captured and stranded green turtles (Chelonia mydas) on the Great Barrier Reef

Abstract

Green turtles (Chelonia mydas) are endangered marine herbivores that break down food particles, primarily sea grasses, through microbial fermentation. However, the microbial community and its role in health and disease is still largely unexplored. In this study, we investigated and compared the fecal bacterial communities of eight wild-captured green turtles to four stranded turtles in the central Great Barrier Reef regions that include Bowen and Townsville. We used high-throughput sequencing analysis targeting the hypervariable V1–V3 regions of the bacterial 16S rRNA gene. At the phylum level, Firmicutes predominated among wild-captured green turtles, followed by Bacteroidetes and Proteobacteria. In contrast, Proteobacteria (Gammaproteobacteria) was the most significantly dominant phylum among all stranded turtles, followed by Bacteroidetes and Firmicutes. In addition, Fusobacteria was also significantly abundant in stranded turtles. No significant differences were found between the wild-captured turtles in Bowen and Townsville. At the family level, the core bacterial community consisted of 25 families that were identified in both the wild-captured and stranded green turtles, while two unique sets of 14 families each were only found in stranded or wild-captured turtles. The predominance of Bacteroides in all groups indicates the importance of these bacteria in turtle gut health. In terms of bacterial diversity and richness, wild-captured green turtles showed a higher bacterial diversity and richness compared with stranded turtles. The marked differences in the bacterial communities between wild-captured and stranded turtles suggest the possible dysbiosis in stranded turtles in addition to potential causal agents.

http://ift.tt/2Ce087v

Acquired myospherulosis secondary to gluteal augmentation on fine needle aspiration cytology: A diagnostic challenge

A 30-year-old female presented with a three-month history of a multilocular cystic lesion over the lumbosacral spine. Fine-needle aspiration biopsy (FNA) of the lesion was performed at an outside institution, and a cytologic diagnosis, suspicious for chordoma, was rendered. The patient presented for surgical consultation at our institution. Repeat FNA demonstrated an unusual fat-like material. Upon further inquiry, the patient provided a recent history of gluteal contour improvement with fibroadipose tissue implants. A diagnosis of myospherulosis was made with a concurrent surgical pathology correlation. No evidence of chordoma was identified. To date, this is the first reported case of acquired myospherulosis in the context of gluteal contour enhancement and represents an important diagnostic pitfall to consider on cytology preparations.

http://ift.tt/2jTxX61

Extra-corporeal normothermic machine perfusion of the porcine kidney: working towards future utilization in Australasia

Background

The ongoing supply-demand gap with respect to donor kidneys for transplantation necessitates the increased use of higher kidney donor profile index and/or donation after circulatory death (DCD) kidneys. Machine perfusion (MP) preservation has become increasingly popular as a means to preserve such organs. Human data regarding normothermic kidney MP (NMP) is in its infancy, and such a system has not been established in the Australasian clinical setting.

Methods

Modified cardio-pulmonary bypass technology was utilized to develop a viable NMP kidney perfusion system using a porcine DCD model. System development and optimization occurred in two stages, with system components added in each experiment to identify optimal perfusion conditions.

Results

Device functionality was demonstrated by the successful perfusion of and urine production by, eight porcine kidneys. Urine production diminished in the presence of colloid in the perfusate. Pressure-controlled (compared with flow-controlled) perfusion is preferable as a safe perfusion pressure range can be maintained. More physiologic perfusion conditions are achieved if oxygenation is provided by an oxygen/carbon dioxide mixture compared to 100% oxygen.

Conclusion

A viable and reproducible NMP system was established and tested in porcine kidneys, which was able to simulate graft function extra-corporeally. Further work is required to identify the most optimal perfusion conditions. Prior to its utilization in clinical transplantation, the system should be tested in non-transplanted human kidneys.

http://ift.tt/2AkI2iJ

High incidence of biliary stricture after associating liver partition and portal vein ligation for staged hepatectomy

Background

Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) is a two-stage procedure most frequently applied in the setting of an extended right-sided hemi-hepatectomy. Initial reports of high mortality have sparked debate regarding the safety and efficacy of the procedure. We describe a higher incidence of early post-operative bile duct strictures after ALPPS, a complication rarely seen after conventional liver resection.

Methods

An institutional review was conducted to assess the incidence of post-operative biliary strictures following conventional right-sided or extended right-sided hemi-hepatectomy and ALPPS. Patient demographics and operative data were obtained from the patient database of Karolinska University Hospital.

Results

Between 2010 and 2015, 528 hemi-hepatectomies or extended hemi-hepatectomies were performed, of which 500 were conventional liver resections and 28 were ALPPS. The incidence of post-operative biliary stricture was 10.7% (n = 3) following ALPPS, 1.4% (n = 2) following extended right-sided hepatectomy (P = 0.023; OR = 8.46; 95% CI 1.35–53.2) and 1.1% following formal right-sided hepatectomy (P = 0.004; OR = 11.0; 95% CI 2.11–57.6). All biliary strictures were at the level of the hilum affecting the left hepatic duct. Pre-operative comorbidity was less in the ALPPS group and post-operative complications were more severe following ALPPS.

Conclusion

Iatrogenic biliary strictures following conventional liver resection is an uncommon complication. It does, however, occur more frequently following ALPPS and is associated with an increased morbidity. Caution should therefore be exercised when dividing the right hilar pedicle at stage 2 of ALPPS.

http://ift.tt/2BmyuHO

Long-term evaluation of quality of life and satisfaction between implant bar overdentures and conventional complete dentures: A 23 years retrospective study

Abstract

Background

Dental implants have been used in edentulous jaws to improve the retention and stability of complete dentures. Attachment to the implants improves stability and function of the prostheses and increases patient satisfaction.

Purpose

The aim of this study was to evaluate quality of life and satisfaction between patients with implant overdentures and complete dentures for more than 20 years.

Methods

Forty patients with overdentures and 40 patients with conventional complete dentures were included in this study. Both groups are carriers of their prosthesis more than 20 years. All patients completed an OHIP-14 and perception and satisfaction questionnaire related their implant prothesis.

Results

Follow-up mean in patients with overdentures were 23.27 ± 1.87 years and 23.20 ± 3.91 years for conventional prosthesis group. A worse quality of life was shown in the group of patients with conventional dentures in the 7 dimensions and in the total value, with statistically significant differences in 6 dimensions and in the total value (P ≤ .05). Patients with implants overdenture were more satisfied than patients with conventional dentures, with statistically significant differences (P < .001).

Conclusions

Implant overdentures on cobalt chrome and gold bars offer an excellent long-term solution for edentulism compared with conventional denture.

http://ift.tt/2zbyl8h

Lifelong behavioral and neuropathological consequences of repetitive mild traumatic brain injury

Abstract

Objective

Exposure to repetitive concussion, or mild traumatic brain injury (mTBI), has been linked with increased risk of long-term neurodegenerative changes, specifically chronic traumatic encephalopathy (CTE). To date, preclinical studies largely have focused on the immediate aftermath of mTBI, with no literature on the lifelong consequences of mTBI in these models. This study provides the first account of lifelong neurobehavioral and histological consequences of repetitive mTBI providing unique insight into the constellation of evolving and ongoing pathologies with late survival.

Methods

Male C57BL/6J mice (aged 2–3 months) were exposed to either single or repetitive mild TBI or sham procedure. Thereafter, animals were monitored and assessed at 24 months post last injury for measures of motor coordination, learning deficits, cognitive function, and anxiety-like behavior prior to euthanasia and preparation of the brains for detailed neuropathological and protein biochemical studies.

Results

At 24 months survival animals exposed to r-mTBI showed clear evidence of learning and working memory impairment with a lack of spatial memory and vestibule-motor vestibulomotor deficits compared to sham animals. Associated with these late behavioral deficits there was evidence of ongoing axonal degeneration and neuroinflammation in subcortical white matter tracts. Notably, these changes were also observed after a single mTBI, albeit to a lesser degree than repetitive mTBI.

Interpretation

In this context, our current data demonstrate, for the first time, that rather than an acute, time limited event, mild TBI can precipitate a lifelong degenerative process. These data therefore suggest that successful treatment strategies should consider both the acute and chronic nature of mTBI.

http://ift.tt/2C3CMjP

Predictors of post-stroke body temperature elevation

Growing evidence indicates that elevated body temperature after stroke is associated with unfavorable outcome. The aim of the current study was to investigate which factors predict temperature elevation within...

http://ift.tt/2AncPLZ

Isolated and repeated stroke-like episodes in a middle-aged man with a mitochondrial ND3 T10158C mutation: a case report

Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) syndrome, is the most common phenotype of mitochondrial disease. It often develops in childhood or adolescence, usually ...

http://ift.tt/2BmK99i

Inbred or Outbred? Genetic Diversity in Laboratory Rodent Colonies

Non-model rodents are widely used as subjects for both basic and applied biological research, but the genetic diversity of the study individuals is rarely quantified. University-housed colonies tend to be small and subject to founder effects and genetic drift and so may be highly inbred or show substantial genetic divergence from other colonies, even those derived from the same source. Disregard for the levels of genetic diversity in an animal colony may result in a failure to replicate results if a different colony is used to repeat an experiment, as different colonies may have fixed alternative variants. Here we use high throughput sequencing to demonstrate genetic divergence in three isolated colonies of Mongolian gerbil (Meriones unguiculatus) even though they were all established recently from the same source. We also show that genetic diversity in allegedly 'outbred' colonies of non-model rodents (gerbils, hamsters, house mice, deer mice, and rats) varies considerably from nearly no segregating diversity, to very high levels of polymorphism. We conclude that genetic divergence in isolated colonies may play an important role in the 'replication crisis'. In a more positive light, divergent rodent colonies represent an opportunity to leverage genetically distinct individuals in genetic crossing experiments. In sum, awareness of the genetic diversity of an animal colony is paramount as it allows researchers to properly replicate experiments and also to capitalize on other, genetically distinct individuals to explore the genetic basis of a trait.

http://ift.tt/2ADQoWS

Dosage-Dependent Expression Variation Suppressed on the Drosophila Male X Chromosome

DNA copy number variation is associated with many high phenotypic heterogeneity disorders. We systematically examined the impact of Drosophila melanogaster deletions on gene expression profiles to ask if increased expression variability due to reduced gene dose might underlie this phenotypic heterogeneity. Indeed, we find that one dose genes have higher gene expression variability relative to two dose genes. We then asked if this increase in variability could be explained by intrinsic noise within cells, due to stochastic biochemical events, or if expression variability is due to extrinsic noise arising from more complex interactions. Our modeling showed that intrinsic gene expression noise averages at the organism level and thus cannot explain increased variation in one dose gene expression simply. Interestingly, expression variability was related to the magnitude of expression compensation, suggesting that gene dose reduction induced regulation is noisy. In a remarkable exception to this rule the single X chromosome of males showed reduced expression variability, even compared to two dose genes. Analysis of sex transformed flies indicates that X expression variability is independent of the male differentiation program. Instead, we uncover a correlation between occupancy of the chromatin modifying protein encoded by males absent on first (mof) and expression variability, linking noise suppression to the specialized X chromosome dosage compensation system. MOF occupancy on autosomes in both sexes lowered transcriptional noise as well. Our results demonstrate that gene deletions can lead to heterogeneous responses, which are often noisy. This has implications for understanding gene network regulatory interactions and phenotypic heterogeneity. Additionally, chromatin modification appears to play a role in dampening transcriptional noise.

http://ift.tt/2yqTK9J

Radium-223 international early access program: results from the Spanish subset

Future Oncology, Ahead of Print.


http://ift.tt/2An4XKo

Validation of the eighth clinical American Joint Committee on Cancer stage grouping for esophageal cancer

Future Oncology, Ahead of Print.


http://ift.tt/2Bl23cx

Pacritinib and its use in the treatment of patients with myelofibrosis who have thrombocytopenia

Future Oncology, Ahead of Print.


http://ift.tt/2An0vLJ

First-decade patient with colorectal cancer carrying both germline and somatic mutations in APC gene

Abstract

Background

Colorectal carcinoma (CRC) is one of the most common causes of cancer-related deaths. The mean age of patients with CRC ranges from 49 to 60 years. Pediatric CRC is unusual, which often escapes early diagnosis because of a lack of awareness of its occurrence in children. The association between the mutation of APC and the occurrence of CRC in the first decade of life remains unknown.

Case presentation

We report a 10-year-old child with CRC; he was diagnosed with stage IIIB advanced transverse colon cancer without distal metastases. We detected a heterozygous germline mutation at c.5465 T > A in both blood and tissue samples and a heterozygous somatic mutation at c.7397C > T in the tissue sample. Both of these mutations can cause CRC tumorigenesis in the first decade of life.

Conclusions

The rare genetic features of this 10-year-old patient might be the predisposing cause of pediatric CRC. Therefore, screening patients with early-onset CRC through clinical and genetic characterizations is suggested.

http://ift.tt/2Bm73Oo

Is inpatient ictal video-electroencephalographic monitoring mandatory in mesial temporal lobe epilepsy with unilateral hippocampal sclerosis? A prospective study

Summary

Objective

To compare surgical outcome in mesial temporal lobe epilepsy (MTLE) patients with unilateral hippocampal sclerosis (MTLE-HS) who had or did not have preoperative video-electroencephalographic monitoring (VEEG).

Methods

A prospective study was undertaken with 166 consecutive pharmacoresistant unilateral MTLE-HS patients. All patients were investigated with detailed seizure semiology, serial routine outpatient EEG, magnetic resonance imaging, neuropsychological evaluation, and if necessary, other examinations. Postoperative follow-up ranged between 2 and 16 years. Patients were divided into: (1) patients operated on based on routine outpatient EEG information, with >80% of EEGs with unilateral interictal epileptiform discharges (IEDs) ipsilateral to HS or ictal events (n = 71); and (2) patients submitted to preoperative VEEG (n = 95). To avoid the bias generated by ictal recordings, we performed a subanalysis of: (1) patients without preoperatively ictal recordings (n = 80) and (2) patients with ictal recordings in VEEG or routine outpatient EEG (n = 86).

Results

Groups were similar regarding gender, age at surgery, seizure onset, preoperative seizure frequency, and duration of follow-up. Overall, 136/166 (81.92%) were classified as Engel I seizure outcome, with no difference between groups; 76.84% and 88.73% of patients with and without VEEG, respectively, had Engel I postoperative seizure outcome (P = .77). The time lag until surgery was shorter in the group without VEEG (80 vs 38 months; P = .01). Considering ictal recordings, 76.74% of patients with seizures recorded and 87.50% without ictal recordings had Engel I outcome (P = .11).

Significance

We performed the first prospective study in a tertiary epilepsy center comparing surgical outcomes in unilateral MTLE-HS patients investigated preoperatively with and without VEEG. Based on the surgical outcome, VEEG is not imperative in patients with unilateral MTLE-HS who have compatible semiology and clearly ipsilateralized IEDs evaluated by a multidisciplinary and experienced epilepsy group.

http://ift.tt/2ADuR0B

Use of PRO measures to inform tolerability in oncology trials: Implications for clinical review, IND safety reporting and clinical site inspections

Cancer therapeutics frequently lead to symptomatic adverse events (AEs) that can affect treatment tolerability. The National Cancer Institute has developed a patient-reported outcome (PRO) version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) to assess symptomatic AEs by direct patient self-report. While longitudinal assessment of patient-reported symptomatic AEs holds promise to better inform treatment tolerability, using PRO measures to assess symptomatic AEs has raised several regulatory and good clinical practice (GCP) issues among those who conduct cancer clinical trials. These include concerns regarding trial monitoring, clinical review of PRO results by investigators and delegated clinical staff, whether PRO data on symptomatic AEs require IND safety reporting, and how the trial conduct and resultant PRO data will be assessed during clinical investigator site inspections. This article addresses current thinking regarding these issues in cancer clinical trials from the Food and Drug Administration, the National Cancer Institute and the Office for Human Research Protections. PRO measures such as PRO-CTCAE that assess symptomatic AEs in cancer trials are considered similar to other PRO assessments of symptoms, function and health-related quality of life, and can generate complementary data that may inform tolerability. Clarity on operational concerns related to incorporating PRO measures to inform tolerability is critical to continue the advancement of rigorous PRO assessment in cancer clinical trials.

http://ift.tt/2C3V1WH

CTCs May Predict Breast Cancer Recurrence [News in Brief]

Detection of CTCs in patients with ER-positive disease linked with nearly 22-fold increase in late recurrence risk.

http://ift.tt/2AospH7

Anti-PD-1 Therapy OK for Most with HIV [News in Brief]

Early pembrolizumab data support inclusion of patients with HIV in oncology drug trials.

http://ift.tt/2BicttL

Vorinostat enhances the anticancer effect of oxaliplatin on hepatocellular carcinoma cells

Abstract

Oxaliplatin-based systemic chemotherapy has been proposed to have efficacy in hepatocellular carcinoma (HCC). We investigated the combination of vorinostat and oxaliplatin for possible synergism in HCC cells. SMMC7721, BEL7402, and HepG2 cells were treated with vorinostat and oxaliplatin. Cytotoxicity assay, tumorigenicity assay in vitro, cell cycle analysis, apoptosis analysis, western blot analysis, animal model study, immunohistochemistry, and quantitative PCR were performed. We found that vorinostat and oxaliplatin inhibited the proliferation of SMMC7721, BEL7402, and HepG2 cells. The combination index (CI) values were all <1, and the dose-reduction index values were all greater than 1 in the three cell lines, indicating a synergistic effect of combination of the two agents. Coadministration of vorinostat and oxaliplatin induced G2/M phase arrest, triggered caspase-dependent apoptosis, and decreased tumorigenicity both in vitro and in vivo. Vorinostat suppressed the expression of BRCA1 induced by oxaliplatin. In conclusion, cotreatment with vorinostat and oxaliplatin exhibited synergism in HCC cells. The combination inhibited cell proliferation and tumorigenicity both in vitro and in vivo through induction of cell cycle arrest and apoptosis. Our results predict that a combination of vorinostat and oxaliplatin may be useful in the treatment of advanced HCC.

In our study, we have proved that the combination of the histone deacetylase inhibitor (HDACi) vorinostat and oxaliplatin had synergism in hepatocellular carcinoma (HCC) cell lines. We found that vorinostat sensitized the HCC cells to oxaliplatin through the inhibition of BRCA1 induced by oxaliplatin. The combination of the two drugs may be a promising strategy in the treatment of HCC.

http://ift.tt/2AmN0vu

SMG-1 inhibition by miR-192/-215 causes epithelial-mesenchymal transition in gastric carcinogenesis via activation of Wnt signaling

Abstract

SMG-1,a member of the phosphoinositide kinase-like kinase family, functioned as a tumor suppressor gene. However, the role of SMG-1 in GC remain uncharacterized. In this study, regulation of SMG-1 by miR-192 and-215, along with the biological effects of this modulation, were studied in GC. We used gene microarrays to screening and luciferase reporter assays were to verify the potential targets of miR-192 and-215. Tissue microarrays analyses were applied to measure the levels of SMG-1 in GC tissues. Western blot assays were used to assess the signaling pathway of SMG-1 regulated by miR-192 and-215 in GC. SMG-1 was significantly downregulated in GC tissues.The proliferative and invasive properties of GC cells were decreased by inhibition of miR-192 and-215, whereas an SMG-1siRNA rescued the inhibitory effects. Finally, SMG-1 inhibition by miR-192 and-215 primed Wnt signaling and induced EMT. Wnt signaling pathway proteins were decreased markedly by inhibitors of miR-192 and-215, while SMG-1 siRNA reversed the inhibition apparently. Meanwhile, miR-192 and-215 inhitibtors increased E-cadherin expression and decreased N-cadherin and cotransfection of SMG-1 siRNA reversed these effects. In summary, these findings illustrate that SMG-1 is suppressed by miR-192 and-215 and functions as a tumor suppressor in GC by inactivating Wnt signaling and suppressing EMT.

In this study, we provide (to our knowledge) the first analysis of (1) SMG-1 as a significant downstream target of miRs-192 and -215 in GC; (2) the participation of SMG-1 in cell proliferation and invasion induced by miR-192 and -215- in vitro and in vivo; and (3) activation of Wnt Signaling by miR-192 and -215 via SMG-1 silencing, leading to EMT.

http://ift.tt/2BmFy7h

BTG2 is a tumor suppressor gene upregulated by p53 and PTEN in human bladder carcinoma cells

Abstract

Although widely deemed as a tumor suppressor gene, the role of B-cell translocation gene 2 (BTG2) in bladder cancer is still inconclusive. We investigated the role and regulatory mechanism of BTG2 in bladder cancer. BTG2 expression in human bladder tissues was determined by RT-qPCR and immunoblotting assays. Expressions of BTG2 and PTEN in bladder carcinoma cells were determined by immunoblotting, RT-qPCR, or reporter assays. The ³H-thymidine incorporation assay, flow cytometry, and the xenograft animal model were used to determine the cell growth. BTG2 expression was lower in human bladder cancer tissues than normal bladder tissues. Highly differentiated bladder cancer cells, RT4, expressed higher BTG2 than the less-differentiated bladder cancer cells, HT1376 and T24. Overexpression of BTG2 in T24 cells inhibited cell growth in vitro and in vivo. Camptothecin and doxorubicin treatments in RT-4 cells or transient overexpression of p53 into p53-mutant HT1376 cells induced p53 and BTG2 expression. Further reporter assays with site-mutation of p53 response element from GGGAAAGTCC to GGAGTCC within BTG2 promoter area showed that p53-induced BTG2 gene expression was dependent on the p53 response element. Ectopic PTEN overexpression in T24 cells blocked the Akt signal pathway which attenuated cell growth via upregualtion of BTG2 gene expression, while reverse effect was found in PTEN-knockdown RT-4 cells. PTEN activity inhibitor (VO-OHpic) treatment decreased BTG2 expression in RT-4 and PTEN-overexpressed T24 cells. Our results suggested that BTG2 functioned as a bladder cancer tumor suppressor gene, and was induced by p53 and PTEN. Modulation of BTG2 expression seems a promising way to treat human bladder cancer.

BTG2 functioned as a bladder cancer tumor suppressor gene and was induced by p53 and PTEN. Modulation of BTG2 expression seems a promising way to treat human bladder cancer.

http://ift.tt/2Alwqfm

Medical management of gastric cancer: a 2017 update

Abstract

Gastric cancer remains a considerable health burden throughout the world. The Cancer Genome Atlas (TCGA) analysis has recently unveiled 4 genotypes of gastric cancer with data not ready to change treatment strategy yet. A multimodality approach to therapy is the cornerstone of screening, diagnosing, staging, treating and supporting patients with gastric cancer. The evidence-based approach to localized gastric cancer (>cT1b) is to use an either preoperative or postoperative strategy to maximize the benefit of surgery. The focus of future research is to optimize chemotherapy regimens, determine the role of radiation therapy and investigate the effect of treatment timing. In metastatic gastric cancer, biologic therapies have been introduced targeting markers shown to be prognostic. The results of ongoing randomized controlled phase 3 trials using targeted and immunotherapy agents, either in combination or alone, have the potential to alter the current treatment landscape of advanced gastric cancer.

A multimodality approach to therapy is critical for patients with gastric cancer. One of the most challenging and exciting field that appears promising is the potential of host's immune system to inhibit signaling pathways.

http://ift.tt/2BitzYr

Simplicity at the cost of predictive accuracy in diffuse large B-cell lymphoma: a critical assessment of the R-IPI, IPI, and NCCN-IPI

Abstract

The international prognostic index (IPI) and similar models form the cornerstone of clinical assessment in newly diagnosed diffuse large B-cell lymphoma (DLBCL). While being simple and convenient to use, their inadequate use of the available clinical data is a major weakness. In this study, we compared performance of the International Prognostic Index (IPI) and its variations (R-IPI and NCCN-IPI) to a Cox proportional hazards (CPH) model using the same covariates in nondichotomized form. All models were tested in 4863 newly diagnosed DLBCL patients from population-based Nordic registers. The CPH model led to a substantial increase in predictive accuracy as compared to conventional prognostic scores when evaluated by the area under the curve and other relevant tests. Furthermore, the generation of patient-specific survival curves rather than assigning patients to one of few predefined risk groups is a relevant step toward personalized management and treatment. A test-version is available on lymphomapredictor.org.

In this study, we show how the prognostic performance of indices for the survival of diffuse large B-cell lymphoma can be greatly improved by considering simple models with continuous variables.

http://ift.tt/2AlwdZC

Oxymatrine inhibits non–small cell lung cancer via suppression of EGFR signaling pathway

Abstract

Epidermal growth factor receptor (EGFR) plays a crucial role in human non–small cell lung cancer (NSCLC) tumorigenesis. In this study, oxymatrine was identified as an EGFR signaling pathway inhibitor in NSCLC. Oxymatrine inhibited anchorage-dependent and independent growth of NSCLC cell lines but had no cytotoxicity in normal lung cells. We found that exposure to oxymatrine not only suppressed the activity of wild-type EGFR but also inhibited the activation of exon 19 deletion and L858R/T790M mutated EGFR. Flow cytometry analysis suggested that oxymatrine-induced cell cycle G0/G1 arrest was dependent on EGFR-Akt signaling. Exogenous overexpression of Myr-Akt rescued cyclin D1 expression in HCC827 cells. Moreover, oxymatrine prominently suppressed tumor growth in a xenograft mouse model. Thus, oxymatrine appears to be a novel therapeutic agent for NSCLC treatment.

For the first time we discovered that oxymatrine inhibited the activation of both wild-type and mutant epidermal growth factor receptor (EGFR). Mechanism studies demonstrated that the inhibition of cell proliferation by oxymatrine was mainly attributed to its effect on EGFR-Akt-cyclin D1 signaling pathway.

http://ift.tt/2BkX9MR

Finasteride treatment and male breast cancer: a register-based cohort study in four Nordic countries

Abstract

A potential link has been suggested between dispensed finasteride and increased risk of male breast cancer (MBC). Due to the rare occurrence of MBC, it remains to be established if such a relationship exists. The purpose of this study was to combine nationwide registers in four countries to assess the potential association between dispensed finasteride and MBC. A cohort of all males with dispensed finasteride in Denmark, Finland, Norway, and Sweden (1,365,088 person years) was followed up for up to 15 years for breast cancer, and compared to a cohort of males unexposed to finasteride. Individual-level register data included country, dates of dispensed finasteride, MBC diagnosis, and death. Incidence rate ratios (IRRs) were estimated using a generalized linear model with a Poisson distribution. An increased risk of MBC was found among finasteride users (IRR = 1.44, 95% confidence interval [95% CI] = 1.11–1.88) compared to nonusers. The IRR increased to 1.60 (95% CI = 1.20–2.13) when users in Norway and Sweden with short follow-up time were excluded. The highest IRR was seen among men with medium duration of dispensed finasteride, medium accumulated consumption of finasteride, and among men with first dispensed finasteride prescription 1–3 years prior to diagnosis. The analyses suggested possible ascertainment bias and did not support a clear relationship between dispensed finasteride and MBC. In conclusion, a significant association between dispensed finasteride and MBC was identified. However, due to limited data for adjustment of potential confounding and surveillance bias in the present study, further research is needed to confirm these results.

A possible link between finasteride use and male breast cancer (MBC) has raised concerns. The present study investigates if an association exists between dispensed finasteride and MBC incidence in Denmark, Finland, Norway and Sweden using register data. An increased risk of MBC was found among finasteride users compared to non-users. Due to limited data for adjustment for potential confounding in the present study, further research is needed to confirm the results.

http://ift.tt/2AopcY5

EM Nerd-The Case of the Tardy Delegate Continues

In 2000 Fazzini et al published a paper comparing the use of ionization vs photoelectric smoke alarms in rural Alaskan homes (1). The authors noted that at the time of the article's publication. the fire fatality rate for native Alaskans was 9.6 times the national rate and 3.5 times higher than the general rate in […]

EMCrit Project by Rory Spiegel.

http://ift.tt/2BmhCRw

Cadmium Testicular Toxicity in Male Wistar Rats: Protective Roles of Zinc and Magnesium

Abstract

Cadmium (Cd) is a highly toxic element, which may cause toxicity to most organs in the body. Zinc (Zn) and magnesium (Mg) are essential minerals with probable benefits on Cd harmful effects. Finding an efficient and non-pathological treatment against Cd toxicity seems promising. Fifty adult rats were divided into ten experimental groups of five rats each. The Cd group was treated with 1 mg Cd/kg and the control group received 0.5 cm³ normal saline. The other eight groups received Zn (0.5 and 1.5 mg/kg) and Mg (0.5 and 1.5 mg/kg) either alone or in combination with 1 mg Cd/kg through IP injection for 3 weeks. Testis malondialdehyde (MDA), sperm parameters, and testis histopathology were investigated. Cd reduced sperm parameters and increased testis MDA. Moreover, Cd exposure caused a significant histological damage in testis of male rats. However, Zn or Mg treatment prevented and reversed Cd toxic alterations in testis. These findings suggest that co-administration of Zn or Mg could improve cadmium testicular toxicity in male Wistar rats.

http://ift.tt/2CbRlCW

Regulation of MAVS activation through post-translational modifications

Bingyu Liu | Chengjiang Gao

http://ift.tt/2ACTV83

Superior Air-Ground Ambulance Service of Michigan, Inc. achieves CAAS Accreditation

WARREN, Mich. — Superior Air-Ground Ambulance Service of Michigan, Inc. in Warren, Michigan has received accreditation from the Commission on Accreditation of Ambulance Services (CAAS) for its compliance with national standards of excellence. Superior Air-Ground Ambulance Service of Michigan, Inc. is now one of over 180 ambulance services in the country to successfully complete the voluntary ...

http://ift.tt/2Aj6QYp

A novel human pain insensitivity disorder caused by a point mutation in ZFHX2

Abstract

Chronic pain is a major global public health issue causing a severe impact on both the quality of life for sufferers and the wider economy. Despite the significant clinical burden, little progress has been made in terms of therapeutic development. A unique approach to identifying new human-validated analgesic drug targets is to study rare families with inherited pain insensitivity. Here we have analysed an otherwise normal family where six affected individuals display a pain insensitive phenotype that is characterized by hyposensitivity to noxious heat and painless bone fractures. This autosomal dominant disorder is found in three generations and is not associated with a peripheral neuropathy. A novel point mutation in ZFHX2, encoding a putative transcription factor expressed in small diameter sensory neurons, was identified by whole exome sequencing that segregates with the pain insensitivity. The mutation is predicted to change an evolutionarily highly conserved arginine residue 1913 to a lysine within a homeodomain. Bacterial artificial chromosome (BAC) transgenic mice bearing the orthologous murine p.R1907K mutation, as well as Zfhx2 null mutant mice, have significant deficits in pain sensitivity. Gene expression analyses in dorsal root ganglia from mutant and wild-type mice show altered expression of genes implicated in peripheral pain mechanisms. The ZFHX2 variant and downstream regulated genes associated with a human pain-insensitive phenotype are therefore potential novel targets for the development of new analgesic drugs.

http://ift.tt/2ADEjRF

Sexual Harassment in Medicine — #MeToo

The news is filled with stories of celebrities who have engaged in egregious sexual misconduct. A recent poll suggested that more than half of U.S. women have experienced "unwanted and inappropriate sexual advances" at some point in their lives. Because I led a study of workplace sexual harassment…

http://ift.tt/2AmpmiD

Massachusetts’ Proposed Medicaid Reforms — Cheaper Drugs and Better Coverage?

While health policy attention in recent months has focused on Washington, D.C. several proposals from individual states have garnered less publicity despite their potentially far-reaching implications. One such proposal comes from Massachusetts, which has applied for a waiver from federal rules in…

http://ift.tt/2AUW1Nm

Daily Consumption of Virgin Coconut Oil Increases High-Density Lipoprotein Cholesterol Levels in Healthy Volunteers: A Randomized Crossover Trial

This open-label, randomized, controlled, crossover trial assessed the effect of daily virgin coconut oil (VCO) consumption on plasma lipoproteins levels and adverse events. The study population was 35 healthy Thai volunteers, aged 18–25. At entry, participants were randomly allocated to receive either (i) 15 mL VCO or (ii) 15 mL 2% carboxymethylcellulose (CMC) solution (as control), twice daily, for 8 weeks. After 8 weeks, participants had an 8-week washout period and then crossed over to take the alternative regimen for 8 weeks. Plasma lipoproteins levels were measured in participants at baseline, week-8, week-16, and week-24 follow-up visits. Results. Of 32 volunteers with complete follow-up (16 males and 16 females), daily VCO intake significantly increased high-density lipoprotein cholesterol by 5.72 mg/dL () compared to the control regimen. However, there was no difference in the change in total cholesterol, low-density lipoprotein cholesterol, and triglyceride levels between the two regimens. Mild diarrhea was reported by some volunteers when taking VCO, but no serious adverse events were reported. Conclusion. Daily consumption of 30 mL VCO in young healthy adults significantly increased high-density lipoprotein cholesterol. No major safety issues of taking VCO daily for 8 weeks were reported.

http://ift.tt/2AkH5Hg

Enhanced cognition and dysregulated hippocampal synaptic physiology in mice with a heterozygous deletion of PSD-95

Abstract

PSD-95 is one of the most abundant proteins of the postsynaptic density of excitatory synapses. It functions as the backbone of protein supercomplexes that mediate signalling between membrane glutamate receptors and intracellular pathways. Homozygous deletion of the Dlg4 gene encoding PSD-95 was previously found to cause a profound impairment in operant and Pavlovian conditioning in Dlg4^−/− mice studied in touchscreen chambers that precluded evaluation of PSD-95′s role in shaping more subtle forms of learning and memory. In the present study, using a battery of touchscreen tests, we investigated cognitive behaviour of mice with a heterozygous Dlg4 mutation. We found that in contrast to learning deficits of Dlg4^−/− mice, Dlg4^+/− animals demonstrated enhanced performance in the Visual Discrimination, Visual Discrimination Reversal and Paired-Associates Learning touchscreen tasks. The divergent directions of learning phenotypes observed in Dlg4^−/− and Dlg4^+/− mice also contrasted with qualitatively similar changes in the amplitude and plasticity of field excitatory postsynaptic potentials recorded in the CA1 area of hippocampal slices from both mutants. Our results have important repercussions for the studies of genetic models of human diseases, because they demonstrate that reliance on phenotypes observed solely in homozygous mice may obscure qualitatively different changes in heterozygous animals and potentially weaken the validity of translational comparisons with symptoms seen in heterozygous human carriers.

This article is protected by copyright. All rights reserved.

http://ift.tt/2zb39Wy

Socioeconomic Status, Frailty, and All-Cause Mortality in Korean Older Adults: A 3-Year Population-Based Prospective Study

Background. Little is known regarding the effects of socioeconomic status (SES) and frailty on mortality in Korea. Objective. This study investigated the combined impact of low SES and frailty on all-cause mortality in Korean older adults. Methods. Study sample at baseline comprised 7,960 community-dwelling adults (56.8% women) aged 65 years and older. The Cox proportional hazards model was used to estimate the hazard ratio (HR) and 95% confidence interval (CI) of low SES and frailty for all-cause mortality. Results. Overall, low SES plus frailty resulted in an increased risk of all-cause mortality (HR = 1.56, 95% CI = 1.09–2.23, ) even after adjustments for all the measured covariates, as compared with high SES plus nonfrailty (HR = 1). Among older adults aged 65–75 years, the increased mortality risk of either low SES plus nonfrailty (HR = 1.37, 95% CI = 1.02–1.84, ) or high SES plus frailty (HR = 2.09, 95% CI = 1.12–3.91, ) remained significant even after adjustments for all the covariates, as compared with high SES plus nonfrailty (HR = 1). Conclusion. The current findings suggest that either low SES or frailty is significantly associated with increased all-cause mortality in Korean older adults.

http://ift.tt/2nZHsp3

Study on Transformation of Ginsenosides in Different Methods

Ginseng is a traditional Chinese medicine and has the extensive pharmacological activity. Ginsenosides are the major constituent in ginseng and have the unique biological activity and medicinal value. Ginsenosides have the good effects on antitumor, anti-inflammatory, antioxidative and inhibition of the cell apoptosis. Studies have showed that the major ginsenosides could be converted into rare ginsenosides, which played a significant role in exerting pharmacological activity. However, the contents of some rare ginsenosides are very little. So it is very important to find the effective way to translate the main ginsenosides to rare ginsenosides. In order to provide the theoretical foundation for the transformation of ginsenoside in vitro, in this paper, many methods of the transformation of ginsenoside were summarized, mainly including physical methods, chemical methods, and biotransformation methods.

http://ift.tt/2Cbko9P

Comparison of the Bone Harvesting Capacity of an Intraoral Bone Harvesting Device and Three Different Implant Drills

The aim of the present study was to compare bone-collecting capacity of bone harvesting device and minimally irrigated low-speed drilling using three implant systems. One bone harvesting device and three commercially available drill systems were compared using the osteotomies on bovine rib bones. The amount of the collected bone particle and particle size (1000 μm: large) were measured. Total wet ( mL) and dry volume ( mL) of the bone particles from bone harvesting device were significantly greater than three drill systems (wet volume: – mL and dry volume: – mL) (). In all groups, the amount of large sized particles in wet and dry state was the greatest compared to that of medium and small particles. The dry weight of the bone particles showed the same tendency to volumetric measurement. In conclusion, total bone particles and large sized particles (>1000 μm) were harvested significantly greater by bone harvesting device than minimally irrigated low-speed drilling. The composition of particle size in all harvesting methods was similar to each other.

http://ift.tt/2nZLfCG

Advance care planning in community dwelling patients with dementia

Little is known about advance care planning (ACP) among community-dwelling patients with dementia.

http://ift.tt/2CbZoQ2

Effects of exercise training on restless legs syndrome, depression, sleep quality and fatigue among hemodialysis patients: A systematic review and meta-analysis

Hemodialysis patients experience a heavy symptom burden that leads to a decreased quality of life. Pharmacological treatment is effective but costly and has adverse effects. Exercise is a promising approach for symptom management, but the effect of exercise on restless legs syndrome, depression, sleep quality and fatigue in hemodialysis patients is still uncertain.

http://ift.tt/2Ama659

Variations in Hospice Utilization and Length of Stay for Medicare Patients with Melanoma

Timely hospice referral is an indicator of high quality end-of-life care for cancer patients. Variations in patient characteristics associated with hospice utilization and length of stay have been demonstrated in studies of other malignancies but not melanoma.

http://ift.tt/2Cf1cHY

Why Is a Psychologist Interested in the Kidneys?

"Why is a psychologist interested in the kidneys?" A question I often hear when conversations with new colleagues ensue. On the surface, it seems reasonable: why would someone who studies human behavior be interested in the kidneys, which seem a fairly enigmatic and emotion-free pair of organs? However, when one starts to delve a little deeper into the disease, the answer reveals itself: cognitive deficits, such as memory and attention impairments, depression, and anxiety, are all far more common in patients with kidney disease than healthy adults.

http://ift.tt/2Aj5FrX

Glucose-6-Phosphate Dehydrogenase Deficiency Mimicking Atypical Hemolytic Uremic Syndrome

A 4-year-old boy presented with nonimmune hemolysis, thrombocytopenia, and acute kidney injury. Investigations for an underlying cause failed to identify a definitive cause and a putative diagnosis of complement-mediated atypical hemolytic uremic syndrome (aHUS) was made. The patient was started initially on plasma exchange and subsequently eculizumab therapy, after which his kidney function rapidly improved. While on eculizumab therapy, despite adequate complement blockade, he presented 2 more times with hemolytic anemia and thrombocytopenia, but without renal involvement.

http://ift.tt/2zawC2R

Specificity of research antibodies: “trust is good, validation is better”

We are writing you in regard to the article "Overexpression of phosphoprotein phosphatase 2A predicts worse prognosis in patients with breast cancer: a 15-year follow-up" by Chen et al., published 16 August 2017 in Human Pathology [1]. The authors used immunohistochemistry to analyze the expression of several signal transduction markers in tissues samples from 672 breast cancer patients and concluded that elevated levels of phosphorylated protein phosphatase 2A (PP2A) catalytic subunit correlate with a shorter 15-year overall survival rate.

http://ift.tt/2CdvWcJ

A Case of Olmesartan-associated Sprue-like Enteropathy

http://ift.tt/2o1V8zG

Deciphering extubation failure in extremely preterm infants: Time to embrace complexity and move forward

We read with interest the article by Chawla et al published in The Journal.1 We commend the authors on conducting a subanalysis aiming to improve our understanding of extubation failure from a large sample of extremely preterm infants enrolled in a randomized trial.1 Despite its rigorous design, 3 important points could have enhanced the usefulness of the reported data: (1) use of more complex analyses, (2) extended definition of extubation success, and (3) inclusion of an important confounder when evaluating associations between failure and morbidities.

http://ift.tt/2ACSUfX

Is Extracorporeal Membrane Oxygenation for a Neonate Ever Ethically Obligatory?

Certain interventions in the neonatal intensive care unit are considered ethically obligatory, and should be provided over parental objections. After reviewing a case, comparative outcome data, and relevant ethical principles, we propose that extracorporeal membrane oxygenation for meconium aspiration syndrome may, in some cases, be an ethically obligatory treatment.

http://ift.tt/2yp2PzP

Coronary Stenosis after Kawasaki Disease: Size Matters

Kawasaki disease is an acute, self-limited vasculitis of unknown etiology that primarily affects infants and young children.1-3 Although fever and mucocutaneous inflammation are self-limited, Kawasaki disease can cause lasting damage to the coronary arteries. Coronary artery aneurysms (CAAs) develop in approximately 25% of untreated patients and approximately 4% of those treated with intravenous immunoglobulin (IVIG) within the first 10 days of illness.4,5 Thus, delayed or missed diagnosis of Kawasaki disease, often in young infants with incomplete clinical criteria, is an important risk factor in the development of CAA.

http://ift.tt/2ADav7P

Diagnostic Accuracy of a New High-Sensitivity Troponin I Assay and Five Accelerated Diagnostic Pathways for Ruling Out Acute Myocardial Infarction and Acute Coronary Syndrome

This diagnostic accuracy study describes the performance of 5 accelerated chest pain pathways, calculated with the new Beckman's Access high-sensitivity troponin I assay.

http://ift.tt/2ACYEq8

Effect of Automated Prescription Drug Monitoring Program Queries on Emergency Department Opioid Prescribing

We assess whether an automated prescription drug monitoring program intervention in emergency department (ED) settings is associated with reductions in opioid prescribing and quantities.

http://ift.tt/2yoUWKS

Outpatient Management of Emergency Department Patients With Acute Pulmonary Embolism: Variation, Patient Characteristics, and Outcomes

Outpatient management of emergency department (ED) patients with acute pulmonary embolism is uncommon. We seek to evaluate the facility-level variation of outpatient pulmonary embolism management and to describe patient characteristics and outcomes associated with home discharge.

http://ift.tt/2ACAKv4

Manual Uterine Aspiration: Adding to the Emergency Physician Stabilization Toolkit

Emergency physicians are often the first physician contact for women with bleeding from first-trimester miscarriage, which is the most common gynecologic emergency; 1 in 4 women experiences miscarriage in her lifetime.1,2 Up to 31% of pregnancies end in miscarriage, contributing to the 1.6% (500,000) of emergency department (ED) visits in the United States annually that are prompted by vaginal bleeding in pregnancy.3-7 Despite the emergency physician's role as a specialist in hemodynamic stabilization, scant emergency medicine literature addresses the management of patients with hemodynamically significant uterine bleeding in the ED.

http://ift.tt/2yoikId

Healthcare Disparities in Cancer Patients Receiving Radiation: Changes in Insurance Status after Medicaid Expansion under the Affordable Care Act

We utilized the SEER database to evaluate changes in uninsurance rates among cancer patients undergoing radiation after Medicaid expansion under the Affordable Care Act. Patients in fully expanded and non-fully expanded states treated with radiation during 2011-2013 were compared to those treated in 2014. Uninsurance rates dropped in all states; however the magnitude was larger in fully expanded states. Non-fully expanded states showed significant racial and county-level poverty disparities in uninsurance levels.

http://ift.tt/2C1Xel7

Biophysical modeling of in vivo glioma response following whole brain radiotherapy in a murine model of brain cancer

In this experimental and computational study, three biophysical models are developed and evaluated for their ability to accurately describe in vivo growth and response following whole brain radiotherapy. Models that include reduced proliferation post-radiotherapy more accurately predicted future tumor growth.

http://ift.tt/2AVhjuh

Protein Flexibility and Synergy of HMG Domains Underlie U-Turn Bending of DNA by TFAM in Solution

Human mitochondrial transcription factor A (TFAM) distorts DNA into a U-turn, as shown by crystallographic studies. The relevance of this U-turn is associated with transcription initiation at the mitochondrial light strand promoter (LSP). However, it has not been yet discerned whether a tight U-turn or an alternative conformation, such as a V-shape, is formed in solution. Here, single-molecule FRET experiments on freely diffusing TFAM/LSP complexes containing different DNA lengths show that a DNA U-turn is induced by progressive and cooperative binding of the two TFAM HMG-box domains and the linker between them.

http://ift.tt/2AiWgAO

Multimodal Measurements of Single-Molecule Dynamics Using FluoRBT

Single-molecule methods provide direct measurements of macromolecular dynamics, but are limited by the number of degrees of freedom that can be followed at one time. High-resolution rotor bead tracking (RBT) measures DNA torque, twist, and extension, and can be used to characterize the structural dynamics of DNA and diverse nucleoprotein complexes. Here, we extend RBT to enable simultaneous monitoring of additional degrees of freedom. Fluorescence-RBT (FluoRBT) combines magnetic tweezers, infrared evanescent scattering, and single-molecule FRET imaging, providing real-time multiparameter measurements of complex molecular processes.

http://ift.tt/2Bl3IiA

Diaphragm Motor Responses to phrenic nerve stimulation in ALS: Surface and Needle Recordings

Motor responses to nerve stimulation are generally recorded by surface electrodes placed on a target muscle using a belly-tendon montage, in which the active electrode is over the muscle end-plate zone. The compound muscle action potential (CMAP) amplitude represents the total number of innervated muscle fibres within motor units recordable by the electrode array. Loss of axons, or of muscle fibres, will reduce CMAP amplitude, as will increased distance between muscle fibres and recording electrode, incorrect electrode positioning and phase cancellation.

http://ift.tt/2nYb5ag

Diminished EEG Habituation to Novel Events Effectively Classifies Parkinson’s Patients

Some of the most debilitating aspects of Parkinson's disease include cognitive and mood disturbances. While it is widely appreciated that cell death in Parkinson's disease somehow contributes to deficits in higher cognitive functioning, the mechanisms underlying these deficits remain unclear. Executive dysfunction is common in Parkinson's disease (Dirnberger and Jahanshahi, 2013; Eberling et al., 2014; Robbins and Cools, 2014), yet one sub-process stands out as being specifically compromised: diminished orienting responses to novel stimuli (Kingstone et al., 2002; Poliakoff et al., 2003; Yamaguchi and Kobayashi, 1998; Zhou et al., 2012).

http://ift.tt/2Cf1mz4

The problem of lack of normative data in paediatric EMG and possible solutions

Paediatric EMG is still an essential part of the efficient and economic examination and treatment of neuromuscular disorders in children. With application, it can rapidly provide information that, if not necessarily diagnostic, can direct further diagnostic studies in the most efficient and effective manner. To some it is an unnecessarily painful experience to expose children to, and the results of interpretation so difficult, as to render the results unhelpful

http://ift.tt/2nYugk3

Abnormal somatosensory temporal discrimination in Parkinson’s disease: Pathophysiological correlates and role in motor control deficits

Ever since it was first described in 'An essay on the shaking palsy'(Parkinson, 1817), Parkinson's disease (PD) has been considered to be a motor disorder characterized by bradykinesia, rigidity, tremor at rest and postural instability (Berardelli et al., 2013; Postuma et al., 2015; Rodriguez-Oroz et al., 2009).However, approximately half of patients with PD complain of various sensory symptoms, including heaviness, numbness, coldness, a burning feeling, tingling, aching and severe pain (Koller, 1984).

http://ift.tt/2CdvFXa

MicroRNA-105 is involved in TNF-α-related tumor microenvironment enhanced colorectal cancer progression

MicroRNA-105 is involved in TNF-α-related tumor microenvironment enhanced colorectal cancer progression

MicroRNA-105 is involved in TNF-α-related tumor microenvironment enhanced colorectal cancer progression, Published online: 13 December 2017; doi:10.1038/s41419-017-0048-x

MicroRNA-105 is involved in TNF-α-related tumor microenvironment enhanced colorectal cancer progression

http://ift.tt/2z9wYGU

circHIPK2-mediated σ-1R promotes endoplasmic reticulum stress in human pulmonary fibroblasts exposed to silica

circHIPK2-mediated σ-1R promotes endoplasmic reticulum stress in human pulmonary fibroblasts exposed to silica

circHIPK2-mediated σ-1R promotes endoplasmic reticulum stress in human pulmonary fibroblasts exposed to silica, Published online: 13 December 2017; doi:10.1038/s41419-017-0017-4

circHIPK2-mediated σ-1R promotes endoplasmic reticulum stress in human pulmonary fibroblasts exposed to silica

http://ift.tt/2AjNwu0

Alternative NHEJ pathway proteins as components of MYCN oncogenic activity in human neural crest stem cell differentiation: implications for neuroblastoma initiation

Alternative NHEJ pathway proteins as components of MYCN oncogenic activity in human neural crest stem cell differentiation: implications for neuroblastoma initiation

Alternative NHEJ pathway proteins as components of <i>MYCN</i> oncogenic activity in human neural crest stem cell differentiation: implications for neuroblastoma initiation, Published online: 13 December 2017; doi:10.1038/s41419-017-0004-9

Alternative NHEJ pathway proteins as components of MYCN oncogenic activity in human neural crest stem cell differentiation: implications for neuroblastoma initiation

http://ift.tt/2z9wQHq

Negative control of the HGF/c-MET pathway by TGF-β: a new look at the regulation of stemness in glioblastoma

Negative control of the HGF/c-MET pathway by TGF-β: a new look at the regulation of stemness in glioblastoma

Negative control of the HGF/c-MET pathway by TGF-β: a new look at the regulation of stemness in glioblastoma, Published online: 13 December 2017; doi:10.1038/s41419-017-0051-2

Negative control of the HGF/c-MET pathway by TGF-β: a new look at the regulation of stemness in glioblastoma

http://ift.tt/2AjNwdu

RIPK3 promotes adenovirus type 5 activity

RIPK3 promotes adenovirus type 5 activity

RIPK3 promotes adenovirus type 5 activity, Published online: 13 December 2017; doi:10.1038/s41419-017-0110-8

RIPK3 promotes adenovirus type 5 activity

http://ift.tt/2z9XMqF

Helicobacter pylori VacA induces autophagic cell death in gastric epithelial cells via the endoplasmic reticulum stress pathway

Helicobacter pylori VacA induces autophagic cell death in gastric epithelial cells via the endoplasmic reticulum stress pathway

<i>Helicobacter pylori</i> VacA induces autophagic cell death in gastric epithelial cells via the endoplasmic reticulum stress pathway, Published online: 13 December 2017; doi:10.1038/s41419-017-0011-x

Helicobacter pylori VacA induces autophagic cell death in gastric epithelial cells via the endoplasmic reticulum stress pathway

http://ift.tt/2AidfTB

Long non-coding RNA MEG3 functions as a competing endogenous RNA to regulate ischemic neuronal death by targeting miR-21/PDCD4 signaling pathway

Long non-coding RNA MEG3 functions as a competing endogenous RNA to regulate ischemic neuronal death by targeting miR-21/PDCD4 signaling pathway

Long non-coding RNA MEG3 functions as a competing endogenous RNA to regulate ischemic neuronal death by targeting miR-21/PDCD4 signaling pathway, Published online: 13 December 2017; doi:10.1038/s41419-017-0047-y

Long non-coding RNA MEG3 functions as a competing endogenous RNA to regulate ischemic neuronal death by targeting miR-21/PDCD4 signaling pathway

http://ift.tt/2z9i97d

Pyridoxine 5′-phosphate oxidase is a novel therapeutic target and regulated by the TGF-β signalling pathway in epithelial ovarian cancer

Pyridoxine 5′-phosphate oxidase is a novel therapeutic target and regulated by the TGF-β signalling pathway in epithelial ovarian cancer

Pyridoxine 5′-phosphate oxidase is a novel therapeutic target and regulated by the TGF-β signalling pathway in epithelial ovarian cancer, Published online: 13 December 2017; doi:10.1038/s41419-017-0050-3

Pyridoxine 5′-phosphate oxidase is a novel therapeutic target and regulated by the TGF-β signalling pathway in epithelial ovarian cancer

http://ift.tt/2AiVofk

FDA Launches New Tool for Sharing Information That Allows Doctors to Better Manage Antibiotic Use

December 13, 2017 -- Today the U.S. Food and Drug Administration is announcing a new approach to get critical updates regarding antibiotics and antifungal drugs to health care professionals as part of an overall effort to combat antimicrobial...

http://ift.tt/2CcjsSt

Inhibitory effect of streptococci on the growth of M. catarrhalis strains and the diversity of putative bacteriocin-like gene loci in the genomes of S. pneumoniae and its relatives

S. pneumoniae is a facultative human pathogen causing a wide range of infections including the life-threatening pneumoniae or meningitis. It colonizes nasopharynx as well as its closest p...

http://ift.tt/2j246Yi

Immuno-fluorescent Labeling of Microtubules and Centrosomal Proteins in Ex Vivo Intestinal Tissue and 3D In Vitro Intestinal Organoids

We present protocols for isolation of intestinal 3D structures from in vivo tissue and in vitro basement matrix embedded organoids, and detail different fixation and staining protocols optimized for immuno-labeling of microtubule, centrosomal, and junctional proteins as well as cell markers including the stem cell protein Lgr5.

http://ift.tt/2nXAXTG

Research of differential expression of sIL1RAP in low-grade gliomas between children and adults

Abstract

Glioma is the most common intracranial malignant tumor. Low-grade gliomas (LGG) occupy almost 80% in all of the gliomas. The prognosis of LGG in children is much better than in adult, however, the molecular mechanism is still unclear. In our investigation, it was first found that the level of soluble IL1RAP (sIL1RAP) was significantly higher in the LGG from children than that from adult. We also revealed that sIL1RAP could induce the apoptosis of U251. In cells with overexpression of sIL-1RAP, the cell proliferation promoted by IL-1 was significantly inhibited. These decreased tumor growth ability and better prognosis of low-grade gliomas in children patients than that in adult patients. The expression level of sIL1RAP may become one of the potential indexes for determining the prognosis of low-grade gliomas.

http://ift.tt/2C8WED3

Flexible Measurement of Bioluminescent Reporters Using an Automated Longitudinal Luciferase Imaging Gas- and Temperature-optimized Recorder (ALLIGATOR)

Genetically encoded luciferase is a popular non-invasive reporter of gene expression. Use of an automated longitudinal luciferase imaging gas- and temperature-optimized recorder (ALLIGATOR) enables longitudinal recording from bioluminescent cells under a wide range of conditions. Here we show how ALLIGATOR may be used in the context of circadian rhythms research.

http://ift.tt/2yn1byG

Fla. family pushes for statewide mandatory CPR training in schools

Students would be required to learn to use cardiopulmonary resuscitation, or CPR, and an AED at least once before graduation

http://ift.tt/2Cc1wHH

The Ubiquitin E3 Ligase TRAF6 Exacerbates Ischemic Stroke by Ubiquitinating and Activating Rac1

Stroke is one of the leading causes of morbidity and mortality worldwide. Inflammation, oxidative stress, apoptosis, and excitotoxicity contribute to neuronal death during ischemic stroke; however, the mechanisms underlying these complicated pathophysiological processes remain to be fully elucidated. Here, we found that the expression of tumor necrosis factor receptor-associated factor 6 (TRAF6) was markedly increased after cerebral ischemia/reperfusion (I/R) in mice. TRAF6 ablation in male mice decreased the infarct volume and neurological deficit scores and decreased proinflammatory signaling, oxidative stress, and neuronal death after cerebral I/R, whereas transgenic overexpression of TRAF6 in male mice exhibited the opposite effects. Mechanistically, we demonstrated that TRAF6 induced Rac1 activation and consequently promoted I/R injury by directly binding and ubiquitinating Rac1. Either functionally mutating the TRAF6 ubiquitination site on Rac1 or inactivating Rac1 with a specific inhibitor reversed the deleterious effects of TRAF6 overexpression during I/R injury. In conclusion, our study demonstrated that TRAF6 is a key promoter of ischemic signaling cascades and neuronal death after cerebral I/R injury. Therefore, the TRAF6/Rac1 pathway might be a promising target to attenuate cerebral I/R injury.

SIGNIFICANCE STATEMENT Stroke is one of the most severe and devastating neurological diseases globally. The complicated pathophysiological processes restrict the translation of potential therapeutic targets into medicine. Further elucidating the molecular mechanisms underlying cerebral ischemia/reperfusion injury may open a new window for pharmacological interventions to promote recovery from stroke. Our study revealed that ischemia-induced tumor necrosis factor receptor-associated factor 6 (TRAF6) upregulation binds and ubiquitinates Rac1 directly, which promotes neuron death through neuroinflammation and neuro-oxidative signals. Therefore, precisely targeting the TRAF6-Rac1 axis may provide a novel therapeutic strategy for stroke recovery.

http://ift.tt/2Cc384d

Conditional Deletion of Ric-8b in Olfactory Sensory Neurons Leads to Olfactory Impairment

The olfactory system can discriminate a vast number of odorants. This ability derives from the existence of a large family of odorant receptors expressed in the cilia of the olfactory sensory neurons. Odorant receptors signal through the olfactory-specific G-protein subunit, Gαolf. Ric-8b, a guanine nucleotide exchange factor, interacts with Gαolf and can amplify odorant receptor signal transduction in vitro. To explore the function of Ric-8b in vivo, we generated a tissue specific knock-out mouse by crossing OMP-Cre transgenic mice to Ric-8b floxed mice. We found that olfactory-specific Ric-8b knock-out mice of mixed sex do not express the Gαolf protein in the olfactory epithelium. We also found that in these mice, the mature olfactory sensory neuron layer is reduced, and that olfactory sensory neurons show increased rate of cell death compared with wild-type mice. Finally, behavioral tests showed that the olfactory-specific Ric-8b knock-out mice show an impaired sense of smell, even though their motivation and mobility behaviors remain normal.

SIGNIFICANCE STATEMENT Ric-8b is a guanine nucleotide exchange factor (GEF) expressed in the olfactory epithelium and in the striatum. Ric-8b interacts with the olfactory Gαolf subunit, and can amplify odorant signaling through odorant receptors in vitro. However, the functional significance of this GEF in the olfactory neurons in vivo remains unknown. We report that deletion of Ric-8b in olfactory sensory neurons prevents stable expression of Gαolf. In addition, we demonstrate that olfactory neurons lacking Ric-8b (and consequently Gαolf) are more susceptible to cell death. Ric-8b conditional knock-out mice display impaired olfactory guided behavior. Our results reveal that Ric-8b is essential for olfactory function, and suggest that it may also be essential for Gαolf-dependent functions in the brain.

http://ift.tt/2nVpbc8

Proficiency testing program for hemoglobin E, A2 and F analysis in Thailand using lyophilized hemoglobin control materials

Authors: Pornprasert, Sakorn / Tookjai, Monthathip / Punyamung, Manoo / Pongpunyayuen, Panida / Treesuwan, Kallayanee


http://ift.tt/2zpWztb

Reply to: Hyperuricemia does not seem to be an independent risk factor for coronary heart disease

Authors: Braga, Federica / Ferraro, Simona / Pasqualetti, Sara / Panteghini, Mauro


http://ift.tt/2zEUUmF

Visual assessment of hemolysis affects patient safety

Authors: Luksic, Ana Helena / Nikolac Gabaj, Nora / Miler, Marijana / Dukic, Lora / Bakliza, Ana / Simundic, Ana-Maria


http://ift.tt/2z7FSmO

Validation of a pneumatic tube system to transport surgical pathology biopsy samples

Authors: Guibourg, Briac / Marcorelles, Pascale / Uguen, Arnaud


http://ift.tt/2iX6JxJ

Reference intervals for stone risk factors in 24-h urine among healthy adults of the Han population in China

Authors: Mai, Zanlin / Li, Xiaoxia / Cui, Zelin / Wu, Wenqi / Liu, Yongda / Ou, Lili / Liang, Yueping / Zhao, Zhijian / Liu, Yang / Mai, Xing / Zhu, Wei / Zhang, Tao / Cai, Chao / Yang, Houmeng / Zeng, Guohua


http://ift.tt/2z70Z8I

Reply to: Analytical evaluation of the performances of Diazyme and BRAHMS procalcitonin applied to Roche Cobas in comparison with BRAHMS PCT-sensitive Kryptor

Authors: Yuan, Chong


http://ift.tt/2iYmVeZ

The SEeMORE strategy: single-tube electrophoresis analysis-based genotyping to detect monogenic diseases rapidly and effectively from conception until birth

Authors: Cariati, Federica / Savarese, Maria / D'Argenio, Valeria / Salvatore, Francesco / Tomaiuolo, Rossella


http://ift.tt/2BnfcOZ

Reference values of fecal calgranulin C (S100A12) in school aged children and adolescents

Authors: Heida, Anke / Kobold, Anneke C. Muller / Wagenmakers, Lucie / van de Belt, Koos / van Rheenen, Patrick F.


http://ift.tt/2j3srwN

α-Defensin point-of-care test for diagnosis of prosthetic joint infections: neglected role of laboratory and clinical pathologists

Authors: Drago, Lorenzo / Toscano, Marco / Tacchini, Lorenza / Banfi, Giuseppe


http://ift.tt/2j1cp7e

Placental protein-13 (PP13) in combination with PAPP-A and free leptin index (fLI) in first trimester maternal serum screening for severe and early preeclampsia

Authors: De Villiers, Carin P. / Hedley, Paula L. / Placing, Sophie / Wøjdemann, Karen R. / Shalmi, Anne-Cathrine / Carlsen, Anting L. / Rode, Line / Sundberg, Karin / Tabor, Ann / Christiansen, Michael


http://ift.tt/2j1c4kY

Rivaroxaban non-responders: do plasma measurements have a place?

Authors: Dideriksen, Dorte / Damkier, Per / Nybo, Mads


http://ift.tt/2BkJjdq

Impact of Antimicrobial Stewardship program on Hospitalized Patients at the Intensive Care Unit: A prospective Audit and feedback Study

Aims

Inappropriate use of antibiotics is one of the most important factors contributing to the emergence of drug resistant pathogens. The purpose of this study was to measure the clinical impact of Antimicrobial Stewardship Program (ASP) interventions on hospitalized patients at the Intensive care unit at Palestinian Medical Complex.

Methods

A prospective audit with intervention and feedback by ASP team within 48-72h of antibiotic administration began in Sep, 2015. Four months of pre-ASP data with 4-months of post-ASP data were compared. Data collected included clinical and demographic data; utilization of antimicrobials measured by Define Daily Doses, duration of therapy, length of stay, readmission and all-cause mortality.

Results

Overall, 176 interventions were made the ASP team with an average acceptance rate of 78.4%. The most accepted interventions were dose optimization (87.0%) followed by de-escalation based on culture results with an acceptance rate of 84.4%. ASP interventions significantly reduces antimicrobial utilization by 24.3% (87.3 DDD/100 bed. vs 66.1 DDD/100 bed p<0.001). The median (IQR) of length of stay was significantly reduced post ASP (11 (3-21) vs. 7 (4-19) days; p <0.01). Also, the median (IQR) of duration of therapy was significantly reduced post-ASP (8 (5-12) days vs. 5 (3-9); p=0.01). There was no significant difference in overall 30-day mortality or readmission between the pre-ASP and post-ASP groups (26.9% vs. 23.9%; p=0.1) and (26.1% vs. 24.6%; p=0.54) respectively.

Conclusions

Our prospective audit and feedback program was associated with positive impact on antimicrobial utilization, duration of therapy and length of stay.

http://ift.tt/2iZlrBd

Extensive Tonotopic Mapping across Auditory Cortex Is Recapitulated by Spectrally Directed Attention and Systematically Related to Cortical Myeloarchitecture

Auditory selective attention is vital in natural soundscapes. But it is unclear how attentional focus on the primary dimension of auditory representation—acoustic frequency—might modulate basic auditory functional topography during active listening. In contrast to visual selective attention, which is supported by motor-mediated optimization of input across saccades and pupil dilation, the primate auditory system has fewer means of differentially sampling the world. This makes spectrally-directed endogenous attention a particularly crucial aspect of auditory attention. Using a novel functional paradigm combined with quantitative MRI, we establish in male and female listeners that human frequency-band-selective attention drives activation in both myeloarchitectonically estimated auditory core, and across the majority of tonotopically mapped nonprimary auditory cortex. The attentionally driven best-frequency maps show strong concordance with sensory-driven maps in the same subjects across much of the temporal plane, with poor concordance in areas outside traditional auditory cortex. There is significantly greater activation across most of auditory cortex when best frequency is attended, versus ignored; the same regions do not show this enhancement when attending to the least-preferred frequency band. Finally, the results demonstrate that there is spatial correspondence between the degree of myelination and the strength of the tonotopic signal across a number of regions in auditory cortex. Strong frequency preferences across tonotopically mapped auditory cortex spatially correlate with R₁-estimated myeloarchitecture, indicating shared functional and anatomical organization that may underlie intrinsic auditory regionalization.

SIGNIFICANCE STATEMENT Perception is an active process, especially sensitive to attentional state. Listeners direct auditory attention to track a violin's melody within an ensemble performance, or to follow a voice in a crowded cafe. Although diverse pathologies reduce quality of life by impacting such spectrally directed auditory attention, its neurobiological bases are unclear. We demonstrate that human primary and nonprimary auditory cortical activation is modulated by spectrally directed attention in a manner that recapitulates its tonotopic sensory organization. Further, the graded activation profiles evoked by single-frequency bands are correlated with attentionally driven activation when these bands are presented in complex soundscapes. Finally, we observe a strong concordance in the degree of cortical myelination and the strength of tonotopic activation across several auditory cortical regions.

http://ift.tt/2CcHjl8

Morphological Constraints on Cerebellar Granule Cell Combinatorial Diversity

Combinatorial expansion by the cerebellar granule cell layer (GCL) is fundamental to theories of cerebellar contributions to motor control and learning. Granule cells (GrCs) sample approximately four mossy fiber inputs and are thought to form a combinatorial code useful for pattern separation and learning. We constructed a spatially realistic model of the cerebellar GCL and examined how GCL architecture contributes to GrC combinatorial diversity. We found that GrC combinatorial diversity saturates quickly as mossy fiber input diversity increases, and that this saturation is in part a consequence of short dendrites, which limit access to diverse inputs and favor dense sampling of local inputs. This local sampling also produced GrCs that were combinatorially redundant, even when input diversity was extremely high. In addition, we found that mossy fiber clustering, which is a common anatomical pattern, also led to increased redundancy of GrC input combinations. We related this redundancy to hypothesized roles of temporal expansion of GrC information encoding in service of learned timing, and we show that GCL architecture produces GrC populations that support both temporal and combinatorial expansion. Finally, we used novel anatomical measurements from mice of either sex to inform modeling of sparse and filopodia-bearing mossy fibers, finding that these circuit features uniquely contribute to enhancing GrC diversification and redundancy. Our results complement information theoretic studies of granule layer structure and provide insight into the contributions of granule layer anatomical features to afferent mixing.

SIGNIFICANCE STATEMENT Cerebellar granule cells are among the simplest neurons, with tiny somata and, on average, just four dendrites. These characteristics, along with their dense organization, inspired influential theoretical work on the granule cell layer as a combinatorial expander, where each granule cell represents a unique combination of inputs. Despite the centrality of these theories to cerebellar physiology, the degree of expansion supported by anatomically realistic patterns of inputs is unknown. Using modeling and anatomy, we show that realistic input patterns constrain combinatorial diversity by producing redundant combinations, which nevertheless could support temporal diversification of like combinations, suitable for learned timing. Our study suggests a neural substrate for producing high levels of both combinatorial and temporal diversity in the granule cell layer.

http://ift.tt/2CeLQ6r

Working Memory and Decision-Making in a Frontoparietal Circuit Model

Working memory (WM) and decision-making (DM) are fundamental cognitive functions involving a distributed interacting network of brain areas, with the posterior parietal cortex (PPC) and prefrontal cortex (PFC) at the core. However, the shared and distinct roles of these areas and the nature of their coordination in cognitive function remain poorly understood. Biophysically based computational models of cortical circuits have provided insights into the mechanisms supporting these functions, yet they have primarily focused on the local microcircuit level, raising questions about the principles for distributed cognitive computation in multiregional networks. To examine these issues, we developed a distributed circuit model of two reciprocally interacting modules representing PPC and PFC circuits. The circuit architecture includes hierarchical differences in local recurrent structure and implements reciprocal long-range projections. This parsimonious model captures a range of behavioral and neuronal features of frontoparietal circuits across multiple WM and DM paradigms. In the context of WM, both areas exhibit persistent activity, but, in response to intervening distractors, PPC transiently encodes distractors while PFC filters distractors and supports WM robustness. With regard to DM, the PPC module generates graded representations of accumulated evidence supporting target selection, while the PFC module generates more categorical responses related to action or choice. These findings suggest computational principles for distributed, hierarchical processing in cortex during cognitive function and provide a framework for extension to multiregional models.

SIGNIFICANCE STATEMENT Working memory and decision-making are fundamental "building blocks" of cognition, and deficits in these functions are associated with neuropsychiatric disorders such as schizophrenia. These cognitive functions engage distributed networks with prefrontal cortex (PFC) and posterior parietal cortex (PPC) at the core. It is not clear, however, what the contributions of PPC and PFC are in light of the computations that subserve working memory and decision-making. We constructed a biophysical model of a reciprocally connected frontoparietal circuit that revealed shared and distinct functions for the PFC and PPC across working memory and decision-making tasks. Our parsimonious model connects circuit-level properties to cognitive functions and suggests novel design principles beyond those of local circuits for cognitive processing in multiregional brain networks.

http://ift.tt/2o0YjaG