Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00306932607174: 10/06/17

Παρασκευή 6 Οκτωβρίου 2017

Rett Syndrome

Among the vast body of literature that has grown around Rett syndrome, this volume is the first to be aimed at both clinicians and researchers. It presents a comprehensive overview of the disorder and examines the areas where gaps in knowledge are most significant. Rett Syndrome is intended to be a guide for both initial examination and in-depth study of the disorder. It is a practical text for the physician approaching the disorder for the first

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Estimating the Effect of Preventable Treatment Discontinuation on Health Outcomes.

Background: There is increased interest in studying the effects of medication adherence on health outcomes. However, if patients appropriately stop treatment because of side effects and treatment failure, it is neither possible nor clinically meaningful to estimate the effect of full medication adherence. Methods: We present an analysis designed to estimate the effect of non-medical (preventable) discontinuation of cinacalcet, an oral medication approved to treat secondary hyperparathyroidism in patients with end stage renal disease on dialysis on mortality and heart failure. The approach involves artificially censoring patients who discontinue treatment for a reason that does not appear to be related to an adverse effect of treatment. We address potential bias from informative censoring through inverse-probability of censoring weighted estimation. Results: Although the analysis is subject to possible residual confounding by the healthy adherer effect and other limitations, we find that potentially preventable discontinuation associates with 2.9 excess deaths at one year per 100 patients treated (95% CI 2.4, 3.5), and 4.6 excess deaths at two years (95% CI 3.5, 5.5). The association between cinacalcet persistence and heart failure hospitalization risk was sensitive to the outcome definition. Conclusions: Inverse-probability of censoring weighted estimation can be used to estimate the effect of potentially preventable treatment discontinuation in populations where treatment can be stopped for both medical and non-medical reasons. Estimates from such approaches may represent an upper bound of what would be achievable by an adherence improvement intervention. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Site-specific solid cancer mortality following exposure to ionizing radiation: a cohort study of workers (INWORKS).

BACKGROUND: There is considerable scientific interest in associations between protracted low-dose exposure to ionizing radiation and the occurrence of specific types of cancer. METHODS: Associations between ionizing radiation and site-specific solid cancer mortality were examined among 308,297 nuclear workers employed in France, the United Kingdom, and the United States. Workers were monitored for external radiation exposure and follow-up encompassed 8.2 million person-years. Radiation-mortality associations were estimated using a maximum likelihood method and using a Markov chain Monte Carlo method, the latter used to fit a hierarchical regression model to stabilize estimates of association. RESULTS: The analysis included 17,957 deaths due to solid cancer, the most common being lung, prostate, and colon cancer. Using a maximum likelihood method to quantify associations between radiation dose and site-specific cancer, we obtained positive point estimates for oral, esophagus, stomach, colon, rectum, pancreas, peritoneum, larynx, lung, pleura, bone and connective tissue, skin, ovary, testis, and thyroid cancer; in addition, we obtained negative point estimates for cancer of the liver and gallbladder, prostate, bladder, kidney, and brain. Most of these estimated coefficients exhibited substantial imprecision. Employing a hierarchical model for stabilization had little impact on the estimated associations for the most commonly observed outcomes, but for less frequent cancer types the stabilized estimates tended to take less extreme values and have greater precision than estimates obtained without such stabilization. CONCLUSIONS: The results provide further evidence regarding associations between low-dose radiation exposure and cancer. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Using Super Learner Prediction Modeling to Improve High-Dimensional Propensity Score Estimation.

The high-dimensional propensity score is a semi-automated variable selection algorithm that can supplement expert knowledge to improve confounding control in non-experimental medical studies utilizing electronic healthcare databases. While the algorithm can be used to generate hundreds of patient-level variables and rank them by their potential confounding impact, it remains unclear how to select the optimal number of variables for adjustment. Super Learner and collaborative targeted maximum likelihood estimation (collaborative targeted MLE) are tools for prediction modeling and causal inference that can be combined with the high-dimensional propensity score to improve propensity score estimation and confounding control in large healthcare databases. We used plasmode simulations based on empirical data to evaluate the performance of combining the high-dimensional propensity score with Super Learner and a scalable version of collaborative targeted MLE. We evaluated performance using bias and mean squared error (MSE) in effect estimates. Results showed that the high-dimensional propensity score can be sensitive to the number of variables included for adjustment and that severe overfitting of the propensity score model can negatively impact the properties of effect estimates. Combining the high-dimensional propensity score with the scalable version of collaborative targeted MLE performed well for many of the scenarios considered, but was sensitive to the parameter specifications within the algorithm. Combining the high-dimensional propensity score with Super Learner was the most consistent strategy, in terms of reducing bias and MSE in the effect estimates, and may be promising for semi-automated data-adaptive propensity score estimation in high-dimensional covariate datasets. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Diarrhoea during checkpoint blockade, not always colitis

Immune checkpoint inhibitors have radically changed the perspectives for many cancer patients. Blockade with antibodies against the checkpoints cytotoxic T-lymphocyte antigen 4, such as ipilimumab, and programmed cell death protein 1, such as pembrolizumab and nivolumab, augment the immunologic reaction against tumour cells. Immune checkpoint inhibitors can cause immune-related adverse events (irAEs) that may appear subclinical, can occur in multiple organs simultaneously and can be serious in nature.

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Future Horizons in Allergy

There are several advances in diagnosis and management for the otolaryngologist treating allergy. These include new technologies and the refinement of current techniques, and reflect overall trends in health care toward personalized medicine. Local immunoglobulin, urinary leukotriene E4, lipidomics, microRNA within extracellular vesicles, and optical rhinometry all offer to improve the diagnostic accuracy of allergy and related nonallergic conditions. New delivery systems for intranasal steroids and antihistamines, recombinant allergens, advances in allergen immunotherapy delivery, and biologics will improve current management options. These developments will aid the otolaryngologist in diagnosing and treating allergy and related diseases.

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The Role of Allergy in Otologic Disease

Allergy is commonly associated with conditions such as rhinitis, sinusitis, and asthma, but the relationship between allergy and otologic diseases is less clear. This article examines the evidence for a relationship between allergic disease and several common otologic conditions, including otitis media with effusion, eosinophilic otitis media, and Ménière's disease.

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The Role of Metabolic Surgery in Non-alcoholic Steatohepatitis Improvement

Abstract

Purpose of review

Non-alcoholic fatty liver disease (NAFLD) is frequently associated with obesity and overweight. It has a broad spectrum of clinical and histological presentations, such as steatosis, inflammation (known as non-alcoholic steatohepatitis or NASH), fibrosis, and cirrhosis. There is increasing evidence that marked weight loss following bariatric surgery is associated with NASH resolution; however, little is known about the mechanisms that may lead to this beneficial condition and if it is due to weight loss alone. In this review, the authors present the latest data regarding NASH resolution following metabolic surgery and try to answer the following questions: is NASH resolution due to weight loss alone or is it related to weight-independent effects similarly to T2D? In such case, can NASH be considered as a sole criterion for metabolic surgery?

Recent findings

Most data evaluating NAFLD and bariatric and metabolic surgery are derived from cohort studies. Available data are extremely variable, but in general show a dramatic regression of steatosis, inflammatory changes, and in some cases even fibrosis that is probably linked to major weight loss following surgery.

Summary

There are no randomized controlled trials evaluating the effects of metabolic surgery over NASH vs. lifestyle modifications. To consider NASH a sole indication for metabolic surgery regardless of BMI, such studies are desperately needed and should be the primary focus of future research in metabolic surgery.

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Future Horizons in Allergy

There are several advances in diagnosis and management for the otolaryngologist treating allergy. These include new technologies and the refinement of current techniques, and reflect overall trends in health care toward personalized medicine. Local immunoglobulin, urinary leukotriene E4, lipidomics, microRNA within extracellular vesicles, and optical rhinometry all offer to improve the diagnostic accuracy of allergy and related nonallergic conditions. New delivery systems for intranasal steroids and antihistamines, recombinant allergens, advances in allergen immunotherapy delivery, and biologics will improve current management options. These developments will aid the otolaryngologist in diagnosing and treating allergy and related diseases.

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The Role of Allergy in Otologic Disease

Allergy is commonly associated with conditions such as rhinitis, sinusitis, and asthma, but the relationship between allergy and otologic diseases is less clear. This article examines the evidence for a relationship between allergic disease and several common otologic conditions, including otitis media with effusion, eosinophilic otitis media, and Ménière's disease.

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The Role of the Sinonasal Epithelium in Allergic Rhinitis

The sinonasal epithelial barrier is comprised of tight and adherens junction proteins. Disruption of epithelial barrier function has been hypothesized to contribute to allergic disease such as allergic rhinitis through increased passage of antigens and exposure of underlying tissue to these stimuli. Several mechanisms of sinonasal epithelial barrier disruption include antigen proteolytic activity, inflammatory cytokine-mediated tight junction breakdown, or exacerbation from environmental stimuli. Mechanisms of sinonasal epithelial barrier stabilization include corticosteroids and nuclear erythroid 2-related factor 2 (Nrf2) cytoprotective pathway activation. Additional studies will aid in determining the contribution of epithelial barrier function in allergic rhinitis pathophysiology and tr...

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Asthma Management for the Otolaryngologist

Asthma is a chronic inflammatory disease that will frequently be encountered by otolaryngologists as they manage their patients with upper respiratory diseases. Symptoms such as cough should alert otolaryngologists to consider more broadly the potential role of asthma in the differential diagnosis. It is critical for otolaryngologists to appreciate that patients with allergic rhinitis and chronic rhinosinusitis will often have asthma, and that many of them may not be diagnosed at the time of presentation. Appropriate diagnosis of the patient with asthma, as well as effective treatment for its symptoms, will improve patient function and enhance quality of life. (Source: Otolaryngologic clinics of North America)

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Advancements and Dilemmas in the Management of Allergy

This article explores recent advances and their clinical implications. (Source: Otolaryngologic clinics of North America)

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Diagnostic flaws in oral lichen planus and related lesions

There has been a constant debate as to the exact prevalence and malignant potential of oral lichen planus (OLP). The present ambiguity is due to the existence of lesions which have a clinicopathological resemblance to OLP [1]. Our research team had conducted a retrospective study on OLP and related lesions like oral epithelial dysplasia (OED), OLP, OLP with dysplasia and oral lichenoid lesions (OLL), and have commented on the possible existence of "oral lichenoid dysplasia" (OLD) which is a primary epithelial dysplasia with secondary lichenoid features as opposed to "OLP with dysplasia" which is a lichen planus with secondary dysplastic features [2].

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Diagnostic flaws in oral lichen planus and related lesions

There has been a constant debate as to the exact prevalence and malignant potential of oral lichen planus (OLP). The present ambiguity is due to the existence of lesions which have a clinicopathological resemblance to OLP [1]. Our research team had conducted a retrospective study on OLP and related lesions like oral epithelial dysplasia (OED), OLP, OLP with dysplasia and oral lichenoid lesions (OLL), and have commented on the possible existence of "oral lichenoid dysplasia" (OLD) which is a primary epithelial dysplasia with secondary lichenoid features as opposed to "OLP with dysplasia" which is a lichen planus with secondary dysplastic features [2].

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Escaping BRAF inhibition: a “linc” with non-coding RNAs?

One of the major challenges in the field remains the defeat of resistance towards BRAF inhibition, mainly caused by the high heterogeneity and plasticity of melanoma cells. Understanding mechanisms of drug resistance and finding new strategies to block the relapse are therefore major concerns in the melanoma field. So far however, most of the focus remained on the identification of genetic events affecting proteins-coding genes.

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Androgen Receptor in Estrogen Receptor Positive Breast Cancer: beyond expression

Despite recent advances and new therapeutic strategies, the molecular mechanisms underlying breast cancer (BC), are yet not fully understood. Breast cancer remains the leading cause of cancer-related death in women. In 2017, the American Cancer Society in the United States estimates that there will be around 252,710 new cases of invasive BC in women and 40,610 deaths [1]. In Europe, 463,800 cases of female BC were estimated in 2012, and 131,200 deaths were related to BC [2].

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Thyroid stimulating hormone

Thyroid stimulating hormone: A hormone produced by the pituitary gland at the base of the brain in response to signals from the hypothalamus gland in the brain. Thyroid stimulating hormone (TSH) promotes the growth of the thyroid gland in the neck and stimulates it to produce more thyroid hormones. When there is an excessive amount of thyroid hormones, the pituitary gland stops producing TSH, reducing thyroid hormone production. This mechanism maintains a relatively constant level of thyroid hormones circulating in the blood.

TSH is also known as thyrotropin.

MedTerms (TM) is the Medical Dictionary of MedicineNet.com.
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Maize

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Micro-autologous fat transplantation for rejuvenation of the dorsal surface of the ageing hand

Rejuvenation of the dorsal surface of the hand for various conditions, such as cutaneous dyschromia, fine wrinkling, skin laxity, visible extensor tendons, and varicosities appear vital to prevent wrist and digit flexion resulting from hiding of the aged appearance of the hand. Numerous fillers have been applied to re-contour the ageing dorsal surface of the hand; the results were variable. The micro-autologous fat transplantation (MAFT) technique, proposed by Lin et al. in 2006, has demonstrated its feasibility in facial rejuvenation.

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Decision-making frameworks and considerations for informing coverage decisions for healthcare interventions: A critical interpretive synthesis

Publication date: Available online 6 October 2017
Source:Journal of Clinical Epidemiology
Author(s): Rebecca L. Morgan, Leah Kelley, Gordon Guyatt, Ana Johnson, John N. Lavis
ObjectiveTo guide decision-making about whether or not to pay for a new healthcare intervention, a number of existing frameworks systematically weigh scientific evidence, cost, and social and ethical values. Each framework has strengths and limitations. This study aims to review and summarize available frameworks, and generate an integrated framework, if and where applicable, highlighting particular issues faced with expensive but effective and desirable healthcare interventions.Study Design and SettingWe conducted a critical interpretive synthesis to inform decision-making about healthcare interventions. We updated prior systematic reviews on decision-making frameworks through 2015. Purposive sampling identified relevant constructs and considerations to facilitate decision-making.ResultsOut of 2980 references, we purposively sampled 19 frameworks. The new framework, which built upon the GRADE Evidence to Decision (EtD) framework, included burden of disease, benefits and harms, values and preferences, resource use, equity, acceptability, and feasibility. Modifications to the EtD framework included adding limitations of alternative technologies considerations in use (expanding benefits and harms) and broadening acceptability and feasibility constructs to include political and health system factors. No modifications appeared necessary to address the situation of effective but expensive and desirable interventions.ConclusionGuideline developers, health technology assessment producers, and decision-makers can use our integrated framework to inform decision-making about healthcare interventions.

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Androgen Receptor in Estrogen Receptor Positive Breast Cancer: beyond expression

Comparative Study of Head and Neck Mucosal Melanoma in 66 patients vs. 226 patients with Cutaneous Melanoma: A survival analysis

Abstract

Sixty-six patients (22%) had HNMM and 226 (78%) HNCM and the higher prevalence was seen in females with a similar distribution amongst the two diagnoses (p=0.8).

Symptoms were present in all patients with HNCM and in only 15% of patients with HNMM (p=0.000).

Lymph node involvement at diagnosis was present in 51% of HNMM vs. 33% of HNCM (p=0.007) and were bilateral in 44% of HNMM while in HNCM they were only ipsilateral (p=0.000).

Metastatic disease at diagnosis was similar in both groups (p=0.9).

Relapses were more frequent in the HNMM group in ~70% of the cases compared with 23% in HNCM group (p=0.000).

When comparing HNCM vs. HNMM, Overall Survival is similar, without statistical difference.

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Revision of the genus complex Gibbula : an integrative approach to delineating the Eastern Mediterranean genera Gibbula Risso, 1826, Steromphala Gray, 1847, and Phorcus Risso, 1826 using DNA-barcoding and geometric morphometrics (Vetigastropoda, Trochoidea)

Abstract

The trochoid genus, Gibbula, is abundant and diverse in the Mediterranean Sea but problematic to identify and delineate. This is due to highly variable shell morphology, vague original descriptions, and missing or unspecific type material. In recent studies, COI barcoding yielded satisfactory results for species delineation. In the present study, a combination of geometric shell morphometric methods and COI barcoding was used to assess the most abundant species of the Eastern Mediterranean. All relevant identification characters were captured via standardised images of the shells in both lateral and ventral views. Agreeing with previous studies, Gibbula was recovered as paraphyletic in the molecular analysis and thus is restricted to the clade encompassing the type species Gibbula magus (Linnaeus, 1758). The geometric morphometric analyses and the barcoding approach clearly distinguish the remaining species into two groups: the genus Steromphala Gray, 1847 and the genus Phorcus Risso, 1826. Type material was used for the geometric morphometric analyses whenever possible. Based on re-examination of the original type descriptions, lectotypes were designated. The joint application of DNA-barcoding and geometric morphometrics not only effectively delineated the sister genera Steromphala and Phorcus but also delineated all analysed species in the Gibbula-Steromphala-Phorcus genus complex. The additional use of geometric morphometrics enables researchers to compare barcoded material with fossil specimens or dry collections in an objective way.

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Detection of genetic alterations in cfDNA as a possible strategy to monitor the neoplastic progression of Barrett’s esophagus

Publication date: Available online 6 October 2017
Source:Translational Research
Author(s): Enrica Rumiato, Elisa Boldrin, Sandro Malacrida, Stefano Realdon, Matteo Fassan, Tiziana Morbin, Giorgio Battaglia, Alberto Amadori, Massimo Rugge, Daniela Saggioro
Barrett's esophagus (BE) is associated with an increased risk of developing esophageal adenocarcinoma (EAC). Despite the low absolute risk of neoplastic progression of BE, probability increases with the diagnosis of dysplasia. For this reason, BE patients undergo an endoscopy-based surveillance that is, however, burdensome for patients, subject to inter-observer subjectivity, and expensive for national health systems. Thus, less invasive and low-cost diagnostic tools are needed. This study is aimed at finding a simple and reliable method to detect in the circulating cell-free DNA (cfDNA) of BE patients evidence of the molecular instability that accompanies BE carcinogenesis. We chose the loss of heterozygosity (LOH) analysis because chromosomal region gains or losses have been described in BE and EAC. Furthermore, this analysis does not require an a priori knowledge of tumor specific mutations and/or rearrangements. Previous data showed a good consistency between tissue and cfDNA alterations. Here, we report that, in the cfDNA of dysplastic BE patients the frequency of genetic alterations is statistically higher than that of metaplastic BE patients (P=0.005). Interestingly, after endoscopic treatment, the alteration frequency dropped, suggesting that cfDNA can also be used to monitor curative effects. Among the used markers, those that map nearby TP53 gene were the most discriminant between metaplastic and dysplastic BE. Furthermore, longitudinal follow-up cases showed that genetic alterations can be found in cfDNA before the appearance of a detectable lesion. Altogether, our data suggest that the use of liquid biopsy could become a minimally-invasive diagnostic tool to implement BE patient monitoring.

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Comparison of the trapping effect and antioxidant enzymatic activities using three different light sources in cockchafers

Abstract

Light traps have been widely used for controlling underground pests. However, very little is known regarding the relationship between trapping effect and antioxidant enzymatic activities using light irradiation in underground pests. Thus, we determined the trapping effect of three light sources of the frequoscillation pest-killing lamp on two species of cockchafers, Serica orientalis Motschulsky (Coleoptera: Melolonthidae) and Anomala corpulenta Motschulsky (Coleoptera: Rutelidae), and evaluated the effect of the same three light sources on the activities of their antioxidant enzymes. The catches of S. orientalis were significantly higher compared to A. corpulenta using light source A in peanut fields in China. After irradiation by light source A, the malondialdehyde (MDA) contents and activities of superoxide dismutase (SOD) and glutathione S-transferases (GST) in S. orientalis were significantly and marginally significantly lower compared to A. corpulenta. Taken together, these results indicated a weaker antioxidant enzyme activity response to light stress and a larger quantity of trapping catches using light irradiation in cockchafers. Thus, we proposed a potential negative relationship between trapping effect and antioxidant enzymatic activities in response to light irradiation in cockchafers.

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Investigating psychological and physiological responses to the Trier social stress test in young adults with insomnia: a preliminary study

Stress and hyperarousal both contribute to insomnia. Elevated stress-related sleep reactivity is associated with hyperarousal, and might constitute a vulnerability to future insomnia. The present study examined acute stress-induced arousal and its association with nocturnal sleep.

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How Frequent Is Itch? Facts and Thoughts of a Long Neglected Aspect of Itch

Abstract

Purpose of Review

Itch is the most frequent symptom of the skin, but its epidemiology including frequency has not been researched until a few years ago. Data is limited due to, e.g., the undulatory pattern of this symptom and the wide clinical spectrum such as itch being associated with a skin disease and itch on normal-looking skin. In addition, itch is an interdisciplinary symptom that is not paid attention to the same way in all clinical disciplines. This diversity may explain the incompleteness of epidemiological data of itch.

Recent Findings

With a recurrent symptom, it is important to consider different prevalence estimates (point-, 12-month, and lifetime prevalence) and to have a clear definition of itch. Recent population-based research demonstrates that more people suffer from chronic itch than previously assumed.

Summary

The chapter summarizes new findings concerning the epidemiology of itch in the general population and in selected patient populations.

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The Regulation of Notch Signaling in Retinal Development and Regeneration

Abstract

Purpose of Review

Notch signaling is an important component of retinal progenitor cell maintenance and Muller glia (MG) specification during development, and its manipulation may be critical for allowing MG to re-enter the cell cycle and regenerate neurons in adults. In mammals, MG respond to retinal injury by undergoing a gliotic response rather than a regenerative one. Understanding the complexities of Notch signaling may allow for strategies that enhance regeneration over gliosis.

Recent Findings

Notch signaling is regulated at multiple levels and is interdependent with various other signaling pathways in both the receptor- and ligand-expressing cells. The precise spatial and temporal patterning of Notch components is necessary for proper retinal development. Regenerative species undergo a dynamic regulation of Notch signaling in MG upon injury, whereas non-regenerative species fail to productively regulate Notch.

Summary

Notch signaling is malleable, such that the altered composition of growth and transcription factors in the developing and mature retinas results in different Notch-mediated responses. Successful regeneration will require the manipulation of the retinal environment to foster a dynamic rather than static regulation of Notch signaling in concert with other reprogramming and differentiation factors.

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Cell-specific expression of runt-related transcription factor 2 contributes to pulmonary fibrosis [Research]

Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease with limited therapeutic options and unknown etiology. IPF is characterized by epithelial cell injury, impaired cellular crosstalk between epithelial cells and fibroblasts, and the formation of fibroblast foci with increased extracellular matrix deposition (ECM). We investigated the role of runt-related transcription factor 2 (RUNX2), a master regulator of bone development that has been linked to profibrotic signaling. RUNX2 expression was up-regulated in lung homogenates from patients with IPF and in experimental bleomycin-induced lung fibrosis. The RUNX2 level correlated with disease severity as measured by decreased diffusing capacity and increased levels of the IPF biomarker, matrix metalloproteinase 7. Nuclear RUNX2 was observed in prosurfactant protein C–positive hyperplastic epithelial cells and was rarely found in myofibroblasts. We discovered an up-regulation of RUNX2 in fibrotic alveolar epithelial type II (ATII) cells as well as an increase of RUNX2-negative fibroblasts in experimental and human pulmonary fibrosis. Functionally, small interfering RNA–mediated RUNX2 knockdown decreased profibrotic ATII cell function, such as proliferation and migration, whereas fibroblasts displayed activation markers and increased ECM expression after RUNX2 knockdown. This study reveals that RUNX2 is differentially expressed in ATII cells vs. fibroblasts in lung fibrosis, which contributes to profibrotic cell function. Cell-specific targeting of RUNX2 pathways may represent a therapeutic approach for IPF.—Mümmler, C., Burgy, O., Hermann, S., Mutze, K., Günther, A., Königshoff, M. Cell-specific expression of runt-related transcription factor 2 contributes to pulmonary fibrosis.

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Groundwater Connectivity of Upland-Embedded Wetlands in the Prairie Pothole Region

Abstract

Groundwater connections from upland-embedded wetlands to downstream waterbodies remain poorly understood. In principle, water from upland-embedded wetlands situated high in a landscape should flow via groundwater to waterbodies situated lower in the landscape. However, the degree of groundwater connectivity varies across systems due to factors such as geologic setting, hydrologic conditions, and topography. We use numerical models to evaluate the conditions suitable for groundwater connectivity between upland-embedded wetlands and downstream waterbodies in the prairie pothole region of North Dakota (USA). Results show groundwater connectivity between upland-embedded wetlands and other waterbodies is restricted when these wetlands are surrounded by a mounding water table. However, connectivity exists among adjacent upland-embedded wetlands where water–table mounds do not form. In addition, the presence of sand layers greatly facilitates groundwater connectivity of upland-embedded wetlands. Anisotropy can facilitate connectivity via groundwater flow, but only if it becomes unrealistically large. These findings help consolidate previously divergent views on the significance of local and regional groundwater flow in the prairie pothole region.

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Non adherence to inhalational medications and associated factors among patients with asthma in a referral hospital in Ethiopia, using validated tool TAI

Asthma is a chronic inflammatory condition of the airways that affects roughly 358 million people globally. It is a serious global health problem with an increasing prevalence worldwide. Most people affected a...

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Comments on “Mapping the scientific research on non-point source pollution: a bibliometric analysis” by Yang et al. (2017)

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NO 2 inhalation enhances asthma susceptibility in a rat model

Abstract

Nitrogen dioxide (NO₂) is a major air pollutant. Epidemiologic studies have found that NO₂ exposure is associated with an increased risk of asthma. Nevertheless, the potential molecular mechanisms remain unclear. In this study, we investigated the effect of NO₂ inhalation on the occurrence of allergic airway inflammation and its underlying mechanisms. Firstly, male Wistar rats were exposed to 2 and 5 mg/m³ NO₂ (28 days, 5 h/day). The results showed that NO₂ exposure could induce pulmonary inflammatory response, mucus formation, and Th1/Th2 imbalance in the lung of normal rats, resulting in allergic asthma-like features. Secondly, male Wistar rats were exposed to 5 mg/m³ NO₂ (42 days, 5 h/day), sensitized with ovalbumin (OVA), challenged with aerosolized OVA, and characterized in asthma models. Results showed that NO₂ exposure aggravated lung inflammation in the OVA-sensitized rats, accompanied by the increase in inflammatory cell infiltration, mucus hypersecretion, and collagen deposition. Furthermore, NO₂ exposure promoted the increase in the expression of mucin gene (MUC5AC) and pro-inflammatory factors [interleukin (IL)-1β, intercellular adhesion molecule-1 (ICAM-1), and IL-6] as well as serum OVA-specific immunoglobulin E (IgE) production. Taken together, we established that NO₂ exposure promotes allergic airway inflammation and increases the asthma susceptibility. The underlying mechanisms involve the promotion of activation of interleukin-4/signal transducer and activator of transcription-6 (IL-4/STAT6) pathway [IL-4 receptor (IL-4R) α, janus kinase (JAK) 1, JAK 3, and STAT6] and related transcription factor [T cell-specific protein-tyrosine kinase (Lck), extracellular-regulated kinase (ERK)1/2, and nuclear factor-κB (NF-κB)]. In particular, the imbalance of Th1/Th2 cell differentiation [IL-4, interferon (IFN)-γ, GATA-binding protein-3 (GATA-3), and T-box expressed in T cells (T-bet)] plays a pivotal role in NO₂-induced inflammatory responses. These findings may provide a better understanding of mechanism of NO₂-associated respiratory diseases.

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Does elevated wall tension cause aortic aneurysm rupture? Investigation using a subject-specific heterogeneous model

Publication date: Available online 6 October 2017
Source:Journal of Biomechanics
Author(s): Timothy K. Chung, Erasmo S. da Silva, Suresh M.L. Raghavan
ObjectiveTo investigate whether peak wall tension in abdominal aortic aneurysm occurs at the site of rupture to test for a causative relationship.MethodsFour ruptured and nine unruptured AAA were harvested whole from cadavers, followed by regional measurements of wall thickness, elastic parameters and failure tension. Finite element models were developed with subject-specific load-free AAA morphology and heterogeneous properties interpolated using a geodesic distance weighted approach from the measurements. The wall tension under uniform pressure and tension to failure tension ratio as an index of susceptibility to rupture were computed. As a secondary aim, the peak wall tension using this heterogeneous model approach was compared to the traditional homogeneous model approach in order to evaluate the reliability of the latter.ResultsThe average peak wall tension in the ruptured group was 43% higher than in the unruptured group without statistical significance even though it was 54% larger in diameter. The site of peak wall tension was in the vicinity of the site of rupture in two ruptured AAA. The peak tension did not breach failure tension at the rupture site in any of the AAA. The traditional population-wide homogeneous model approach overestimated peak wall tension by just 3% compared to the subject-specific heterogeneous model approach.ConclusionWe failed to find adequate evidence of a causative relationship between peak wall tension and AAA rupture. The findings are not conclusive owing to study limitations such as ignoring intraluminal thrombus, sparse distribution of specimens procured and small study population.

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A Model-based Approach for Estimation of Changes in Lumbar Segmental Kinematics Associated with Alterations in Trunk Muscle Forces

Publication date: Available online 6 October 2017
Source:Journal of Biomechanics
Author(s): Iman Shojaei, Navid Arjmand, Judith R. Meakin, Babak Bazrgari
The kinematics information from imaging, if combined with optimization-based biomechanical models, may provide a unique platform for personalized assessment of trunk muscle forces (TMFs). Such a method, however, is feasible only if differences in lumbar spine kinematics due to differences in TMFs can be captured by the current imaging techniques. A finite element model of the spine within an optimization procedure was used to estimate segmental kinematics of lumbar spine associated with five different sets of TMFs. Each set of TMFs was associated with a hypothetical trunk neuromuscular strategy that optimized one aspect of lower back biomechanics. For each set of TMFs, the segmental kinematics of lumbar spine was estimated for a single static trunk flexed posture involving, respectively, 40° and 10° of thoracic and pelvic rotations. Minimum changes in the angular and translational deformations of a motion segment with alterations in TMFs ranged from 0° to 0.7° and 0 mm to 0.04 mm, respectively. Maximum changes in the angular and translational deformations of a motion segment with alterations in TMFs ranged from 2.4° to 7.6° and 0.11 mm to 0.39 mm, respectively. The differences in kinematics of lumbar segments between each combination of two sets of TMFs in 97% of cases for angular deformation and 55% of cases for translational deformation were within the reported accuracy of current imaging techniques. Therefore, it might be possible to use image-based kinematics of lumbar segments along with computational modeling for personalized assessment of TMFs.

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Urethral lumen occlusion by artificial sphincteric device: evaluation of degraded tissues effects

Publication date: Available online 6 October 2017
Source:Journal of Biomechanics
Author(s): Arturo Nicola Natali, Chiara Giulia Fontanella, Silvia Todros, Emanuele Luigi Carniel
Urinary incontinence can be surgically treated by means of artificial sphincters, based on a cuff that provides a pressure around the urethra to occlude the lumen. Considering the frequent access of elderly patients to this surgical practice, tissue degradation phenomena must be investigated, since they could affect treatment reliability and durability. The potential degradation can be interpreted considering a variation within soft tissue constitutive formulation, by means of a correlation between mechanical properties and tissues ageing. The overall compressibility varies, as characteristics aspect of soft tissue mechanical response with age, as well as the stiffness. The investigation is performed by means of a three dimensional numerical model of the urethral duct. The effects of the interaction phenomenon with a cuff is interpreted considering the changes, within the constitutive models, of the basic parameters that define the potential degradation process. The deformation related to compressibility is recalled, ranging between ten and fifty percent in dependence on the degradation level considered. This parameter, reported mostly as representative of the aging effect, shows a large variation that confirms the relevance of the investigation performed toward a sensitivity of the mechanical response of the urethral duct referred to the lumen occlusion.

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A computational model of the hepatic circulation applied to analyze the sensitivity of hepatic venous pressure gradient (HVPG) in liver cirrhosis

Publication date: Available online 6 October 2017
Source:Journal of Biomechanics
Author(s): Tianqi Wang, Fuyou Liang, Zunqiang Zhou, Lu Shi
Measurement of hepatic venous pressure gradient (HVPG) is currently widely adopted to provide an estimate of portal pressure gradient (PPG) in the diagnosis and treatment of portal hypertension associated with liver cirrhosis. Despite the well-documented clinical utility of HVPG, it remains poorly understood how the relationship between HVPG and PPG is affected by factors involved in the pathogenesis and progression of cirrhosis. In the study, a computational model of the hepatic circulation calibrated to in vivo data was developed to simulate the procedure of HVPG measurement and quantitatively investigate the error of HVPG relative to PPG under various pathophysiological conditions. Obtained results confirmed the clinical consensus that HVPG is applicable to the assessment of portal hypertension caused by increased vascular resistance located primarily at the sinusoidal and postsinusoidal sites rather than at the presinusoidal site. On the other hand, our study demonstrated that the accuracy of HVPG measurement was influenced by many factors related to hepatic hemodynamics even in the case of sinusoidal portal hypertension. For instance, varying presinusoidal portal vascular resistance significantly altered the difference between HVPG and PPG, while an enhancement in portosystemic collateral flow tended to improve the accuracy of HVPG measurement. Moreover, it was found that presinusoidal and postsinusoidal vascular resistances interfered with each other with respect to their influence on HVPG measurement. These findings suggest that one should take into account patient-specific pathological conditions in order to achieve a better understanding and utilization of HVPG in the clinical practice.

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Inter- and intra-rater reliability of 3D kinematics during maximum mouth opening of asymptomatic subjects.

Publication date: Available online 6 October 2017
Source:Journal of Biomechanics
Author(s): Leticia Bojikian Calixtre, Theresa Helissa Nakagawa, Francisco Alburquerque-Sendín, Bruno Leonardo da Silva Grüninger, Lianna Ramalho de Sena Rosa, Ana Beatriz Oliveira
Previous studies evaluated 3D human jaw movements using kinematic analysis systems during mouth opening, but information on the reliability of such measurements is still scarce. The purpose of this study was to analyze within- and between-session reliabilities, inter-rater reliability, standard error of measurement (SEM), minimum detectable change (MDC) and consistency of agreement across raters and sessions of 3D kinematic variables during maximum mouth opening (MMO). Thirty-six asymptomatic subjects from both genders were evaluated on two different days, five to seven days apart. Subjects performed three MMO movements while kinematic data were collected. Intraclass correlation coefficient (ICC), SEM and MDC were calculated for all variables, and Bland-Altman plots were constructed. Jaw radius and width were the most reproducible variables (ICC>0.81) and demonstrated minor error. Incisor displacement during MMO and angular movements in the sagittal plane presented good reliability (ICC from 0.61 to 0.8) and small errors and, consequently, could be used in future studies with the same methodology and population. The variables with smaller amplitudes (condylar translations during mouth opening and closing and mandibular movements on the frontal and transversal planes) were less reliable (ICC<0.61) and presented larger SEM and MDC. Although ICC, SEM and MDC showed less between-session reproducibility than within-session and inter-rater, the limits of agreement were larger in inter-rater comparisons. In future studies care must be taken with variables collected on different days and with mandibular movements in the frontal and transversal planes.

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A comparison and update of direct kinematic-kinetic models of leg stiffness in human running.

Publication date: Available online 6 October 2017
Source:Journal of Biomechanics
Author(s): Bernard X.W. Liew, Susan Morris, Ashleigh Masters, Kevin Netto
Direct kinematic-kinetic modelling currently represents the "Gold-standard" in leg stiffness quantification during three-dimensional (3D) motion capture experiments. However, the medial-lateral components of ground reaction force and leg length have been neglected in current leg stiffness formulations. It is unknown if accounting for all 3D would alter healthy biologic estimates of leg stiffness, compared to present direct modelling methods. This study compared running leg stiffness derived from a new method (multiplanar method) which includes all three Cartesian axes, against current methods which either only include the vertical axis (line method) or only the plane of progression (uniplanar method). Twenty healthy female runners performed shod overground running at 5.0 m/s. Three-dimensional motion capture and synchronised in-ground force plates were used to track the change in length of the leg vector (hip joint centre to centre of pressure) and resultant projected ground reaction force. Leg stiffness was expressed as dimensionless units, as a percentage of an individual's bodyweight divided by standing leg length (BW/LL). Leg stiffness using the line method was larger than the uniplanar method by 15.6%BW/LL (P < 0.001), and multiplanar method by 24.2%BW/LL (P < 0.001). Leg stiffness from the uniplanar method was larger than the multiplanar method by 8.5%BW/LL (6.5kN/m) (P < 0.001). The inclusion of medial-lateral components significantly increased leg deformation magnitude, accounting for the reduction in leg stiffness estimate with the multiplanar method. Given that limb movements typically occur in 3D, the new multiplanar method provides the most complete accounting of all force and length components in leg stiffness calculation.

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Estimation of in vivo inter-vertebral loading during motion using fluoroscopic and magnetic resonance image informed finite element models

Publication date: Available online 6 October 2017
Source:Journal of Biomechanics
Author(s): Sahand Zanjani-Pour, Judith R. Meakin, Alex Breen, Alan Breen
Finite element (FE) models driven by medical image data can be used to estimate subject-specific spinal biomechanics. This study aimed to combine magnetic resonance (MR) imaging and quantitative fluoroscopy (QF) in subject-specific FE models of upright standing, flexion and extension. Supine MR images of the lumbar spine were acquired from healthy participants using a 0.5 T MR scanner. Nine 3D quasi-static linear FE models of L3 to L5 were created with an elastic nucleus and orthotropic annulus. QF data was acquired from the same participants who performed trunk flexion to 60^o and trunk extension to 20^o. The displacements and rotations of the vertebrae were calculated and applied to the FE model. Stresses were averaged across the nucleus region and transformed to the disc co-ordinate system (S1 = mediolateral, S2 = anteroposterior, S3 = axial). In upright standing S3 was predicted to be -0.7 ± 0.6 MPa (L3L4) and -0.6 ± 0.5 MPa (L4L5). S3 increased to -2.0 ± 1.3 MPa (L3L4) and -1.2 ± 0.6 MPa (L4L5) in full flexion and to -1.1 ± 0.8 MPa (L3L4) and -0.7 ± 0.5 MPa (L4L5) in full extension. S1 and S2 followed similar patterns; shear was small apart from S23. Disc stresses correlated to disc orientation and wedging. The results demonstrate that MR and QF data can be combined in a participant-specific FE model to investigate spinal biomechanics in vivo and that predicted stresses are within ranges reported in the literature.

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A Comprehensive Assessment of the Musculoskeletal System: The CAMS-Knee Data Set

Publication date: Available online 6 October 2017
Source:Journal of Biomechanics
Author(s): William R. Taylor, Pascal Schütz, Georg Bergmann, Renate List, Barbara Postolka, Marco Hitz, Jörn Dymke, Philipp Damm, Georg Duda, Hans Gerber, Verena Schwachmeyer, Seyyed Hamed Hosseini Nasab, Adam Trepczynski, Ines Kutzner
Combined knowledge of the functional kinematics and kinetics of the human body is critical for understanding a wide range of biomechanical processes including musculoskeletal adaptation, injury mechanics, and orthopaedic treatment outcome, but also for validation of musculoskeletal models. Until now, however, no datasets that include internal loading conditions (kinetics), synchronized with advanced kinematic analyses in multiple subjects have been available. Our goal was to provide such datasets and thereby foster a new understanding of how in vivo knee joint movement and contact forces are interlinked – and thereby impact biomechanical interpretation of any new knee replacement design. In this collaborative study, we have created unique kinematic and kinetic datasets of the lower limb musculoskeletal system for worldwide dissemination by assessing a unique cohort of 6 subjects with instrumented knee implants (Charité – Universitätsmedizin Berlin) synchronized with a moving fluoroscope (ETH Zürich) and other measurement techniques (including whole body kinematics, ground reaction forces, video data, and electromyography data) for multiple complete cycles of 5 activities of daily living. Maximal tibio-femoral joint contact forces during walking (mean peak 2.74BW), sit-to-stand (2.73BW), stand-to-sit (2.57BW), squats (2.64BW), stair descent (3.38BW), and ramp descent (3.39BW) were observed. Internal rotation of the tibia ranged from 3° external to 9.3° internal. The greatest range of anterio-posterior translation was measured during stair descent (medial 9.3±1.0mm, lateral 7.5±1.6mm), and the lowest during stand-to-sit (medial 4.5±1.1mm, lateral 3.7±1.4mm). The complete and comprehensive datasets will soon be made available online for public use in biomechanical and orthopaedic research and development.

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Combining amino amide salts in mucoadhesive films enhances needle-free buccal anesthesia in adults

Publication date: 28 November 2017
Source:Journal of Controlled Release, Volume 266
Author(s): Renê Oliveira do Couto, Camila Cubayachi, Paulo Linares Calefi, Renata Fonseca Vianna Lopez, Vinícius Pedrazzi, Cristiane Masetto De Gaitani, Osvaldo de Freitas
Needle-phobia is usually a great concern in dentistry, and the replacement of painful injections by patient-friendly needle-free topical formulations would bring several advantages in dental practice worldwide. In this pursuit, the effects of combining prilocaine hydrochloride (PCL) and lidocaine hydrochloride (LCL) in different proportions in mucoadhesive films on their in vitro permeation and retention through porcine esophageal mucosa was studied. Complementarily, the permeation and retention of isolated LCL was investigated. The in vitro model used for evaluating buccal anesthetic penetration and retention in buccal epithelium was validated. In addition, the feasibility of a novel in vivo model to evaluate the painful sensation due to puncture "needle-shaped" gum jaw of adults at shallow and deep levels was demonstrated. The in vivo clinical survey revealed the efficiency of the films, which had onset of anesthesia at 5min, peak of anesthetic effect within 15 and 25min and anesthesia duration of 50min after being placed in maxillary sites. The in vitro drug flux, permeability coefficient and retention in the epithelium significantly correlated with in vivo onset, peak and extent of shallow and deep anesthetic effect. At shallow level, the permeation of LCL has shown to be closely related to the onset of anesthesia, while the penetration of PCL has a significant impact in the peak of anesthetic effect. Concerning the deep level, the penetration of PCL is required to attain the onset of anesthetic effect. The total amount of drug retained in the epithelium showed to modulate the extent of both shallow and deep anesthesia. Thus, the combination of LCL and PCL in mucoadhesive films may offer dentists and their patients a safe improvement for pain management during dental procedures.

Graphical abstract

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Copper Chelation Inhibits BRAFV600E-driven Melanomagenesis and Counters Resistance to BRAFV600E and MEK1/2 Inhibitors

MEK1/2 and BRAFV600E inhibitors are used to treat BRAFV600E-positive melanoma, with other cancers under evaluation. Genetic perturbation of copper import or pharmacological reduction of copper with the clinical copper chelator TTM inhibits MEK1/2 kinase activity and reduces BRAFV600E-driven tumorigenesis. In this study, we report that TTM inhibited transformed growth of melanoma cell lines resistant to BRAF or MEK1/2 inhibitors and enhanced the antineoplastic activity of these inhibitors. TTM also provided a survival advantage in a genetically engineered mouse model of melanoma, and when accounting for putative overdosing, trended towards an increase in the survival benefit afforded by BRAF inhibition. This effect was phenocopied by genetically inhibiting copper import in tumors, which was linked to a reduction in MAPK signaling. Thus, TTM reduces copper levels and MAPK signaling, thereby inhibiting BRAFV600E-driven melanoma tumor growth. These observations inform and support clinical evaluation of TTM in melanoma.

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Loss of FOXO1 cooperates with TMPRSS2-ERG overexpression to promote prostate tumorigenesis and cell invasion

E26 transformation-specific (ETS) transcription factor ERG is aberrantly overexpressed in approximately 50% of all human PCa due to TMPRSS2-ERG gene rearrangements. However, mice with prostate-specific transgenic expression of PCa-associated ERG alone fail to develop PCa, highlighting that ERG requires other lesions to drive prostate tumorigenesis. Forkhead box (FOXO) transcription factor FOXO1 is a tumor suppressor that is frequently inactivated in human PCa. Here we demonstrate that FOXO1, but not other FOXO proteins (FOXO3 and FOXO4), binds and inhibits the transcriptional activity of PCa-associated ERG independently of FOXO1 transcriptional activity. Knockdown of endogenous FOXO1 increased invasion of TMPRSS2-ERG fusion positive VCaP cells, an effect completely abolished by ERG knockdown. Patient specimen analysis demonstrated that FOXO1 and ERG protein expression inversely correlated in a subset of human PCa. Although human ERG transgene expression or homozygous deletion of Foxo1 alone in the mouse prostate failed to promote tumorigenesis, concomitant ERG transgene expression and Foxo1 deletion resulted in upregulation of ERG target genes, increased cell proliferation and formation of high-grade prostatic intraepithelial neoplasia (HGPIN). Overall, we provide biochemical and genetic evidence that aberrantly activated ERG cooperates with FOXO1 deficiency to promote prostate tumorigenesis and cell invasion. Our findings enhance understanding of PCa etiology and suggest that the FOXO1-ERG signaling axis can be a potential target for treatment of PCa.

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Chemotherapeutic dose scheduling based on tumor growth rates provide a case for low-dose metronomic high entropy therapies

We extended the classical tumor regression models such as Skipper's laws and the Norton-Simon hypothesis from instantaneous regression rates to the cumulative effect over repeated cycles of chemotherapy. To achieve this end, we used a stochastic Moran process model of tumor cell kinetics coupled with a prisoner's dilemma game-theoretic cell-cell interaction model to design chemotherapeutic strategies tailored to different tumor growth characteristics. Using the Shannon entropy as a novel tool to quantify the success of dosing strategies, we contrasted maximum tolerated dose (MTD) strategies as compared with low-dose, high-density metronomic strategies (LDM) for tumors with different growth rates. Our results show that LDM strategies outperformed MTD strategies in total tumor cell reduction (TCR). This advantage was magnified for fast growing tumors that thrive on long periods of unhindered growth without chemotherapy drugs present and was not evident after a single cycle of chemotherapy but grew after each subsequent cycle of repeated chemotherapy. The evolutionary growth/regression model introduced in this paper agrees well with murine models. Overall, this model supports the concept of designing different chemotherapeutic schedules for tumors with different growth rates and develops quantitative tools to optimize these schedules for maintaining low volume tumors.

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Astrocytes promote medulloblastoma progression through hedgehog secretion

Astrocytes, the most abundant type of glial cells in the brain, play critical roles in supporting neuronal development and brain function. While astrocytes have been frequently detected in brain tumors, including medulloblastoma (MB), their functions in tumorigenesis are not clear. Here we demonstrate that astrocytes are essential components of the MB tumor microenvironment. Tumor-associated astrocytes (TAA) secreted the ligand sonic hedgehog (Shh), which is required for maintaining MB cell proliferation despite the absence of its primary receptor Patched-1 (Ptch1). Shh drove expression of Nestin in MB cells through a Smoothened-dependent, Gli1-independent mechanism. Ablation of TAA dramatically suppressed Nestin expression and blocked tumor growth. These findings demonstrate an indispensable role for astrocytes in MB tumorigenesis and reveal a novel Ptch1-independent Shh pathway involved in MB progression.

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Innate Immune Recognition of Double-stranded RNA Triggers Increased Expression of NKG2D Ligands After Virus Infection. [Immunology]

Self/non-self discrimination by the innate immune system relies on germline-encoded, non-rearranging receptors expressed by innate immune cells recognizing conserved pathogen-associated molecular patterns. The natural killer group 2D (NKG2D) receptor is a potent immune-activating receptor that binds human genome-encoded ligands, whose expression is negligible in normal tissues, but increased in stress and disease conditions for reasons that are incompletely understood. Here it is not clear how the immune system reconciles receptor binding of self-proteins with self/non-self discrimination to avoid autoreactivity. We now report that increased expression of NKG2D ligands after virus infection depends on interferon response factors (IRFs) activated by the detection of viral double-stranded RNA by pattern-recognition receptors (RIG-I/MDA-5) and that NKG2D ligand upregulation can be blocked by the expression of viral dsRNA-binding proteins. Thus, innate immunity-mediated recognition of viral nucleic acids triggers the infected cell to release interferon for NK cell recruitment and to express NKG2D-ligands to become more visible to the immune system. Finally, the observation that NKG2D-ligand induction is a consequence of signalling by pattern-recognition receptors that have been selected over evolutionary time to be highly pathogen specific explains how the risks of autoreactivity in this system are minimized.

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An improved Escherichia coli screen for Rubisco identifies a protein-protein interface that can enhance CO2-fixation kinetics. [Plant Biology]

An overarching goal of photosynthesis research is to identify how components of the process can be improved to benefit crop productivity, global food security and renewable energy storage. Improving carbon fixation has mostly focused on enhancing the CO2 fixing enzyme Ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco). This grand challenge has mostly proved ineffective due to catalytic mechanism constraints and required chaperone complementarity that hinder Rubisco biogenesis in alternative hosts. Here we refashion Escherichia coli metabolism by expressing a phosphoribulokinase-neomycin phosphotransferase fusion protein to produce a high fidelity, high throughput Rubisco directed evolution (RDE2) screen that negates false positive selection. Successive evolution rounds using the plant-like Te-Rubisco from the cyanobacterium Thermosynechococcus elongatus BP1 identified two large subunit and six small subunit mutations that improved carboxylation rate, efficiency and specificity. Structural analysis revealed the amino acids clustered in an unexplored subunit interface of the holoenzyme. To study its effect on plant growth the Te-Rubisco was transformed into tobacco by chloroplast transformation. As previously seen for Synechocccus PCC6301 Rubisco, the specialized folding and assembly requirements of Te-Rubisco hinder its heterologous expression in leaf chloroplasts. Our findings suggest that the ongoing efforts to improve crop photosynthesis by integrating components of a cyanobacteria CO2-concentrating mechanism will necessitate co-introduction of the ancillary molecular components required for Rubisco biogenesis.

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The SecA protein deeply penetrates into the SecYEG channel during insertion, contacting most channel transmembrane helices and periplasmic regions [Cell Biology]

The bacterial Sec-dependent system is the major protein-biogenic pathway for protein secretion across the cytoplasmic membrane or insertion of integral membrane proteins into the phospholipid bilayer. The mechanism of SecA-driven protein transport across the SecYEG channel complex has remained controversial with conflicting claims from biochemical and structural studies regarding the depth and extent of SecA insertion into SecYEG during ongoing protein transport. Here we utilized site-specific in vivo photo-crosslinking to thoroughly map SecY regions that are in contact with SecA during its insertion cycle. An arabinose-inducible, rapidly-folding OmpA-GFP chimera was utilized to jam the SecYEG channels with an arrested substrate protein to "freeze" them in their SecA-inserted state. Examination of 117 sites distributed throughout SecY indicated that SecA not only interacts extensively with the cytosolic regions of SecY as shown previously, but it also interacts with most of the transmembrane helices and periplasmic regions of SecY, with a clustering of interaction sights around the lateral gate and pore ring regions. Our observations support previous reports of SecA membrane insertion during in vitro protein transport as well as those documenting the membrane penetration properties of this protein. They suggest that one or more SecA regions transiently integrate into the heart of the SecY channel complex to span the membrane in order to promote the protein transport cycle. These findings indicate that high-resolution structural information about the membrane-inserted state of SecA is still lacking and will be critical for elucidating the bacterial protein transport mechanism.

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STAP-2 promotes prostate cancer growth by enhancing EGFR stabilization [Signal Transduction]

Signal-transducing adaptor family member-2 (STAP-2) is an adaptor protein that regulates various intracellular signaling pathways and promotes tumorigenesis in melanoma and breast cancer cells. However, the contribution of STAP-2 to the behavior of other types of cancer cells is unclear. Here, we show that STAP-2 promotes tumorigenesis of prostate cancer cells through upregulation of EGFR signaling. Tumor growth of a prostate cancer cell line, DU145, was strongly decreased by STAP-2 knockdown. EGF-induced gene expression and phosphorylation of AKT, ERK, and STAT3 were significantly decreased in STAP-2-knockdown DU145 cells. Mechanistically, we found that STAP-2 interacted with EGFR and enhanced its stability by inhibiting c-CBL-mediated EGFR ubiquitination. Our results indicate that STAP-2 promotes prostate cancer progression via facilitating EGFR activation.

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Mfd translocase is necessary and sufficient for transcription-coupled repair in Escherichia coli [Computational Biology]

Nucleotide excision repair in E. coli is stimulated by transcription, specifically in the transcribed strand (TS). Previously, it was shown that this transcription-coupled repair (TCR) is mediated by the Mfd translocase. Recently, it was proposed that in fact the majority of TCR in E. coli is catalyzed by a second pathway ('backtracking-mediated TCR') that is dependent on the UvrD helicase and the ppGpp alarmone/stringent response regulator. Recently, we reported that as measured by the Excision Repair-Sequencing XR-seq), UvrD plays no role in TCR genome-wide. Here, we tested the role of ppGpp and UvrD in TCR genome-wide and in the lacZ operon using the XR-seq method which directly measures repair. We find that the mfd mutation abolishes TCR genome-wide and in the lacZ operon. In contrast, the relA-spoT-mutant deficient in ppGpp synthesis carries out normal TCR. We conclude that UvrD and ppGpp play no role in TCR in E. coli.

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Is dental insurance worth the cost?

Fair or not, many of us take other people at face value - literally. One of the things we first notice about someone is their face, including their teeth.

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Is there a need for a postgraduate military healthcare qualification?

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Sarcopenia in Oncology or Gerontology: What Is the Difference?

Abstract

Purpose of Review

Low muscle mass, commonly known as sarcopenia, has been a focus of gerontologic research for many years and is related to reduced health-related quality of life, functional impairment, and shortened survival.

Recent Findings

In oncology, body composition research, including sarcopenia, has emerged as an area of particular interest in the last several years, as sarcopenia is highly prevalent in patients with cancer regardless of age and is correlated with adverse treatment outcomes and shorter survival.

Summary

In this review, we discuss the differences between sarcopenia in gerontology and oncology, including the differences in definition, diagnosis, pathophysiology, outcomes, and future directions.

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A phase IB dose-escalation study of the safety and pharmacokinetics of pictilisib in combination with either paclitaxel and carboplatin (with or without bevacizumab) or pemetrexed and cisplatin (with or without bevacizumab) in patients with advanced non–small cell lung cancer

Publication date: November 2017
Source:European Journal of Cancer, Volume 86
Author(s): Jean-Charles Soria, Alex A. Adjei, Rastilav Bahleda, Benjamin Besse, Charles Ferte, David Planchard, Jing Zhou, Joseph Ware, Kari Morrissey, Geetha Shankar, Wei Lin, Jennifer L. Schutzman, Grace K. Dy, Harry J.M. Groen
AimThe phosphatidylinositol 3-kinase (PI3K) pathway is a potential therapeutic target in non–small cell lung cancer (NSCLC). This study aimed to evaluate the pan-PI3K inhibitor pictilisib in combination with first-line treatment regimens that were the standard of care at the time of study, in patients with NSCLC.Patients and methodsA 3 + 3 dose-escalation study was performed using a starting daily dose of 60 mg pictilisib on days 1–14 of a 21-day cycle. Depending on bevacizumab eligibility and NSCLC histology, patients also received either paclitaxel + carboplatin or pemetrexed + cisplatin, ± bevacizumab every 3 weeks. The primary objectives of the study were to assess safety and tolerability and to identify dose-limiting toxicities (DLTs), the maximum tolerated dose (MTD) and a recommended phase II dose (RP2D), for each combination.ResultsAll 66 treated patients experienced at least one adverse event (AE). Grade ≥III AEs, serious AEs and deaths occurred in 57 (86.4%), 56 (84.8%) and 9 (13.6%) patients, respectively. Three patients reported DLTs across the four arms of the study. The MTD was not reached in any arm and the RP2D of pictilisib was determined to be 330 mg (capsules) or 340 mg (tablets) on a '14 days on, 7 days off' schedule. The best confirmed response was partial response in 29 (43.9%) patients and stable disease in 20 (30.9%) patients.ConclusionCombining pictilisib with various standard-of-care first-line treatment regimens is feasible from a safety perspective in patients with NSCLC, and encouraging preliminary anti-tumour activity was observed.

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Diarrhoea during checkpoint blockade, not always colitis

Publication date: Available online 6 October 2017
Source:European Journal of Cancer
Author(s): Josephine J. Koldenhof, Karijn P.M. Suijkerbuijk

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Potential role of polymorphisms in the transporter genes ENT1 and MATE1/OCT2 in predicting TAS-102 efficacy and toxicity in patients with refractory metastatic colorectal cancer

Publication date: November 2017
Source:European Journal of Cancer, Volume 86
Author(s): Mitsukuni Suenaga, Marta Schirripa, Shu Cao, Wu Zhang, Dongyun Yang, Vincenzo Dadduzio, Lisa Salvatore, Beatrice Borelli, Filippo Pietrantonio, Yan Ning, Satoshi Okazaki, Martin D. Berger, Yuji Miyamoto, Roel Gopez, Afsaneh Barzi, Toshiharu Yamaguchi, Fotios Loupakis, Heinz-Josef Lenz
BackgroundTrifluridine (FTD) is an active cytotoxic component of the metastatic colorectal cancer (mCRC) drug TAS-102, and thymidine phosphorylase inhibitor (TPI) inhibits the rapid degradation of FTD. We tested whether single nucleotide polymorphisms (SNPs) in genes involved in FTD metabolism and TPI excretion could predict outcome in patients with mCRC treated with TAS-102.Patients and methodsWe investigated three different cohorts: a training cohort (n = 52) and a testing cohort (n = 129) both receiving TAS-102 and a control cohort (n = 52) receiving regorafenib. SNPs of TK1, ENT1, CNT1, MATE1, MATE2 and OCT2 were analysed by polymerase chain reaction-based direct DNA sequencing.ResultsIn the training cohort, patients with any ENT1 rs760370 G allele had a significantly longer progression-free survival (PFS; 3.5 versus 2.1 months, respectively, hazard ratio [HR] 0.44, P = 0.004) and overall survival (OS; 8.7 versus 5.3 months, respectively, HR 0.27, P = 0.003) than the A/A genotype. These findings were validated in the testing cohort (P = 0.021 and 0.009 for PFS and OS, respectively). In addition, the combination of ENT1 rs760370, MATE1 rs2289669 and OCT2 rs316019 SNPs significantly stratified patients with the risk of PFS and OS in both cohorts (P < 0.001 for PFS and OS in the training cohort; P = 0.053 and 0.025 for PFS and OS, respectively, in the testing cohort). No significant differences were observed in the control group.ConclusionsThe combination of ENT1, MATE1 and OCT2 SNPs may serve as a predictive and prognostic marker in mCRC patients treated with TAS-102.

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Bridging the gap between the randomised clinical trial world and the real world by combination of population-based registry and electronic health record data: A case study in haemato-oncology

Publication date: November 2017
Source:European Journal of Cancer, Volume 86
Author(s): R.E. Kibbelaar, B.E. Oortgiesen, A.M. van der Wal-Oost, K. Boslooper, J.W. Coebergh, N.J.G.M. Veeger, P. Joosten, H. Storm, E.N. van Roon, M. Hoogendoorn
Randomised clinical trials (RCTs) are considered the basis of evidence-based medicine. It is recognised more and more that application of RCT results in daily practice of clinical decision-making is limited because the RCT world does not correspond with the clinical real world. Recent strategies aiming at substitution of RCT databases by improved population-based registries (PBRs) or by improved electronic health record (EHR) systems to provide significant data for clinical science are discussed. A novel approach exemplified by the HemoBase haemato-oncology project is presented. In this approach, a PBR is combined with an advanced EHR, providing high-quality data for observational studies and support of best practice development. This PBR + EHR approach opens a perspective on randomised registry trials.

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KiSS1 gene as a novel mediator of TGFβ-mediated cell invasion in triple negative breast cancer

Publication date: Available online 6 October 2017
Source:Cellular Signalling
Author(s): Jun Tian, Amal A. Al-Odaini, Yun Wang, Juliana Korah, Meiou Dai, Lan Xiao, Suhad Ali, Jean Jacques Lebrun
The invasive and metastatic phenotypes of breast cancer correlate with high recurrence rates and poor survival outcomes. Transforming growth factor-β (TGFβ) promotes tumor progression and metastasis in aggressive breast cancer. Here, we identified the kisspeptin KiSS1 as a downstream target of canonical TGFβ/Smad2 pathway in triple negative breast cancer cells. We also found KiSS1 expression to be required for TGFβ-induced cancer cell invasion. Indeed, knockdown expression of KiSS1 blocked TGFβ-mediated cancer cell invasion as well as metalloproteinase (MMP9) expression and activity. Interestingly, Kisspeptin-10 (KP-10), the smallest active form of kisspeptin also stimulates cancer cell invasive behavior through activation of MAPK/Erk pathway. We described a positive feedback loop between KiSS1 and p21 downstream of TGFβ, further contributing to TGFβ-induced cancer cell invasion. Lastly, we explored both the clinical utility of KiSS1 as a lymph node involvement predictive tool and its potential as a therapeutic target. We found KiSS1 high expression to correlate with lymph node positive status. Furthermore, blocking KiSS1 using a specific small peptide antagonist (p234) impaired TGFβ-mediated cell invasion and MMP9 induction. Together, our results define an essential role of KiSS1 in regulating TGFβ pro-invasive effects and define KiSS1 as a therapeutic new target for triple negative breast cancer.

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Development and Application of Two Semi-Automated Tools for Targeted Medical Product Surveillance in a Distributed Data Network

Abstract

Purpose of Review

An important component of the Food and Drug Administration's Sentinel Initiative is the active post-market risk identification and analysis (ARIA) system, which utilizes semi-automated, parameterized computer programs to implement propensity-score adjusted and self-controlled risk interval designs to conduct targeted surveillance of medical products in the Sentinel Distributed Database. In this manuscript, we review literature relevant to the development of these programs and describe their application within the Sentinel Initiative.

Recent Findings

These quality-checked and publicly available tools have been successfully used to conduct rapid, replicable, and targeted safety analyses of several medical products. In addition to speed and reproducibility, use of semi-automated tools allows investigators to focus on decisions regarding key methodological parameters. We also identified challenges associated with the use of these methods in distributed and prospective datasets like the Sentinel Distributed Database, namely uncertainty regarding the optimal approach to estimating propensity scores in dynamic data among data partners of heterogeneous size.

Summary

Future research should focus on the methodological challenges raised by these applications as well as developing new modular programs for targeted surveillance of medical products.

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Development and Application of Two Semi-Automated Tools for Targeted Medical Product Surveillance in a Distributed Data Network

Abstract

Purpose of Review

Recent Findings

Summary

Future research should focus on the methodological challenges raised by these applications as well as developing new modular programs for targeted surveillance of medical products.

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Whole Foods Market Issues Nationwide Allergy Alert on Undeclared Peanuts in 365 Everyday Value Organic Raisin Bran

Whole Foods Market stores is voluntarily recalling 365 Everyday Value Organic Raisin Bran because the product contains undeclared peanuts that were not listed on the product label. People who have an allergy or severe sensitivity to peanuts run the risk of serious or life-threatening allergic reaction if they consume this product.

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Giant python receives CT scan

Medical staff performed a CT scan on an 8-ft python at Modern Health Care Clinic...

Patients’ preferences for headache acute and preventive treatment

We aimed to explore patients' preferences for headache treatments with a self-administered questionnaire including the Q-No questionnaire for nocebo.

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Patients with glycogen storage diseases undergoing anesthesia: a case series

Glycogen storage diseases are rare genetic disorders of glycogen synthesis, degradation, or metabolism regulation. When these patients are subjected to anesthesia, perioperative complications can develop, incl...

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Acute transient spinal paralysis and cardiac symptoms following an accidental epidural potassium infusion – a case report

To describe a case of an accidental epidural potassium infusion leading to an acute transient spinal paralysis and cardiac symptoms and review the literature on that topic.

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Correction to: Breast cancer metastases to the thyroid gland - An uncommon sentinel for diffuse metastatic disease: A case report and literature review

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HSE contacts parents after dental clinic health scare

The Health Service Executive in the Mid West has confirmed it is in contact with the parents of up to 43 children to see if they were affected by an apparent problem a dental clinic in Ennis in Co Clare. It is understood that drain cleaning fluid, diluted with water, was used to clean instruments during dental surgery at the dental clinic on Bindon Street in Ennis.

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H/D exchange mass spectrometry and statistical coupling analysis reveal a role for allostery in a ferredoxin-dependent bifurcating transhydrogenase catalytic cycle

Publication date: Available online 6 October 2017
Source:Biochimica et Biophysica Acta (BBA) - General Subjects
Author(s): Luke Berry, Saroj Poudel, Monika Tokmina-Lukaszewska, Daniel R. Colman, Diep M.N. Nguyen, Gerrit J. Schut, Michael W.W. Adams, John W. Peters, Eric S. Boyd, Brian Bothner
Recent investigations into ferredoxin-dependent transhydrogenases, a class of enzymes responsible for electron transport, have highlighted the biological importance of flavin-based electron bifurcation (FBEB). FBEB generates biomolecules with very low reduction potential by coupling the oxidation of an electron donor with intermediate potential to the reduction of high and low potential molecules. Bifurcating systems can generate biomolecules with very low reduction potentials, such as reduced ferredoxin (Fd), from species such as NADPH. Metabolic systems that use bifurcation are more efficient and confer a competitive advantage for the organisms that harbor them. Structural models are now available for two NADH-dependent ferredoxin-NADP⁺ oxidoreductase (Nfn) complexes. These models, together with spectroscopic studies, have provided considerable insight into the catalytic process of FBEB. However, much about the mechanism and regulation of these multi-subunit proteins remains unclear. Using hydrogen/deuterium exchange mass spectrometry (HDX-MS) and statistical coupling analysis (SCA), we identified specific pathways of communication within the model FBEB system, Nfn from Pyrococus furiosus, under conditions at each step of the catalytic cycle. HDX-MS revealed evidence for allosteric coupling across protein subunits upon nucleotide and ferredoxin binding. SCA uncovered a network of co-evolving residues that can provide connectivity across the complex. Together, the HDX-MS and SCA data show that protein allostery occurs across the ensemble of iron‑sulfur cofactors and ligand binding sites using specific pathways that connect domains allowing them to function as dynamically coordinated units.

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Theoretical approaches for dynamical ordering of biomolecular systems

Publication date: Available online 6 October 2017
Source:Biochimica et Biophysica Acta (BBA) - General Subjects
Author(s): Hisashi Okumura, Masahiro Higashi, Yuichiro Yoshida, Hirofumi Sato, Ryo Akiyama
BackgroundLiving systems are characterized by the dynamic assembly and disassembly of biomolecules. The dynamical ordering mechanism of these biomolecules has been investigated both experimentally and theoretically. The main theoretical approaches include quantum mechanical (QM) calculation, all-atom (AA) modeling, and coarse-grained (CG) modeling. The selected approach depends on the size of the target system (which differs among electrons, atoms, molecules, and molecular assemblies). These hierarchal approaches can be combined with molecular dynamics (MD) simulation and/or integral equation theories for liquids, which cover all size hierarchies.Scope of reviewWe review the framework of quantum mechanical/molecular mechanical (QM/MM) calculations, AA MD simulations, CG modeling, and integral equation theories. Applications of these methods to the dynamical ordering of biomolecular systems are also exemplified.Major conclusionsThe QM/MM calculation enables the study of chemical reactions. The AA MD simulation, which omits the QM calculation, can follow longer time-scale phenomena. By reducing the number of degrees of freedom and the computational cost, CG modeling can follow much longer time-scale phenomena than AA modeling. Integral equation theories for liquids elucidate the liquid structure, for example, whether the liquid follows a radial distribution function.General significanceThese theoretical approaches can analyze the dynamic behaviors of biomolecular systems. They also provide useful tools for exploring the dynamic ordering systems of biomolecules, such as self-assembly. This article is part of a Special Issue entitled "Biophysical Exploration of Dynamical Ordering of Biomolecular Systems" edited by Dr. Koichi Kato.

Graphical abstract

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Risk factors and outcomes of candidemia caused by Candida parapsilosis complex in a medical center in northern Taiwan

Publication date: Available online 6 October 2017
Source:Diagnostic Microbiology and Infectious Disease
Author(s): Yen-Mu Wu, Po-Yen Huang, Jang-Jih Lu, Shian-Sen Shie, Jung-Jr Ye, Ting-Shu Wu, Ching-Tai Huang
To investigate the risk factors and outcomes associated with Candida parapsilosis candidemia, a retrospective study was conducted at a tertiary medical center in northern Taiwan. Patients with C. parapsilosis candidemia and corresponding controls with C. albicans candidemia were chosen and their demographics, comorbidities, risk factors, and clinical outcomes were reviewed. Antifungal susceptibility tests were performed using the Sensititre YeastOne colorimetric system. Matrix-assisted laser desorption ionization–time of flight mass spectrometry was used to classify the genomic species. Of the 270 candidemias found in 253 patients, C. albicans was the most common Candida species isolated (43.0%), followed by C. parapsilosis (22.6%), C. tropicalis (17.4%), and C. glabrata (10.0%). The 30-day mortality of C. parapsilosis candidemia was significantly lower than that of C. albicans candidemia (21.7% vs. 53.9%, p<0.001). C. parapsilosis was positively associated with antifungal agent exposure [OR 7.261 (95% CI, 1.603–32.879), p=0.010], but negatively associated with Candida colonization [OR 0.303 (95% CI, 0.123–0.745), p=0.009], and immunosuppressant use [OR 0.264 (95% CI, 0.099–0.705), p=0.008]. In-hospital mortality was associated with the Sequential Organ Failure Assessment Score [OR 1.255 (95% CI, 1.002–1.573), p=0.048]. The clinical outcomes did not differ across genomic species and in the minimum inhibitory concentrations of fluconazole.

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The convergent roles of the nuclear factor I transcription factors in development and cancer

Publication date: 1 December 2017
Source:Cancer Letters, Volume 410
Author(s): Kok-Siong Chen, Jonathan W.C. Lim, Linda J. Richards, Jens Bunt
The nuclear factor I (NFI) transcription factors play important roles during normal development and have been associated with developmental abnormalities in humans. All four family members, NFIA, NFIB, NFIC and NFIX, have a homologous DNA binding domain and function by regulating cell proliferation and differentiation via the transcriptional control of their target genes. More recently, NFI genes have also been implicated in cancer based on genomic analyses and studies of animal models in a variety of tumours across multiple organ systems. However, the association between their functions in development and in cancer is not well described. In this review, we summarise the evidence suggesting a converging role for the NFI genes in development and cancer. Our review includes all cancer types in which the NFI genes are implicated, focusing predominantly on studies demonstrating their oncogenic or tumour-suppressive potential. We conclude by presenting the challenges impeding our understanding of NFI function in cancer biology, and demonstrate how a developmental perspective may contribute towards overcoming such hurdles.

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GRP78 inhibition enhances ATF4-induced cell death by the deubiquitination and stabilization of CHOP in human osteosarcoma

Publication date: 1 December 2017
Source:Cancer Letters, Volume 410
Author(s): Jie Luo, Yuanzheng Xia, Jun Luo, Junhe Li, Chao Zhang, Hao Zhang, Ting Ma, Lei Yang, Lingyi Kong
New targeted therapies are urgently needed to improve the survival of patients with refractory osteosarcoma (OS). In this study, we show that bortezomib (BTZ), not for OS treatment in the clinic, induces endoplasmic reticulum (ER) stress in U-2 OS cells. Loss of GRP78 sensitizes OS to BTZ with concomitant upregulation of ATF4 and CHOP, which indicates excessive protein synthesis. The relevance of these findings is confirmed in vivo as shown by GRP78 knockdown that delays the growth of U-2 OS xenografts in the presence of BTZ. Here, we demonstrate that MG7, a natural polyyne, can trigger apoptosis. Of note, the apoptotic response to MG7 is dependent on ATF4 but not on the upstream PERK signaling pathway. Interestingly, MG7-induced ATF4 expression does not result in an increase in the levels of CHOP. We demonstrate for the first time that GRP78 physically interacts with the N-terminal domain of CHOP to accelerate its ubiquitination in a p300-dependent manner, which in turn desensitize the tumors to ER stress. Overall, inhibiting GRP78 to strengthen the molecular mechanism of ATF4 via stabilizing CHOP protein may provide a potential vulnerability in OS.

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Tubulin-binding anticancer polysulfides induce cell death via mitotic arrest and autophagic interference in colorectal cancer

Publication date: 1 December 2017
Source:Cancer Letters, Volume 410
Author(s): Esma Yagdi Efe, Aloran Mazumder, Jin-Young Lee, Anthoula Gaigneaux, Flavia Radogna, Muhammad Jawad Nasim, Christo Christov, Claus Jacob, Kyu-Won Kim, Mario Dicato, Patrick Chaimbault, Claudia Cerella, Marc Diederich
Polysulfanes show chemopreventive effects against gastrointestinal tumors. We identified diallyl tetrasulfide and its derivative, dibenzyl tetrasulfide (DBTTS), to be mitotic inhibitors and apoptosis inducers. Here, we translate their application in colorectal cancer (CRC). MALDI-TOF-MS analysis identified both compounds as reversible tubulin binders, validated by in cellulo α-tubulin degradation. BRAF(V600E)-mutated HT-29 cells were resistant to DBTTS, as evidenced by mitotic arrest for 48 h prior to apoptosis induction compared to KRAS(G12V)-mutated SW480/620 cells, which committed to death earlier. The prolonged mitotic block correlated with autophagy impairment and p62 protein accumulation in HT-29 but not in SW480/620 cells, whereas siRNA-mediated p62 inhibition sensitized HT-29 cells to death. In silico analysis with 484 colorectal cancer patients associated higher p62 expression and reduced autophagic flux with greater overall survival. Accordingly, we hypothesized that DBTTS targets CRC survival/death through autophagy interference in cell types with differential autophagic capacities. We confirmed the therapeutic potential of DBTTS by the inhibition of spheroid and colony formation capacities in CRC cells, as well as in HT-29 zebrafish xenografts in vivo.

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Hepatitis C Virus (HCV) genotypes distribution among hepatocellular carcinoma patients in Southern Italy: a three year retrospective study

Hepatocellular carcinoma (HCC) is one of the major cause for cancer in the world. Aim of this case-control study was to investigate the distribution pattern of HCV genotypes among HCC patients and suggest whet...

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Correction to: mouse mammary tumour virus (MMTV) and human breast cancer with neuroendocrine differentiation

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Porcine model of progressive cardiac hypertrophy and fibrosis with secondary postcapillary pulmonary hypertension

Meaningful translational large animal models for cardiac diseases are indispensable for studying disease mechanisms, development of novel therapeutic strategies, and evaluation of potential drugs.

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A lipidated peptide of Mycobacterium tuberculosis resuscitates the protective efficacy of BCG vaccine by evoking memory T cell immunity

The current BCG vaccine induces only short-term protection against Mycobacterium tuberculosis (Mtb), suggesting its failure to generate long-lasting memory T cells. Previously, we have demonstrated that a self-ad...

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Bilayer Plots for Accurately Determining the Chirality of Single-Walled Carbon Nanotubes Under Complex Environments

TOC Graphic

ACS Nano

DOI: 10.1021/acsnano.7b05860

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Seal pups get separated from their mums by icebreaker ships

When icebreakers push through the sea ice on which Caspian seals nurse their young, mothers and pups flee and often get separated in the confusion

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The Surgical Apgar Score Predicts Not Only Short-Term Complications But Also Long-Term Prognosis After Esophagectomy

Abstract

Background

The surgical Apgar score (SAS) quantifies three intraoperative factors and predicts postoperative complications, but few reports describe its usefulness in esophagectomy, and no studies to date show its correlation with long-term prognosis after esophagectomy.

Methods

This study investigated 400 cases in which esophagectomy was performed on esophageal malignant tumors at the authors' hospital from January 2007 to January 2017. In this study, SAS was defined as the sum of the scores of three parameters, namely, estimated blood loss, lowest mean arterial pressure, and lowest heart rate, with values extracted from medical records. Postoperative complications classified as Clavien–Dindo grade 3 or higher were also extracted. The study retrospectively compared the relationship of SAS to postoperative complications and survival.

Results

Univariate analysis showed that postoperative complications were significantly associated with hypertension (p = 0.017), thoracotomy (p = 0.012), and SAS ≤ 5 (p < 0.0001), and multivariate analysis showed that hypertension (p = 0.049) and SAS ≤ 5 (p < 0.0001) were significant predictive factors for complications. In the prognostic analysis, log-rank analysis showed that patients with an SAS ≤ 5 had a significantly poorer prognosis than those with a SAS > 5 (p = 0.043), especially for complications classified as clinical stage 2 or higher (p = 0.027). In the multivariate analysis, SAS ≤ 5 was identified as a significantly poor prognostic factor for complications classified as clinical stage 2 or higher (p = 0.029).

Conclusion

In this study, SAS was useful not only for predicting short-term complications, but also as a long-term prognostic factor after esophagectomy.

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Αρχειοθήκη ιστολογίου

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Αναζήτηση αυτού του ιστολογίου

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