External validation of the DASH prediction rule: a retrospective cohort study.
Essentials Predicting recurrences may guide therapy after unprovoked venous thromboembolism (VTE). We evaluated the DASH score in 827 patients with unprovoked VTE to verify prediction accuracy. A DASH score ≤ 1 had a cumulative recurrence risk at 1 year of 3.6%, as predicted by the model. The DASH score performed better in younger (< 65 years old) subjects. Background The DASH prediction model has been proposed as a guide to identify patients at low risk of recurrence of venous thromboembolism (VTE), but has never been validated in an independent cohort. Aims To validate the calibration and discrimination of the DASH prediction model, and to evaluate the DASH score in a predefined patient subgroup aged > 65 years. Methods Patients with a proximal unprovoked deep vein thrombosis (DVT) or pulmonary embolism (PE) who received a full course of vitamin K antagonist or direct oral anticoagulant (> 3 months) and had D-dimer measured after treatment withdrawal were eligible. The DASH score was computed on the basis of the D-dimer level after therapy withdrawal and personal characteristics at the time of the event. Recurrent VTE events were symptomatic proximal or distal DVT/PE, and were analyzed with a time-dependent analysis. Observed 12-month and 24-month recurrence rates were compared with recurrence rates predicted by the DASH model. Results We analyzed a total of 827 patients, of whom 100 (12.1%) had an objectively documented recurrence. As compared with the original DASH cohort, there was a greater proportion of subjects with a 'low-risk' (≤ 1) DASH score (66.3% versus 51.6%, P < 0.001). The slope of the observed versus expected cumulative incidence at 2 years was 0.71 (95% confidence interval 0.51-1.45). The c-statistic was lower for subjects aged > 65 years (0.54) than for younger subjects (0.72). Conclusions These results confirm the validity of DASH prediction model, particularly in young subjects. The recurrence risk in elderly patients (> 65 years) was, however, > 5% even in those with the lowest DASH scores.


Dexamethasone treatment of virilizing congenital adrenal hyperplasia: the ability to achieve normal growth.
To assess whether treatment of virilizing congenital adrenal hyperplasia (CAH) with long-acting glucocorticoids is associated with favorable growth outcomes. We examined the long-term growth of 17 boys and 9 girls with CAH treated with dexamethasone (.27 +/-.01 mg/m(2)/day). For individuals with comparable bone age (BA) and chronological age (CA) at the onset of dexamethasone therapy, males were 2.8 +/-.8 years (mean +/- standard error of the mean; n = 13) and females were 2.4 +/- 1.0 years (n = 6). Males were treated for 7.3 +/- 1.1 years (DeltaCA) over which time the change in BA (DeltaBA) was 7.0 +/- 1.3 years, and the change in height age (DeltaHA) was 6.9 +/- 1.1 years. Females were treated for 6.8 +/- 1.3 years, over which time the DeltaBA was 6.5 +/- 1.0 years, and the DeltaHA was 6.3 +/-.8 years. During treatment 17 ketosteroid excretion rates were normal for age and 17-hydroxyprogesterone values were 69.6 +/- 18 ng/dL. Testicular enlargement was first detected at 10.7 +/-.8 years and breast tissue at 9.9 +/- 1.2 years. Three boys and 1 girl had final heights of 171. 8 +/- 6 cm and 161 cm, respectively, compared with midparental heights of 176.1 +/- 4.1 cm and 160 cm. Predicted adult heights for 6 other boys and 5 girls were 176.8 +/- 2.0 cm and 161.4 +/- 2.8 cm, respectively, compared with midparental heights of 174.6 +/- 1.4 cm and 158.2 +/- 2.0 cm. Statural outcomes were less favorable for 7 children started on dexamethasone when BAs were considerably advanced, although height predictions increased during therapy. These observations show that children treated with dexamethasone for CAH can achieve normal growth with the convenience of once-a-day dosing in most cases.congenital adrenal hyperplasia, dexamethasone, growth.


[Maternal morbidity and mortality in HELLP Syndrome].
To describe the maternal morbidity and mortality in pregnancies complicated by HELLP Syndrome. This is a descriptive and prospective study of women with HELLP Syndrome managed at our center from January 1998 through March 2000. Patients are grouped into 3-class system of Mississippi classification. 170 cases were analysed, 156 (92%), ocurred ante partum and 14 (8%) postpartum; 15 cases (9%) developed at < 27 weeks, 112 (66%) between 28 to 36 weeks of gestational age and 43 (25%) at term. Maternal morbidity included acute renal failure (13.5%), abruptio placentae (6.6%), pneumonia (3%), subcapsular liver hematoma (2.3%), pulmonary edema (2.3%), diseminated intravascular coagulopathy (1.7%) and cerebral hemorrhage (1.2%). Maternal mortality was 4.7% (8 patients), 7 deaths ocurred in patients with class I disease and only one with class II HELLP Syndrome. 6 maternal deaths (75%) were associated to eclampsia. Up to 85% of the maternal morbidity and mortality developed with class I disease (platelet nadir < 50,000 mm3. There is a progressive rise in maternal morbidity and mortality as the pregnancy moves from class III to class I HELLP Syndrome. 75% of maternal mortality was associated with eclampsia. Early diagnosis of this syndrome could improve maternal prognosis and outcome.


Medical therapy of pituitary adenomas: effects on tumor shrinkage.
The efficacy of dopamine-agonists (DA) in patients with prolactinomas and that of somatostatin analogues (SSA) in those with GH- and TSH-secreting adenomas is well established. More recently, data are accumulating suggesting a potential therapeutic role of DA also in patients with ACTH-secreting and clinically non-functioning (NFA) pituitary adenomas. This review aims at summarizing published results of DA and SSA on tumor shrinkage in patients with different histotypes of pituitary adenomas. Results of tumor shrinkage are of clinical relevance as tumor size is the one of the most important determinant of surgical outcome. While reduction of tumor size more than 50% of baseline size in macroprolactinomas treated with DA is a frequent finding in patients with GH-secreting adenomas treated with SSA tumor shrinkage only recently is becoming frequent thanks to the availability of depot formulations. Data on tumor shrinkage in patients with TSH-secreting adenomas treated with SSA are limited because of the rarity of these tumors. Very recently, DA have been reported of some efficacy also in patients with ACTH-secreting adenomas but data are still very limited. NFA respond very scantly to both DA and SSA even if receptors targeting these drugs are present. Whether this is due to limited receptor number or alterations of post-receptor pathway is still unknown.


Protein B23/nucleophosmin/numatrin nuclear dynamics in relation to protein kinase CK2 and apoptotic activity in prostate cells.
Protein B23/nucleophosmin/numatrin (B23) is a key nucleolar/nuclear matrix-associated protein required for cell growth-related functions, such as rRNA synthesis. Protein kinase CK2 (CK2) (formerly casein kinase 2, a protein Ser/Thr kinase signal that is involved in cell growth and cell death) mediates phosphorylation of B23, thereby influencing its functional activity. Here we have delineated the dynamics of B23 and its link to CK2 status in response to altered growth stimuli and induction of apoptosis in cultured prostate cells and in rat prostate cells in vivo. Our studies employing PC-3 and ALVA-41 prostate cancer cells demonstrated colocalization of CK2 and B23 in the nucleus. Further, CK2 and B23 underwent coordinate modulation in the nucleus related to their nucleocytoplasmic shuttling in response to induction of apoptotic activity in cells caused by downregulation of CK2 or by treatment with other apoptosis-inducing agents. These alterations in nuclear association of B23 occurred in the absence of a significant change in the level of cytoplasmic B23. Similar studies in the in vivo model of rat prostate epithelial cells subjected to androgen deprivation (that resulted in loss of nuclear CK2 and induction of apoptosis) demonstrated dynamic modulation of nuclear matrix-associated B23 without a significant change in its cytoplasmic level. These changes were reversed by androgen-mediated growth response in the prostate. Our results suggest that CK2-mediated phosphorylation of B23 is essential for its retention in the nucleus and that coordinated nuclear localization of B23 and CK2 is dynamically regulated in response to altered growth status in the cell.


Serum osteocalcin level and its association with carotid atherosclerosis in patients with type 2 diabetes.
To investigate the association of serum osteocalcin with carotid atherosclerosis in patients with type 2 diabetes. We performed a cross-sectional community-based study in metropolitan area. Serum total osteocalcin was measured by radioimmunoassay in 382 men and 435 postmenopausal women. The carotid artery intima-media thickness (IMT) and carotid plaques (PLQ) were measured by B-mode ultrasound. The crude mean of serum osteocalcin concentrations were 4.52±2.43 ng/ml for men and 5.75±2.92 ng/ml for postmenopausal women (P <0.001), respectively. Osteocalcin levels were associated inversely with age, fasting serum insulin, HOMA-IR, ALT, triglycerides, total cholesterol, LDL- cholesterol, CRP (all P<0.001) and positively with adiponectin and HOMA-B (all P<0.05). After multiple adjustment, the odds ratios (ORs) were substantially higher risk for carotid plaques (OR 1.77 for 1 SD decrease in osteocalcin, 95% CI 1.23-2.76, p=0.005). These associations remained significant after further adjustment for potential confounder. Serum osteocalcin levels is an independent risk factor for carotid atherosclerosis in patients with type 2 diabetes.


Rheumatoid arthritis with rheumatoid heart disease and granulomatous aortitis.
Aortic insufficiency and aortitis are frequent complications of ankylosing spondylitis but are considered rare in rheumatoid arthritis. A 49-year-old woman with severe rheumatoid arthritis had the cardiovascular changes common to both diseases. At autopsy, the heart and aorta showed granulomatous ane fibrinous pericarditis and epicarditis, "core" granulomas in the aortic valve cusps and mitral valve leaflets, and coronary arteritis. These are considered to be classical changes of rheumatoid carditis. In addition, there were mesoaortitis with obliterative endarteritis of the vasa vasorum and fibrosis of the aortic cusps with separation of the commissures. These are considered to be changes of ankylosing spondylitis. This case, therefore, represents a mixed form of cardiovascular involvement within the spectrum of the rheumatoid diseases.


Radio frequency responsive nano-biomaterials for cancer therapy.
Radiofrequency (RF)-assisted cancer therapy is well-known in the medical field as it is non-hazardous and can penetrate tissues, enabling a deeply rooted cancer treatment. However, the current treatment regimen is non-specific and invasive, making it difficult for patients to undergo the RF ablation procedure. Recently, there has been tremendous attention given on replacing RF probes (through which the RF current passes into the tumors) with metallic nanoparticles (NPs) such as gold and iron oxide. These metallic NPs can be combined with stimuli responsive polymers to have a simultaneous drug delivery to tumors and better thermal ablation. This review will give a brief overview on the various nanobiomaterials based on metals and polymers and their composites in RF-assisted cancer therapy. Special attention has been given on RF responsive composite nanomaterials. Besides these, the importance of RF-assisted drug delivery using the nanobiomaterials for cancer therapy, as well as the advantages and future perspectives of these materials are discussed in detail.


Resveratrol inhibits invasion and metastasis of colorectal cancer cells via MALAT1 mediated Wnt/β-catenin signal pathway.
Resveratrol, extracted from Chinese herbal medicine Polygonum cuspidatum, is known to inhibit invasion and metastasis of human colorectal cancer (CRC), in which long non-coding Metastasis Associated Lung Adenocarcinoma Transcript 1 (RNA-MALAT1) also plays an important role. Using MALAT1 lentiviral shRNA and over-expression constructs in CRC derived cell lines, LoVo and HCT116, we demonstrated that the anti-tumor effects of resveratrol on CRC are through inhibiting Wnt/β-catenin signaling, thus the expression of its target genes such as c-Myc, MMP-7, as well as the expression of MALAT1. In detail, resveratrol down-regulates MALAT1, resulting in decreased nuclear localization of β-catenin thus attenuated Wnt/β-catenin signaling, which leads to the inhibition of CRC invasion and metastasis. This finding of ours surely provides important pre-clinical evidence supporting future use of resveratrol in prevention and treatment of CRC.


Mediterranean Diet Adherence in a Sample of Italian Adolescents Attending Secondary School-The "#facciamoComunicAzione" Project.
Our aim was to assess adherence to the Mediterranean diet in a group of 726 secondary school students (336 girls, 390 boys) who completed the web-based Medi-Lite questionnaire simultaneously, during school hours, at the "Istituto Professionale per l'Enogastronomia e l'Ospitalità Alberghiera Marco Polo" in Genoa, Italy. The mean adherence score was 9.28 ± 2.29, with significantly (p = 0.017) higher values in girls (9.5 ± 2.2) than boys (9.1 ± 2.4). As to the individual food components of the Medi-Lite score, 84% of students reported non-optimal consumption (i.e., the choice that yielded ≤ 1 point) of meat and meat products, and over 50% reported non-optimal consumption of vegetables, legumes, dairy products, and fish. Significant differences between girls and boys were observed for fruit (p = 0.003), cereals (p < 0.001), meat and meat products (p < 0.001), and dairy products (p = 0.003). By conducting a principal component analysis, we observed that Medi-Lite items on the consumption of some animal products (meat and meat products and dairy products) and some plant products (fruit, vegetables, and legumes) generated contrasting patterns of responses, denoting excessive consumption in the first case and underconsumption in the second. This result suggests the need for effective actions to promote healthy eating habits in young people.


Murine endothelioma cell lines transformed by polyoma middle T oncogene as target for and producers of cytokines.
We studied cytokine-related functional properties of four mouse endotheliomas from different anatomical sites obtained by transformation with middle T oncogene. We examined mRNA expression of IL-6, IL-1 alpha, macrophage-CSF, granulocyte/macrophage-CSF, and two members of an emerging super-family of chemotactic cytokines (JE/monocyte chemoattractant protein-1 (MCP-1) and KC). Exposure to IL-1 augmented or induced cytokine gene transcripts in three endothelioma lines (eEnd.1, sEnd.1, and tEnd) with maximal expression in tEnd.1 cells. Endothelioma cells also responded to TNF-alpha and LPS. Levels of IL-6 and monocyte chemotactic activity (a JE/MCP activity) correlated with mRNA expression. IL-1 also induced production of procoagulant activity and platelet-activating factor in endothelioma cells, with heterogeneity in the levels of response among individuals lines. Murine melanoma B16-F1, human colon carcinoma HT29 cells, CB33MT lymphoblastoid cells, and monocytes adhered to endothelioma monolayers and the adhesive properties of these cell lines were modulated by IL-1 beta, with marked differences among themselves. Murine EC derived from brain capillaries, used as control, shared several properties with bEnd.4 line. Endothelioma lines cause tumors by recruiting host cells. The capacity to produce cytokines that directly or indirectly attract host vascular cells, may play an important role in hemangioma induction in vivo. Murine endothelioma lines, generated by transformation with the polyoma middle T oncogene, retain functional properties of normal endothelium, and may represent an invaluable tool for analysis of the immunobiology and heterogeneity of EC in different tissues.


The estimation of tree posterior probabilities using conditional clade probability distributions.
In this article I introduce the idea of conditional independence of separated subtrees as a principle by which to estimate the posterior probability of trees using conditional clade probability distributions rather than simple sample relative frequencies. I describe an algorithm for these calculations and software which implements these ideas. I show that these alternative calculations are very similar to simple sample relative frequencies for high probability trees but are substantially more accurate for relatively low probability trees. The method allows the posterior probability of unsampled trees to be calculated when these trees contain only clades that are in other sampled trees. Furthermore, the method can be used to estimate the total probability of the set of sampled trees which provides a measure of the thoroughness of a posterior sample.


Routine use of fluorescent incisionless cholangiography as a new imaging modality during laparoscopic cholecystectomy.
Intraoperative incisionless fluorescent cholangiography (IOIFC) has been described to identify extrahepatic biliary anatomy. Potential advantages of the routine use of intraoperative incisionless fluorescent cholangiography were evaluated in a consecutive series of cases. A total of 45 patients undergoing laparoscopic cholecystectomy between January and July 2013 were consented and included in this study. We analyzed a prospectively collected database for feasibility, cost, time, usefulness, teaching tool, safety, learning curve, X-ray exposure, complexity, and real-time surgery of IOIFC. A single dose of 0.05 mg/kg of Indocyanine green was administered prior to surgery. During the procedure, a laparoscopic fluorescence system was used. IOIFC could be performed in all 45 patients, whereas intraoperative cholangiography could be performed in 42 (93 %). Individual median cost of performing IOFC was cheaper than IOC (13.97 ± 4.3 vs 778.43 ± 0.4 USD) per patient, p = 0.0001). IOFC was faster than IOC (0.71 ± 0.26 vs 7.15 ± 3.76 minutes, p < 0.0001). The cystic duct was identified by IOFC in 44 out of 45 patients (97.77 %). IOIFC appears to be a feasible, low-cost, expeditious, useful, and effective imaging modality when performing LC. It is safe, easy to perform and interpret, and does not require a learning curve or X-ray. It can be used for real time surgery to delineate the extrahepatic biliary structures.


Improving characteristics of biochar produced from collagen-containing solid wastes based on protease application in leather production.
Preparation of biochar from industrial solid wastes is receiving increasing attention in recent years. In this paper, alkaline protease, neutral protease and collagenolytic protease are used in preliminary steps of leather production, which are expected to replace the traditional chemical agents while preserving quality of the finished leather. The protease application has remarkable positive influence towards characteristics of biochar prepared by collagen-containing solid wastes produced in preliminary steps. The enzymatic action time should be more than 3 h for complete permeation and catalysis, and the diameters of treated collagen fibers were in the range of 10 to 20 nm. The micro-cracks occurring on collagen fibers would have an obviously impact on the formation of biochar. The application of proteases reduce the pollution of traditional production through replacing traditional polluted chemicals, and the characteristics of biochars are obviously improved with good surface area and high carbon content approximately 70%. Its surface area can reach 967 m2/g. These biochars contain oxygen-containing functional groups, and the oxygen content of biochars are all over 20%. The enzyme application in leather production are effective to the properties of biochars prepared by collagen-containing solid wastes. This research can serve as a basis for the preparation of biochar derived from of natural bio-wastes thereby promoting the development of biomaterials.


Health, lifestyle, and gender influences on aging well: an Australian longitudinal analysis to guide health promotion.
A primary societal goal for aging is enabling older people to continue to live well as long as possible. The evidence base around aging well ("healthy," "active," and "successful" aging) has been constructed mainly from academic and professional conceptualizations of mortality, morbidity, functioning, and psychological well-being with some attention to lay views. Our study aims to inform action on health promotion to achieve aging well as conceptualized by qualitative research identifying what older Australians themselves value most: continuing to live as long as possible in the community with independence in daily living, and good self-rated health and psychological well-being. Multivariate survival analyses from the Melbourne longitudinal studies on healthy aging program found that important threats to aging well for the total sample over a 12-year period were chronological age, multi-morbidity, low perceived social support, low nutritional score, and being under-weight. For men, threats to aging well were low strain, perceived inadequacy of social activity, and being a current smoker. For women, urinary incontinence, low physical activity and being under-weight were threats to aging well. The findings indicate that healthy lifestyles can assist aging well, and suggest the value of taking gender into account in health promotion strategies.


mTOR hyperactivity mediates lysosomal dysfunction in Gaucher's disease iPSC-neuronal cells.
Bi-allelic GBA1 mutations cause Gaucher's disease (GD), the most common lysosomal storage disorder. Neuronopathic manifestations in GD include neurodegeneration, which can be severe and rapidly progressive. GBA1 mutations are also the most frequent genetic risk factors for Parkinson's disease. Dysfunction of the autophagy-lysosomal pathway represents a key pathogenic event in GBA1-associated neurodegeneration. Using an induced pluripotent stem cell (iPSC) model of GD, we previously demonstrated that lysosomal alterations in GD neurons are linked to dysfunction of the transcription factor EB (TFEB). TFEB controls the coordinated expression of autophagy and lysosomal genes and is negatively regulated by the mammalian target of rapamycin complex 1 (mTORC1). To further investigate the mechanism of autophagy-lysosomal pathway dysfunction in neuronopathic GD, we examined mTORC1 kinase activity in GD iPSC neuronal progenitors and differentiated neurons. We found that mTORC1 is hyperactive in GD cells as evidenced by increased phosphorylation of its downstream protein substrates. We also found that pharmacological inhibition of glucosylceramide synthase enzyme reversed mTORC1 hyperactivation, suggesting that increased mTORC1 activity is mediated by the abnormal accumulation of glycosphingolipids in the mutant cells. Treatment with the mTOR inhibitor Torin1 upregulated lysosomal biogenesis and enhanced autophagic clearance in GD neurons, confirming that lysosomal dysfunction is mediated by mTOR hyperactivation. Further analysis demonstrated that increased TFEB phosphorylation by mTORC1 results in decreased TFEB stability in GD cells. Our study uncovers a new mechanism contributing to autophagy-lysosomal pathway dysfunction in GD, and identifies the mTOR complex as a potential therapeutic target for treatment of GBA1-associated neurodegeneration.


Bone-mineral losses in oophorectomized women.
The bone-mineral content of oophorectomized and non-oophorectomized women was assayed by x-ray spectrophotometry in five different parts of the skeleton. The patients had previously been treated for mammary cancer and were clinically free from disease. In the five to ten-year postoperative period the oophorectomized women had significantly lower mineral content in mainly trabecular parts of the skeleton (average, -18 per cent; p less than 0.01), whereas the mineral content in cortical parts of the skeleton was not significantly lower (average, -7 per cent; p greater than 0.01). The mineral loss in axial and peripheral trabecular bone was of the same magnitude. The results indicate that cessation of ovarian function will lead to an increased fracture risk in the wrist and the femoral neck, as well as in the spine.


Movement and function of the pectoral fins of the larval zebrafish (Danio rerio) during slow swimming.
Pectoral fins are known to play important roles in swimming for many adult fish; however, their functions in fish larvae are unclear. We examined routine pectoral fin movement during rhythmic forward swimming and used genetic ablation to test hypotheses of fin function in larval zebrafish. Fins were active throughout bouts of slow swimming. Initiation was characterized by asymmetric fin abduction that transitioned to alternating rhythmic movement with first fin adduction. During subsequent swimming, fin beat amplitude decreased while tail beat amplitude increased over swimming speeds ranging from 1.47 to 4.56 body lengths per second. There was no change in fin or tail beat frequency with speed (means ± s.d.: 28.2±3.5 and 29.6±1.9 Hz, respectively). To examine potential roles of the pectoral fins in swimming, we compared the kinematics of finless larvae generated with a morpholino knockdown of the gene fgf24 to those of normal fish. Pectoral fins were not required for initiation nor did they significantly impact forward rhythmic swimming. We investigated an alternative hypothesis that the fins function in respiration. Dye visualization demonstrated that pectoral fin beats bring distant fluid toward the body and move it caudally behind the fins, disrupting the boundary layer along the body's surface, a major site of oxygen absorption in larvae. Larval zebrafish also demonstrated more fin beating in low oxygen conditions. Our data reject the hypothesis that the pectoral fins of larval zebrafish have a locomotor function during slow, forward locomotion, but are consistent with the hypothesis that the fins have a respiratory function.


Policy Stringency, Handwashing and COVID-19 cases: Evidence from Global dataset.
: Since the COVID-19 pandemic, many governments globally have introduced policy measures to contain the spread of the virus. Popular COVID-19 containment measures include lockdowns of various forms (aggregated into government response stringency index [GRSI]) and handwashing (HWF). The effectiveness of these policy measures remains unclear in the academic literature. This study, therefore, examines the effect of government policy stringency and handwashing on total daily reported COVID-19 cases. : We use a comprehensive dataset of 176 countries to investigate the effect of government policy stringency and handwashing on daily reported COVID-19 cases. In this study, we apply the Lewbel (2012) two-stage least squares technique to control endogeneity. : Our results indicated that GRSI significantly contributes to the increase in the total and new confirmed cases of COVI-19. Sensitivity analyses revealed that the 1st, 4th, and 5th quintiles of GRIS significantly reduce total confirmed cases of COVID-19. Also, the result indicated that while the 1st quintile of GRIS contributes significantly to reducing the new confirmed cases of COVID-19, the 3rd, 4th, and 5th quintiles of GRSI contribute significantly to increasing the new confirmed cases of COVID-19. The results indicated that HWF reduces total and new confirmed cases of COVID-19; however, such effect is not robust to income and regional effects. Nonlinear analysis revealed that while GRSI has an inverted U-shaped relationship with total and new confirmed cases of COVID-19, HWF has a U-shaped relationship. : We suggest that policymakers should focus on raising awareness and full engagement of all members of society in implementing public health policies rather than using stringent lockdown measures.


Dose-dependent effects of FK506 on neuroregeneration in a rat model.
This study explored the effects of different doses of FK506 on peripheral nerve regeneration, to determine whether neuroregeneration could be enhanced without the toxicity of systemic immunosuppression. In the first part of the study, subimmunosuppressive doses of FK506 were determined by examining skin allograft survival in a rat model. Full-thickness skin grafts (2 cm2) from Wistar rats were grafted to recipient Lewis rats. The procedure was performed for six groups (n = 6). The control group received no FK506, and the other five groups received daily doses of FK506 of 0.125, 0.25, 0.5, 1.0, or 2.0 mg/kg. Animals that received 2.0 mg/kg FK506 per day exhibited complete skin graft take, whereas all other groups demonstrated complete rejection. After determination of the immunosuppressive dose of FK506, the neuroregenerative effects of different doses of FK506 were explored by assessing nerve regeneration in 80 rats after tibial nerve transection and repair. The control group received no FK506, whereas the other four groups were given daily doses of FK506 of 0.25, 0.5, 1.0, or 2.0 mg/kg. Rats were euthanized at three time points (25, 30, and 35 days), to fully investigate the effects of different FK506 dosing regimens on neuroregeneration. Histomorphometric analyses performed on postoperative days 30 and 35 demonstrated statistically significant improvements in neuroregeneration with subimmunosuppressive FK506 doses of 0.5 and 1.0 mg/kg per day. Therefore, the study demonstrated that neuroregeneration was enhanced at low doses of FK506 that were not sufficient to prevent skin allograft rejection.


An Integrated Method Based on Wasserstein Distance and Graph for Cancer Subtype Discovery.
Due to the complexity of cancer pathogenesis at different omics levels, it is necessary to find a comprehensive method to accurately distinguish and find cancer subtypes for cancer treatment. In this paper, we proposed a new cancer multi-omics subtype identification method, which is based on variational autoencoder measured by Wasserstein distance and graph autoencoder (WVGMO). This method depends on two foremost models. The first model is a variational autoencoder measured by Wasserstein distance (WVAE), which is used to extract potential spatial information of each omic data type. The second model is the graph autoencoder (GAE) with the second-order proximity. It has the capability to retain the topological structure information and feature information of the multi-omics data. And then, the identification of cancer subtypes via k-means clustering. Extensive experiments were conducted on seven different cancers based on four omics data from TCGA. The results show that WVGMO provides equivalent or even better results than the most of advanced synthesis methods.


Pathophysiology of Cardiopulmonary Bypass: Current Strategies for the Prevention and Treatment of Anemia, Coagulopathy, and Organ Dysfunction.
The techniques and equipment of cardiopulmonary bypass (CPB) have evolved over the past 60 years, and numerous numbers of cardiac surgical procedures are conducted around the world using CPB. Despite more widespread applications of percutaneous coronary and valvular interventions, the need for cardiac surgery using CPB remains the standard approach for certain cardiac pathologies because some patients are ineligible for percutaneous procedures, or such procedures are unsuccessful in some. The ageing patient population for cardiac surgery poses a number of clinical challenges, including anemia, decreased cardiopulmonary reserve, chronic antithrombotic therapy, neurocognitive dysfunction, and renal insufficiency. The use of CPB is associated with inductions of systemic inflammatory responses involving both cellular and humoral interactions. Inflammatory pathways are complex and redundant, and thus, the reactions can be profoundly amplified to produce a multiorgan dysfunction that can manifest as capillary leak syndrome, coagulopathy, respiratory failure, myocardial dysfunction, renal insufficiency, and neurocognitive decline. In this review, pathophysiological aspects of CPB are considered from a practical point of view, and preventive strategies for hemodilutional anemia, coagulopathy, inflammation, metabolic derangement, and neurocognitive and renal dysfunction are discussed.


[Optimising surgery for rectal cancer].
The crucial aspect of open as well as laparoscopic rectal cancer surgery is to find the correct dissection plane to avoid damage of the nerves and to create a perfect specimen. By doing so, a "specimen oriented" resection will be achieved and the risk of a positive circumferential resection margin minimized. Currently, and for the foreseeable future, open surgery remains optimal for complex cases and in cases where a low difficult restorative resection is needed. Optimal surgery remains a crucial part in the curative treatment of this technically challenging cancer.


Three Dimensional Bioprinting for Hepatic Tissue Engineering: From In Vitro Models to Clinical Applications.
Fabrication of functional organs is the holy grail of tissue engineering and the possibilities of repairing a partial or complete liver to treat chronic liver disorders are discussed in this review. Liver is the largest gland in the human body and plays a responsible role in majority of metabolic function and processes. Chronic liver disease is one of the leading causes of death globally and the current treatment strategy of organ transplantation holds its own demerits. Hence there is a need to develop an in vitro liver model that mimics the native microenvironment. The developed model should be a reliable to understand the pathogenesis, screen drugs and assist to repair and replace the damaged liver. The three-dimensional bioprinting is a promising technology that recreates in vivo alike in vitro model for transplantation, which is the goal of tissue engineers. The technology has great potential due to its precise control and its ability to homogeneously distribute cells on all layers in a complex structure. This review gives an overview of liver tissue engineering with a special focus on 3D bioprinting and bioinks for liver disease modelling and drug screening.


Intramuscular angiomatous tumors associated with periosteal changes and pain.
This case report discusses two cases in which patients present with the uncommon triad of extremity pain, focal periosteal reaction on imaging studies, and intramuscular hemangioma on pathologic examination. Both patients presented in this article were older than those previously reported in the literature. Neither patient reported complete resolution of pain following excision, although there was marked improvement.


Neurodevelopmental disease genes implicated by de novo mutation and copy number variation morbidity.
We combined de novo mutation (DNM) data from 10,927 individuals with developmental delay and autism to identify 253 candidate neurodevelopmental disease genes with an excess of missense and/or likely gene-disruptive (LGD) mutations. Of these genes, 124 reach exome-wide significance (P < 5 × 10-7) for DNM. Intersecting these results with copy number variation (CNV) morbidity data shows an enrichment for genomic disorder regions (30/253, likelihood ratio (LR) +1.85, P = 0.0017). We identify genes with an excess of missense DNMs overlapping deletion syndromes (for example, KIF1A and the 2q37 deletion) as well as duplication syndromes, such as recurrent MAPK3 missense mutations within the chromosome 16p11.2 duplication, recurrent CHD4 missense DNMs in the 12p13 duplication region, and recurrent WDFY4 missense DNMs in the 10q11.23 duplication region. Network analyses of genes showing an excess of DNMs highlights functional networks, including cell-specific enrichments in the D1+ and D2+ spiny neurons of the striatum.


Colonic content: effect of diet, meals, and defecation.
The metabolic activity of colonic microbiota is influenced by diet; however, the relationship between metabolism and colonic content is not known. Our aim was to determine the effect of meals, defecation, and diet on colonic content. In 10 healthy subjects, two abdominal MRI scans were acquired during fasting, 1 week apart, and after 3 days on low- and high-residue diets, respectively. With each diet, daily fecal output and the number of daytime anal gas evacuations were measured. On the first study day, a second scan was acquired 4 hours after a test meal (n=6) or after 4 hours with nil ingestion (n=4). On the second study day, a scan was also acquired after a spontaneous bowel movement. On the low-residue diet, daily fecal volume averaged 145 ± 15 mL; subjects passed 10.6 ± 1.6 daytime anal gas evacuations and, by the third day, non-gaseous colonic content was 479 ± 36 mL. The high-residue diet increased the three parameters to 16.5 ± 2.9 anal gas evacuations, 223 ± 19 mL fecal output, and 616 ± 55 mL non-gaseous colonic content (P<.05 vs low-residue diet for all). On the low-residue diet, non-gaseous content in the right colon had increased by 41 ± 11 mL, 4 hours after the test meal, whereas no significant change was observed after 4-hour fast (-15 ± 8 mL; P=.006 vs fed). Defecation significantly reduced the non-gaseous content in distal colonic segments. Colonic content exhibits physiologic variations with an approximate 1/3 daily turnover produced by meals and defecation, superimposed over diet-related day-to-day variations.


Breastfeeding knowledge, attitudes, and practices among providers in a medical home.
Breastfeeding offers numerous health advantages to children, mothers, and society. From obstetrics to pediatrics, breastfeeding dyads come in contact with a wide range of healthcare providers. The American Academy of Pediatrics (AAP) calls for pediatricians to support breastfeeding enthusiastically and for all children to have a medical home. We studied an inner-city healthcare system with a Dyson Community Pediatrics Training Initiative Model Medical Home clinic, to explore how a breastfeeding/baby-friendly medical home might be built upon this framework. We describe breastfeeding knowledge, attitudes, and practices among a full range of providers and healthcare system-level barriers to effective and coordinated breastfeeding services. We conducted eight focus groups using semistructured interviews: (1) pediatricians; (2) obstetricians; (3) pediatric nurses and allied health professionals; (4) obstetric nurses and allied health professionals; (5) 24-hour telephone triage answering service nurses; (6) public health nurses; (7) Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) personnel; and (8) lactation consultants and peer counselors. We identified gaps in providers' breastfeeding knowledge, counseling skills, and professional education and training. Providers' cultures and attitudes affect breastfeeding promotion and support. Providers used their own breastfeeding experiences to replace evidence-based knowledge and AAP policy statement recommendations for breastfeeding dyads. There were communication disconnects between provider groups. Providers underestimated their own, and overestimated others', influence on breastfeeding. The system lacked a coordinated breastfeeding mission. This study illuminated key disconnectedness challenges (and, hence, opportunities) for a model medical home in fostering continuous, comprehensive, coordinated, culturally effective, and evidence-based breastfeeding promotion and support.


LGR4 deficiency results in delayed puberty through impaired Wnt/β-catenin signaling.
The initiation of puberty is driven by an upsurge in hypothalamic gonadotropin-releasing hormone (GnRH) secretion. In turn, GnRH secretion upsurge depends on the development of a complex GnRH neuroendocrine network during embryonic life. Although delayed puberty (DP) affects up to 2% of the population, is highly heritable, and is associated with adverse health outcomes, the genes underlying DP remain largely unknown. We aimed to discover regulators by whole-exome sequencing of 160 individuals of 67 multigenerational families in our large, accurately phenotyped DP cohort. LGR4 was the only gene remaining after analysis that was significantly enriched for potentially pathogenic, rare variants in 6 probands. Expression analysis identified specific Lgr4 expression at the site of GnRH neuron development. LGR4 mutant proteins showed impaired Wnt/β-catenin signaling, owing to defective protein expression, trafficking, and degradation. Mice deficient in Lgr4 had significantly delayed onset of puberty and fewer GnRH neurons compared with WT, whereas lgr4 knockdown in zebrafish embryos prevented formation and migration of GnRH neurons. Further, genetic lineage tracing showed strong Lgr4-mediated Wnt/β-catenin signaling pathway activation during GnRH neuron development. In conclusion, our results show that LGR4 deficiency impairs Wnt/β-catenin signaling with observed defects in GnRH neuron development, resulting in a DP phenotype.


[Topographic features of the ultrastructure of parietal cells of the gastric mucosa (morphometric study)].
A new methodical approach to the study of the ultrastructure of the parietal cells of the gastric mucosa is suggested. Electron microscopic study of peculiarities of the submicroscopic cell organization at the three main levels (the generative zone, the zone of the most active cells, and the gland floor) is necessarily followed by the morphometric analysis of the results obtained. Marked differences in the ultrastructural morphometric indices of the parietal cells located at various levels of the glands were demonstrated with the aid of the mentioned method. Despite certain difficulties, such approach can be also applied to the study of other cell elements of the gastric mucosa and also of many other tissues with continuous quick cell renewal.


The conserved YAGL motif in human metapneumovirus is required for higher-order cellular assemblies of the matrix protein and for virion production.
YXXL motifs in cellular and viral proteins have a variety of functions. The matrix (M) protein of the respiratory pathogen human metapneumovirus (hMPV) contains two such conserved motifs--YSKL and YAGL. We mutated these sequences to analyze their contributions to hMPV infectivity. The mutant clones were capable of intracellular replication; however, the YAGL but not YSKL mutants were defective at spreading in infected cultures. We improved the reverse genetics system for hMPV and generated cell lines that stably expressed selectable, replicating full-length genomes for both the wild type and the mutant clones, allowing microscopic and biochemical analyses of these viruses. YAGL mutants produced normal cellular levels of M protein but failed to release virions, while ectopic coexpression of wild-type M generated particles that were restricted to a single cycle of infection. The YAGL motif did not act as a late (L) domain, however, since hMPV budding was independent of the cellular endosomal sorting complex required for transport (ESCRT) machinery and because replacement of the YAGL motif with classical L domains generated defective viruses. Instead, the YAGL mutants had defective M assemblies lacking a normal filamentous appearance and showed poor extractability from the cell compared to the wild-type protein. The mutant proteins were not grossly misfolded, however, as they interacted with cellular membranes and coassembled with wild-type M proteins. Thus, the YAGL motif is an important determinant of hMPV assembly. Furthermore, the selectable hMPV genomes described here should extend the use of reverse genetics systems in the analysis of spreading-defective viruses.


[Information-activation relations and mental work capacity of operators].
This paper presents the results of studying diagnostic potentials of the method used to assess mental performance of operators based on a combined application of the information carrying capacity and psychophysiological expenditures of man. Three groups of operators (45 subjects) that differed in their health status and motivation when performing sensorimotor tests were examined. Psychophysiological cost was measured with respect to autonomic responses (heart rate, respiration frequency, minute respiration volume, arm temperature) combined into an integrated parameter of psychic stress. It was found that the extremes of the relationship between information and activation parameters were invariant. The data obtained suggest that the information-activation relationship may be used to advantage in the clinical and physiological expertise of operators.


Priority threat management of invasive animals to protect biodiversity under climate change.
Climate change is a major threat to global biodiversity, and its impacts can act synergistically to heighten the severity of other threats. Most research on projecting species range shifts under climate change has not been translated to informing priority management strategies on the ground. We develop a prioritization framework to assess strategies for managing threats to biodiversity under climate change and apply it to the management of invasive animal species across one-sixth of the Australian continent, the Lake Eyre Basin. We collected information from key stakeholders and experts on the impacts of invasive animals on 148 of the region's most threatened species and 11 potential strategies. Assisted by models of current distributions of threatened species and their projected distributions, experts estimated the cost, feasibility, and potential benefits of each strategy for improving the persistence of threatened species with and without climate change. We discover that the relative cost-effectiveness of invasive animal control strategies is robust to climate change, with the management of feral pigs being the highest priority for conserving threatened species overall. Complementary sets of strategies to protect as many threatened species as possible under limited budgets change when climate change is considered, with additional strategies required to avoid impending extinctions from the region. Overall, we find that the ranking of strategies by cost-effectiveness was relatively unaffected by including climate change into decision-making, even though the benefits of the strategies were lower. Future climate conditions and impacts on range shifts become most important to consider when designing comprehensive management plans for the control of invasive animals under limited budgets to maximize the number of threatened species that can be protected.


Pregnancy complicated by maternal neural tube defect and an ileal conduit: a case report.
A case report is presented of a patient with severe neurologic defects associated with repaired meningomyelocele whose pregnancy was complicated in addition by prior urihary diversion and subsequent ureteral obstruction. The obstetric problem related to ileal conduits and the genetic aspects of neural tube defects are reviewed.


Diagnostic potential of prostate-specific antigen expressing epithelial cells in blood of prostate cancer patients.
Prostate-specific antigen (PSA) test has become a widely used screening test in prostate cancer (CaP). However, low specificity of serum PSA leads to many false-positive and false-negative results and clinical uncertainty. Development of CaP-specific diagnostic and prognostic markers is needed. Detection of circulating PSA-expressing cells (CPECs) in blood and bone marrow of CaP patients has potential in molecular diagnosis and prognosis. Our novel observations of the frequent presence of CPECs in CaP patients with organ-confined disease by reverse transcription (RT)-PCR-PSA assay in epithelial cells enriched from peripheral blood (ERT-PCR/PSA) have led us to test the hypothesis that CPECs have diagnostic potential for CaP. Epithelial cells from peripheral blood of radical prostatectomy patients or prostate biopsy patients were isolated using antiepithelial cell antibody, Ber-EP4-coated magnetic beads, and total RNA specimens from these cells were analyzed for PSA expression by RT-PCR. Peripheral blood specimens of 108 of 135 (80.0%) CaP patients were positive in ERT-PCR/PSA assay. Peripheral blood specimens from 45 control men were virtually negative (97.8%). In the blinded investigation, 84 patients who had biopsy for suspicion of CaP were evaluated by ERT-PCR/PSA assay. Eighteen of 22 (81.8%) patients with biopsy-proven CaP were positive, and 54 of 62 (87.1%) patients with biopsy negative for CaP were negative in this assay (P < 0.001). Our study provides intriguing novel results showing that the majority of patients with clinically organ-confined CaP contain CPECs. Strong concordance between the biopsy results and ERT-PCR/PSA assay (sensitivity 81.8%; specificity 87.1%) suggests a potentially new diagnostic application of this type of assay in CaP diagnosis.


Beta-adrenergic effects on carbohydrate metabolism in the unweighted rat soleus muscle.
The effects of insulin on carbohydrate metabolism in atrophied rat soleus muscle are increased after unweighting by tail-cast suspension. This work has been extended by testing the effect of unweighting on the response of carbohydrate metabolism to isoproterenol, a beta-adrenergic agonist. Isoproterenol promoted glycogen degradation more in the unweighted than in the weight-bearing soleus but showed no differences in the extensor digitorum longus, which is unresponsive to hindlimb unweighting. In soleus muscles depleted of glycogen, to avoid varied inhibitory effects of glycogen on glycogen synthesis, isoproterenol inhibited this process more in the unweighted muscle. Isoproterenol did not have a greater inhibitory effect on net uptake of 2-deoxy-D[1,2-3H]glucose by the unweighted muscle. Measurements of intracellular 2-deoxy-[3H]glucose 6-phosphate and 3-O-methyl-D-[1-3H]glucose, which cannot be phosphorylated, showed that isoproterenol inhibited glucose phosphorylation but not transport. This effect could be explained by an increase of glucose 6-phosphate, an inhibitor of hexokinase. At 100 microU insulin/ml but not at a lower amount (10 microU/ml), isoproterenol inhibited hexose phosphorylation more in the control than in the unweighted muscle. This result may be explained by greater insulin antagonism in the unweighted muscle owing to increased insulin sensitivity. However, insulin antagonism of isoproterenol stimulation of glycogenolysis or inhibition of glycogenesis was not altered by unweighting. Therefore, for some aspects of carbohydrate metabolism, the unweighted muscle has an increased response to beta-adrenergic activation, just as this muscle shows increased responses to insulin.


Treatment of osteoarthritis with aspartame.
The binding of sweet-tasting compounds in a human (Mcg) Bence-Jones dimer has been characterized by x-ray crystallography. Aspartame binding in this immunoglobulin fragment is remarkable. Unexpected pain relief noted by A.B.E., a crystallographer with diagnosed osteoarthritis, suggested that the accommodation of aspartame in the active site of the dimer may represent surrogate binding by other proteins, with analgesia as the outcome. X-ray analysis of the complex of aspartame and the Bence-Jones dimer was conducted with crystalline Mcg protein and pure aspartame. A single-blind (n = 1) study to confirm analgesia was completed by administration of aspartame to A.B.E. A controlled double-blind trial was performed in patients with x-ray-documented osteoarthritis. Pain and performance changes were evaluated with use of two doses of placebo and two doses of aspartame. Effects on bleeding time were then evaluated by determination of template bleeding times in 34 normal volunteers. Finally, antipyretic effects were studied in Sprague-Dawley rats given intramuscular turpentine injections. Aspartame binding in the Bence-Jones dimer was verified by x-ray crystallography. Improvements in performance and pain relief were observed in A.B.E. at p < 0.001. Decreased pain and improved performance were also observed in patients with osteoarthritis (p < 0.001). Mild antihemostatic responses were observed in bleeding times after aspartame treatment. Modified template bleeding times increased at p < 0.01. Aspartame blocked the turpentine-mediated febrile responses in the treated rats (p < 0.01). L-Aspartyl-L-phenylalanine methyl ester is biologically active and appears to relieve pain, induce mild antithrombotic effects in humans, and decrease fever in animals.


Computational Fluid Dynamics of Stent-Mounted Neural Interfaces in an Idealized Cerebral Venous Sinus.
Hemodynamic changes in stented blood vessels play a critical role in stent-associated complications. The majority of work on the hemodynamics of stented blood vessels has focused on coronary arteries but not cerebral venous sinuses. With the emergence of endovascular electrophysiology, there is a growing interest in stenting cerebral blood vessels. We investigated the hemodynamic impact of a stent-mounted neural interface inside the cerebral venous sinus. The stent was virtually implanted into an idealized superior sagittal sinus (SSS) model. Local venous blood flow was simulated. Results showed that blood flow was altered by the stent, generating recirculation and low wall shear stress (WSS) around the device. However, the effect of the electrodes on blood flow was not prominent due to their small size. This is an early exploration of the hemodynamics of a stent-mounted neural interface. Future work will shed light on the key factors that influence blood flow and stenting outcomes.Clinical Relevance-The study investigates blood flow through a stent-based electrode array inside the cerebral venous sinus. The hemodynamic impact of the stent can provide insight into neointimal growth and thrombus formation.


["Healthy cities"--requirements and performance. Questionnaire results and a suggestion on quality monitoring (healthy-cities-barometer)].
The overall goal of the WHO Healthy Cities Project was to translate some key points of the Ottawa Charter for Health Promotion (1986) into reality such as public health policies, creating health-promoting environments, strengthening community action through active public participation (empowerment of communities) and equity in health at the local level. These should be anchored within the local political administrative system (PAS), which means health should be on the agenda of policymakers in all sectors. To figure out how far this has been attained after almost 15 years of "healthy cities" policy in Germany was the focal point of the first questioning of local project coordinators. A written questionnaire containing 128 items has been developed in collaboration with the Healthy Cities Network-Coordinator. The questionnaire consists of 78 standardised questions and some (23) open-ended questions for more specific qualitative information. Also included are 27 ten-point rating scales to evaluate the coordinators' view of some aspects of their healthy cities work and to assess its progress. Based on 30 questions of the questionnaire we generated six quality indices, summarised to a quality index for a monitoring model. 47 (90 %) project-coordinators from a list of 52 took part in the first German Healthy Cities survey in the spring 2002. Selected results of the network questioning concerning the local "healthy cities" offices, work priorities and methods demonstrate differences between East and West Germany and general weakpoints of the "healthy cities" projects. Data analysis based on six quality dimensions of the "Healthy Cities" work, Programme Equipment and Commitment (Structure), Concept Quality and Integration within the Network (Process), Self-reported Success and Integration within the City/Municipality (Outcome), revealed some weak points of the " Healthy Cities" work as follows: Basing on the six quality dimensions we present a monitoring model (Healthy-Cities Barometer) which can also be used for strategic controlling (benchmarking) within the German Healthy Cities Network. Based on the data we identified 13 Cities at an A-level (excellent), 22 Cities at a B-level (satisfactory) and 12 Cities at a C-level (INADEQUATE). The "Healthy-Cities Barometer" provides a surveillance instrument which - if constantly used over several years - could offer data for a longitudinal analysis of the Healthy Cities' development. With its help the Healthy Cities Network-Coordinator could gain more information for a better performance and a continuous quality improvement process of the local Healthy Cities projects.


Glutathione as an endogenous sulphur source in the yeast Saccharomyces cerevisiae.
Glutathione-deficient mutants (gshA) of the yeast Saccharomyces cerevisiae, impaired in the first step of glutathione (GSH) biosynthesis were studied with respect to the regulation of enzymes involved in GSH catabolism and cysteine biosynthesis. Striking differences were observed in the content of the sulphur amino acids when gshA mutants were compared to wild-type strains growing on the same minimal medium. Furthermore, all mutants examined showed a derepression of gamma-glutamyltranspeptidase (gamm-GT), the enzyme initiating GSH degradation. However, gamma-cystathionase and cysteine synthase were unaffected by the GSH deficiency as long as the nutrient sulphate source was not exhausted. The results suggest that the mutants are probably not impaired in the sulphate assimilation pathway, but that the gamma-glutamyl cycle could play a leading role in the regulation of the sulphur fluxes. Studies of enzyme regulation showed that the derepression of gamma-GT observed in the gshA strains was most probably due to an alteration of the thiol status. The effectors governing the biosynthesis of cysteine synthase and gamma-cystathionase seemed different from those playing a role in gamma-GT regulation and it was only under conditions of total sulphate deprivation that all these enzymes were derepressed. As a consequence the endogenous pool of GSH was used in the synthesis of cysteine. GSH might, therefore, fulfil the role of a storage compound.


Genome-wide functional analyses of plant coiled-coil NLR-type pathogen receptors reveal essential roles of their N-terminal domain in oligomerization, networking, and immunity.
The ability to induce a defense response after pathogen attack is a critical feature of the immune system of any organism. Nucleotide-binding leucine-rich repeat receptors (NLRs) are key players in this process and perceive the occurrence of nonself-activities or foreign molecules. In plants, coevolution with a variety of pests and pathogens has resulted in repertoires of several hundred diverse NLRs in single individuals and many more in populations as a whole. However, the mechanism by which defense signaling is triggered by these NLRs in plants is poorly understood. Here, we show that upon pathogen perception, NLRs use their N-terminal domains to transactivate other receptors. Their N-terminal domains homo- and heterodimerize, suggesting that plant NLRs oligomerize upon activation, similar to the vertebrate NLRs; however, consistent with their large number in plants, the complexes are highly heterometric. Also, in contrast to metazoan NLRs, the N-terminus, rather than their centrally located nucleotide-binding (NB) domain, can mediate initial partner selection. The highly redundant network of NLR interactions in plants is proposed to provide resilience to perturbation by pathogens.


Gulf of Maine Harmful Algal Bloom in summer 2005 - Part 2: Coupled Bio-physical Numerical Modeling.
A coupled physical/biological modeling system was used to hindcast the 2005 Alexandrium fundyense bloom in the Gulf of Maine and investigate the relative importance of factors governing the bloom's initiation and development. The coupled system consists of a state-of-the-art, free-surface primitive equation Regional Ocean Modeling System (ROMS) tailored for the Gulf of Maine (GOM) using a multi-nested configuration, and a population dynamics model for A. fundyense. The system was forced by realistic momentum and buoyancy fluxes, tides, river runoff, observed A. fundyense benthic cyst abundance, and climatological nutrient fields. Extensive comparisons were made between simulated (both physical and biological) fields and in-situ observations, revealing that the hindcast model is capable of reproducing the temporal evolution and spatial distribution of the 2005 bloom. Sensitivity experiments were then performed to distinguish the roles of three major factors hypothesized to contribute to the bloom: 1) the high abundance of cysts in western GOM sediments; 2) strong northeaster storms with prevailing downwelling-favorable winds; and 3) a large amount of fresh water input due to abundant rainfall and heavy snowmelt. Results suggested that the high abundance of cysts in western GOM was the primary factor of the 2005 bloom. Wind forcing was an important regulator, as episodic bursts of northeast winds caused onshore advection of offshore populations. These downwelling favorable winds accelerated the alongshore flow, resulting in transport of high cell concentrations into Massachusetts Bay. A large regional bloom would still have happened, however, even with normal or typical winds for that period. Anomalously high river runoff in 2005 resulted in stronger buoyant plumes/currents, which facilitated the transport of cell population to the western GOM. While affecting nearshore cell abundance in Massachusetts Bay, the buoyant plumes were confined near to the coast, and had limited impact on the gulf-wide bloom distribution.


[Laparoscopic exeresis of a completely duplicated kidney].
During the '80s, laparoscopy in general has undergone an enormous boom as representative of minimally invasive surgery, urology standing out in that progression as the specialty leading the endoscopic approach both for the tradition and profusion of techniques developed. In Spain, major scope laparoscopic surgery started with lymphadenectomy in which we are the second Spanish and first Andalusian group to perform it. The experience accumulated by our group has allowed us to perform and present one case of laparoscopic nephrectomy, this being the first time in Andalusia and second in Spain that an Urology Unit develops this technique, the distinct feature being the presence of complete duplicity of the kidney. The procedure had no peri or post-operative complications and the patient was discharged four days later. We conclude that although presently the indications of renal exeresis for this procedure are limited, these will soon be expanded thanks to the urologists' concern, the accumulation of experience and the improvement of the instrumentarium.


Rat beta casein cDNA: sequence analysis and evolutionary comparisons.
The complete sequence of a 1072 nucleotide rat beta-casein cDNA insertion in the hybrid plasmid pC beta 23 has been determined. Primer extension was employed to determine the sequence of an additional 82 5'-terminal nucleotides in beta-casein mRNA. Rat beta-casein mRNA consists of a 696 nucleotide coding region, flanked by 52 nucleotide 5' and 406 nucleotide 3' noncoding regions, including a 40 nucleotide poly(A) tail. The derived 216 amino acid sequence of rat beta-casein was compared to the previously determined sequences of beta-caseins from several other species. Approximately 38% of the amino acids have been conserved among the rat, ovine, bovine and human sequences and these conserved amino acids occurred in clusters throughout the protein. One such cluster containing the majority of the potential casein phosphorylation sites was located near the amino terminus. Contrary to the considerable divergence observed for the processed beta-casein, 14 of 15 amino acids in the signal peptide sequence of the precasein were identical between the rat and ovine caseins.


NRF2 signaling cascade in amyotrophic lateral sclerosis: bridging the gap between promise and reality.
Amyotrophic lateral sclerosis is a very disabling disease due to the degeneration of motor neurons. Symptoms include muscle weakness and atrophy, spasticity, and progressive paralysis. Currently, there is no treatment to reverse damage to motor neurons and cure amyotrophic lateral sclerosis. The only two treatments actually approved, riluzole and edaravone, have shown mitigated beneficial effects. The difficulty to find a cure lies in the complexity and multifaceted pattern of amyotrophic lateral sclerosis pathogenesis. Among mechanisms, abnormal RNA metabolism, nucleocytoplasmic transport defects, accumulation of unfolded protein, and mitochondrial dysfunction would in fine induce oxidative damage and vice versa. A potent therapeutic strategy will be to find molecules that break this vicious circle. Sharpening the nuclear factor erythroid-2 related factor 2 signaling may fulfill this objective since nuclear factor erythroid-2 related factor 2 has a multitarget profile controlling antioxidant defense, mitochondrial functioning, and inflammation. We here discuss the interest of developing nuclear factor erythroid-2 related factor 2-based therapy in regard to the pathophysiological mechanisms and we provide a general overview of the attempted clinical assays in amyotrophic lateral sclerosis.


[Investigation of bacterial translocation regularities in diffuse peritonitis using labeled radionuclide colibacillus].
The investigation of the regularities of translocation of opportunistic pathogenic microflora from the small intestine lumen and abdominal cavity in diffuse peritonitis using labeled radionuclide colibacillus has shown that in normal condition the intestinal barrier is not permeable for bacteria. Under conditions of diffuse peritonitis the bacterial translocation and peritoneal resorption are developing since the first minutes of the disease. During the development of the pathological process the priority of the foci of bacterial toxemia is changed from peritoneal to intestinal. Relaparotomy with manipulations on the intestine in peritonitis induces sharp activation of bacteria translocation into the portal blood flow and systemic circulation.


A new Riff: Rif1 eats its cake and has it too.
Rif1 protein is present in eukaryotic cells from yeast to human. In yeast, Rif1 is important for telomere homeostasis. Despite conservation in its domain organization, human Rif1 is not part of the telomere complex but was recently reported to work at DNA double‐strand breaks (DSBs) with 53BP1 to inhibit 5′ strand degradation (resection) and stimulate a subset of nonhomologous end‐joining (NHEJ) reactions. Martina et al report in this issue of EMBO reports that yeast Rif1 is also recruited to DSBs, but in contrast to its human counterpart, it promotes resection. The authors propose that Rif1 stimulates resection by limiting the access of Rad9, an ortholog of 53BP1, to DSBs.


Isoflavones stimulate estrogen receptor-mediated core histone acetylation.
The isoflavones genistein and daidzein and the daidzein metabolite equol have been reported to interact with estrogen receptors (ERs). Some studies indicate that they behave clinically like estrogen in some estrogen-deficiency diseases. However, the detailed molecular mechanism used by these compounds to create beneficial effects in patients with estrogen-related diseases has not been clarified. Using histone acetyltransferase (HAT) assay, we found that equol, genistein, and AglyMax had significant effects on ERalpha-mediated histone acetylation. Although 17beta-estradiol (E2)-dependent HAT activity of steroid receptor coactivators 2 (SRC2) and p300 mediated by ERbeta could be detected, it was weaker than that mediated by ERalpha. Equol, genistein, AglyMax, and daidzein all markedly stimulated ERbeta-mediated histone acetylation. On the other hand, anti-estrogenic compounds ICI 182,780 (ICI) and tamoxifen (TA) did not have an effect on HAT activity mediated by either ERalpha or ERbeta. Our data indicate that estrogenic ligands exert their effects by elevating histone acetylation and coactivator activity of ER, and suggest that the risk of estrogen-related diseases might be reduced by a sufficient amount of genistein or AglyMax supplements.


The hexosamine biosynthetic pathway can mediate myocardial apoptosis in a rat model of diet-induced insulin resistance.
Type 2 diabetes is characterized by deranged metabolic pathways that may result in cardiovascular complications. For example, hyperglycaemia promotes flux through the hexosamine biosynthetic pathway (HBP) leading to greater O-GlcNAcylation of target proteins, with pathophysiological outcomes. This study investigated mechanisms whereby increased HBP flux elicits myocardial apoptosis in a rat model of diet-induced hyperglycaemia/insulin resistance. Four-week-old male Wistar rats were fed a high-fat diet (86 days) after which insulin resistance was assessed vs. matched controls. Oxidative stress was evaluated, and apoptotic peptide levels, BAD phosphorylation and overall O-GlcNAcylation assessed by immunoblotting. Protein-specific O-GlcNAcylation and BAD-Bcl-2 dimerization were determined by immunoprecipitation and Western blotting. Rats consuming the high-fat diet exhibited a moderate elevation in body weight, higher fasting insulin and glucose levels, and insulin resistance vs. controls. Overall protein O-GlcNAcylation was increased in hyperglycaemic/insulin-resistant hearts. In parallel, myocardial peptide levels of apoptotic markers (caspase-3, cytochrome-c, BAD) were significantly higher with insulin resistance. To gain mechanistic insight into our findings, we evaluated O-GlcNAcylation of BAD, a pro-apoptotic Bcl-2 homolog. Here we found increased BAD O-GlcNAcylation and decreased BAD phosphorylation (Ser136) in hyperglycaemic/insulin-resistant rat hearts. These data are in agreement with competition by phosphorylation and O-GlcNAcylation for the same or neighbouring site(s) on target proteins. Moreover, we observed increased BAD-Bcl-2 dimerization in hyperglycaemic/insulin-resistant hearts. The main finding of this study is that increased apoptosis in hyperglycaemic/insulin-resistant hearts can also be mediated through HBP-induced BAD O-GlcNAcylation and greater formation of BAD-Bcl-2 dimers (pro-apoptotic).


Orbital ordering in LaMnO3 investigated by resonance Raman spectroscopy.
Orbital ordering leads to an unconventional excitation spectrum that we investigate by resonance Raman scattering using incident photon energies between 1.7 and 5.0 eV. We use spectral ellipsometry to determine the corresponding dielectric function. Our results show resonant behavior of the phonon Raman cross section when the laser frequency is close to the orbiton-excitation energy of 2 eV in LaMnO3. We show an excellent agreement between theoretical calculations based on the Franck-Condon mechanism activating multiphonon Raman scattering in first order of the electron-phonon coupling and the experimental data of phonons with different symmetries.


Suitability of the shrub-steppe habitat of Eastern Washington for Halyomorpha halys (Hemiptera: Pentatomidae).
The invasive brown marmorated stink bug, Halyomorpha halys Stål (Hemiptera: Pentatomidae), has spread throughout most of Washington (WA) State since its detection in 2012. While it has emerged as a major agricultural and nuisance pest in the Pacific Northwest (PNW) west of the Cascade Mountains, pest pressure in the major tree fruit-growing areas in semi-arid northern and central WA State remains low. The reasons for this are unclear, although both biotic and abiotic conditions may be contributing factors. We evaluated the suitability of a common shrub-steppe/riparian corridor plant assemblage for supporting H. halys development from egg to adult in summer and fall through controlled feeding studies. Nymphs successfully completed development on this diet of PNW native plants, though it generally resulted in lower survivorship and adult weight and longer developmental times than a modified colony diet or a diet of known hosts from the eastern United States. These developmental data were used to parameterize stage-structured matrix models to predict the impact of diet and extreme heat events on H. halys population growth. The predicted net reproductive rate (R0) of H. halys was consistently and substantially reduced by a diet of PNW native plants, and heat shock imposed further severe reductions in R0. Our results suggest that the combined population effects of suboptimal plant host quality and regional heat waves may explain the lack of landscape-level H. halys pest pressure in semi-arid regions of the PNW.


Structural neuroimaging in psychosis: a systematic review and economic evaluation.
To establish the clinical effectiveness and cost-effectiveness of structural neuroimaging [structural magnetic resonance imaging (MRI) or computed tomography (CT) scanning] for all patients with psychosis, particularly a first episode of psychosis, relative to the current UK practice of selective screening only where it is clinically indicated. Major electronic databases were searched from inception to November 2006. A systematic review of studies reporting the additional diagnostic benefit of structural MRI, CT or combinations of these in patients with psychosis was conducted. The economic assessment consisted of a systematic review of economic evaluations and the development of a threshold analysis to predict the gain in quality-adjusted life-years (QALYs) required to make neuroimaging cost-effective at commonly accepted threshold levels (20,000 pounds and 30,000 pounds per QALY). Sensitivity analyses of several parameters including prevalence of psychosis were performed. The systematic review included 24 studies of a diagnostic before-after type of design evaluating the clinical benefit of CT, structural MRI or combinations in treatment-naive, first-episode or unspecified psychotic patients, including one in schizophrenia patients resistant to treatment. Also included was a review of published case reports of misidentification syndromes. Almost all evidence was in patients aged less than 65 years. In most studies, structural neuroimaging identified very little that would influence patient management that was not suspected based on a medical history and/or physical examination and there were more incidental findings. In the four MRI studies, approximately 5% of patients had findings that would influence clinical management, whereas in the CT studies, approximately 0.5% of patients had these findings. The review of misidentification syndromes found that 25% of CT scans affected clinical management, but this may have been a selected and therefore unrepresentative sample. A threshold analysis with a 1-year time horizon was undertaken. This combined the incremental cost of routine scanning with a threshold cost per QALY value of 20,000 pounds and 30,000 pounds to predict the QoL gain required to meet these threshold values. Routine scanning versus selective scanning appears to produce different results for MRI and CT. With MRI scanning the incremental cost is positive, ranging from 37 pounds to 150 pounds; however, when scanning routinely using CT, the result is cost saving, ranging from 7 pounds to 108 pounds with the assumption of a 1% prevalence rate of tumours/cysts or other organic causes amenable to treatment. This means that for the intervention to be viewed as cost-effective, the QALY gain necessary for MRI scanning is 0.002-0.007 and with CT scanning the QALY loss that can be tolerated is between 0.0003 and 0.0054 using a 20,000 pounds threshold value. These estimates were subjected to sensitivity analysis. With a 3-month time delay, MRI remains cost-incurring with a small gain in QoL required for the intervention to be cost-effective; routine scanning with CT remains cost-saving. When the sensitivity of CT is varied to 50%, routine scanning is both cost-incurring or cost-saving depending on the scenario. Finally, the results have been shown to be sensitive to the assumed prevalence rate of brain tumours in a psychotic population. The evidence to date suggests that if screening with structural neuroimaging was implemented in all patients presenting with psychotic symptoms, little would be found to affect clinical management in addition to that suspected by a full clinical history and neurological examination. From an economic perspective, the outcome is not clear. The strategy of neuroimaging for all is either cost-incurring or cost-saving (dependent upon whether MRI or CT is used) if the prevalence of organic causes is around 1%. However, these values are nested within a number of assumptions, and so have to be interpreted with caution. The main research priorities are to monitor the current use of structural neuroimaging in psychosis in the NHS to identify clinical triggers to its current use and subsequent outcomes; to undertake well-conducted diagnostic before-and-after studies on representative populations to determine the clinical utility of structural neuroimaging in this patient group, and to determine whether the most appropriate structural imaging modality in psychosis should be CT or MRI.


Factors influencing management of bilateral femur fractures: A multicenter retrospective cohort of early versus delayed definitive Fixation.
The purpose of our study was to evaluate the factors that influence the timing of definitive fixation in the management of bilateral femoral shaft fractures and the outcomes for patients with these injuries. Patients with bilateral femur fractures treated between 1998 to 2019 at ten level-1 trauma centers were retrospectively reviewed. Patients were grouped into early or delayed fixation, which was defined as definitive fixation of both femurs within or greater than 24 hours from injury, respectively. Statistical analysis included reversed logistic odds regression to predict which variable(s) was most likely to determine timing to definitive fixation. The outcomes included age, sex, high-volume institution, ISS, GCS, admission lactate, and admission base deficit. Three hundred twenty-eight patients were included; 164 patients were included in the early fixation group and 164 patients in the delayed fixation group. Patients managed with delayed fixation had a higher Injury Severity Score (26.8 vs 22.4; p<0.01), higher admission lactate (4.4 and 3.0; p<0.01), and a lower Glasgow Coma Scale (10.7 vs 13; p<0.01). High-volume institution was the most reliable influencer for time to definitive fixation, successfully determining 78.6% of patients, followed by admission lactate, 64.4%. When all variables were evaluated in conjunction, high-volume institution remained the strongest contributor (X2 statistic: institution: 45.6, ISS: 8.83, lactate: 6.77, GCS: 0.94). In this study, high-volume institution was the strongest predictor of timing to definitive fixation in patients with bilateral femur fractures. This study demonstrates an opportunity to create a standardized care pathway for patients with these injuries. Level III.


Customary physical activity and survival in later life: a study in Nottingham, UK.
To assess the value of broadly based customary physical activity scores, derived from a questionnaire inventory, in predicting 10 year mortality among elderly people. A 10 year survival analysis of participants in the first wave of the Nottingham longitudinal study of activity and ageing who, in face to face interviews in 1985, provided detailed information on customary physical activity, health, and lifestyle. Urban and suburban Nottingham A total of 1042 people aged 65 years and over randomly sampled from general practitioner records. On the basis of factor scores derived from the interview questionnaire, activity levels were graded as "high", "intermediate", or "low". In Cox regression models controlling for age, health status, and cigarette smoking at the time of the activity assessment, these gradings were significantly related to 10 year survival. Relative to the "high" activity groups, the risk of dying was significantly increased in both the "intermediate" (hazard ratio (HR) 1.53; 95% CI 1.12, 2.09) and "low" (HR 2.07; 95% CI 1.53, 2.79) groups for women, and in the "low" group (HR 1.59; 95% CI 1.12, 2.25) for men (p < 0.01 throughout). Since the survival model controlled for age, health status, and cigarette smoking, it is unlikely that the activity gradings used here are simple proxies for physical health. It is concluded, therefore, that within the elderly population, recall based survey assessments covering a wide range of customary or habitual physical activities, can provide indices showing both cross sectional utility and predictive validity.


[Brain function peculiarities in premature babies and infants with perinatal encephalopathy and cerebral palsy].
Eighty five children with perinatal encephalopathy and cerebral palsy have been studied. EEG analysis showed functional imbalances of cortical and subcortical structures. A delay of cortical electrogenesis development and cortical functional activity were reduced, particularly in its sensomotor areas and left hemisphere with insufficient efferent impulse flow into underlying structures and predominance of electrical subcortical and stem structure activity. The changes discovered may relate directly to psychomotor retardation.


[Spectral characteristics of muscle aspartyl- and valyl-tRNA- synthetases in normal animals and in an experimental model of prolonged starvation].
Conformational differences between asparagyl- and valyl-tRNA synthetases from normal (ARSn) and long-fasting (ARSf) rabbit's muscle were revealed by means of UV fluorescence and differential spectroscopy. The fluorescence spectra indicate more hydrophobic environment of tryptophan residues in the ARSf's at similar quantum yields. The differential absorption spectra reveal the distinctions between tryptophanyl microenvironments for ARS's of different amino acid specificity and for ARSn's and ARSf's of the same specificity. Lower accessibility of tryptophan residues in ARSn's in comparison with ARSf's was shown by selective fluorescence quenching with Cs+ and I- ions. The effect of long-wave shift of fluorescence spectra at the edge excitation was used for studies on microenvironment of chromophors and the rate of the dipole-orientational relaxation of this microenvironment.


"Uniformed" consent and the wealthy volunteer: an analysis of patient volunteers in a clinical trial of a new anti-inflammatory drug.
After a 16-week clinical trial of a new anti-inflammatory drug, the participants were given a factual test to determine whether they had understood and remembered the information given them when consent was solicited. They filled out a questionnaire about their reasons for volunteering and their views on clinical studies and on medical practice in general. Demographic information was also obtained. Two thirds of the participants did not remember that they had been informed about potential risk (gastrointestinal ulceration). Some subjects remembered, but misunderstood, what they had been told; others developed erroneous ideas about the trial and the study drug. The volunteers agreed to participate in the study to help both their own arthritis and that of other patients. They took pride in their self-sacrifice and in being commended by their friends for their altruism. Analysis of the demographic data shows that indigent persons are not necessarily the most likely to participate in clinical trials. Two thirds of the subjects were from the middle class. The median family income was $13,000. To improve the informed consent procedure, we recommend group meetings in which the participants in a clinical trial can discuss the protocol and the risks of the study. Obtaining consent again, after initial anxiety has decreased, may improve comprehension.


The Histological Detection of Ulcerative Colitis Using a No-Code Artificial Intelligence Model.
Ulcerative colitis (UC) is an intractable disease that affects young adults. Histological findings are essential for its diagnosis; however, the number of diagnostic pathologists is limited. Herein, we used a no-code artificial intelligence (AI) platform "Teachable Machine" to train a model that could distinguish between histological images of UC, non-UC coloproctitis, adenocarcinoma, and control. A total of 5100 histological images for training and 900 histological images for testing were prepared by pathologists. Our model showed accuracies of 0.99, 1.00, 0.99, and 0.99, for UC, non-UC coloproctitis, adenocarcinoma, and control, respectively. This is the first report in which a no-code easy AI platform has been able to comprehensively recognize the distinctive histologic patterns of UC.


Evaluation of white cell count and differential in synovial fluid for diagnosing infections after total hip or knee arthroplasty.
The accuracy of synovial fluid (SF) white cell count (WCC) and polymorphonuclear (PMN) cell evaluation for predicting prosthetic joint infection (PJI) at the total hip arthroplasty (THA) or total knee arthroplasty (TKA) site is unknown. Therefore, we performed a meta-analysis to summarize the diagnostic validity of SF-WCC and SF-PMN for diagnosing PJI. The MEDLINE, EMBASE, and OVID databases were searched for studies that had evaluated the diagnostic validity of SF-WCC and SF-PMN between January 1990 and May 2013. Meta-analysis methods were used to pool sensitivity, specificity, diagnostic odd ratios (DORs), the area under the receiver-operating characteristic curve (AUC), positive likelihood ratios (PLR), negative likelihood ratios (NLR), and post-test probability. We also conducted heterogeneity, publication bias, subgroup, and meta-regression analyses. Fifteen articles (15 SF-WCC and 14 SF-PMN) that included a total of 2787 patients fulfilled the inclusion criteria and were considered for analysis. The pooled sensitivity and specificity for PJI detection was 0.88 (95% confidence intervals [CI], 0.81-0.93) and 0.93 (95% CI, 0.88-0.96) for SF-WCC and 0.90 (95% CI, 0.84-0.93) and 0.88 (95% CI, 0.83-0.92) for SF-PMN, respectively. The AUC was 0.96 for SF-WCC and 0.95 for SF-PMN. PLR and NLR were 13.3 and 0.13 for SF-WCC, and 7.6 and 0.12 for SF-PMN, respectively. There was no evidence of publication bias. Low-clinical-scenario (pre-test probability, 20%) post-test probabilities were 3% for both negative SF-WCC and SF-PMN results. The subgroup analyses indicated that the sensitivity/specificity of THA were 0.73/0.96 for SF-WCC and 0.85/0.83 for SF-PMN, whereas those of TKA were 0.90/0.91 for SF-WCC and 0.90/0.88 for SF-PMN. We also found that collection of SF-WCC preoperatively had a higher sensitivity than that obtained intraoperatively (0.91 vs. 0.77). SF-WCC and SF-PMN have an adequate and clinically acceptable diagnostic value for detecting PJI, particularly after TKA.


Modified Recurrence Quantification Analysis for Objective Assessment of Cerebellar Ataxia.
Cerebellar Ataxia (CA) is a neurological condition that affects coordination, balance and speech. Assessing its severity is important for developing effective treatment and rehabilitation plans. Traditional assessment methods involve a clinician instructing a person with ataxia to perform tests and assigning a severity score based on their performance. However, this approach is subjective as it relies on the clinician's experience, and can vary between clinicians. To address this subjectivity, some researchers have developed automated assessment methods using signal processing and data-driven approaches, such as supervised machine learning. These methods still rely on subjective ground truth and can perform poorly in real-world scenarios. This research proposed an alternative approach that uses signal processing to modify recurrence plots and compare the severity of ataxia in a person with CA to a control cohort. The highest correlation score obtained was 0.782 on the back sensor with the feet-apart and eyes-open test. The contributions of the research include modifying the recurrence plot as a measurement tool for assessing CA severity, proposing a new approach to assess severity by comparing kinematic data between people with CA and a control reference group, and identifying the best subtest and sensor position for practical use in CA assessments.


Health Literacy, Education, and Internal Consistency of Psychological Scales.
Measurement error might lead to biased estimates, causing ineffective interventions and service delivery. Identifying measurement error of health-related instruments helps develop accurate assessment of health-related constructs. We compared the internal consistency of eight psychological scales used in health research in groups with adequate versus limited health literacy and in groups with higher versus lower education. Participants (N = 1,005) from a nationally representative internet panel completed eight self-report scales: (1) information avoidance, (2) cognitive causation, (3) unpredictability, (4) perceived severity, (5) time orientation, (6) internal health locus of control, (7) need for cognition, and (8) social desirability. The first four assess beliefs about diabetes and colon cancer. We used the Newest Vital Sign to categorize participants' health literacy (limited vs. adequate). We also categorized participants' education (high school or less vs. more than high school). We compared the Cronbach's alpha for each psychological scale between groups with different health literacy and education levels using the Feldt test. Among all the 13 subscales, scale internal consistency was significantly lower among people with limited health literacy than those with adequate health literacy for five subscales: information avoidance for colon cancer (0.80 vs. 0.88), unpredictability of diabetes (0.84 vs. 0.88), perceived severity for diabetes (0.66 vs. 0.75), need for cognition (0.63 vs. 0.82), and social desirability (0.52 vs. 0.68). Internal consistency was significantly lower among people who had a high school education or less than among those with more than a high school education for four scales: perceived severity of diabetes (0.70 vs. 0.75), present orientation (0.60 vs. 0.66), need for cognition (0.73 vs. 0.80), and social desirability (0.61 vs. 0.70). Several psychological instruments demonstrated significantly lower internal consistency when used in a sample with limited health literacy or education. To advance health disparities research, we need to develop new scales with alternative conceptualizations of the constructs to produce a measure that is reliable among multiple populations. [HLRP: Health Literacy Research and Practice. 2021;5(3):e244-e255.] Plain Language Summary: We compared the internal consistency of several psychological scales in groups with adequate versus limited health literacy and higher versus lower education. For several scales, internal consistency was significantly lower among (1) people with limited health literacy compared those who have adequate health literacy and/or (2) people who had a high school education or less compared to those with more than a high school education.


Risk factors for tube exposure as a late complication of glaucoma drainage implant surgery.
The purpose of this study was to evaluate the risk factors for tube exposure after glaucoma drainage implant surgery. This was a retrospective case-controlled observational study of 64 eyes from 64 patients. Thirty-two eyes of 32 patients with tube erosion requiring surgical revision were compared with 32 matched control eyes of 32 patients. Univariate and multivariate risk factor analyses were performed. Mean age was significantly younger in the tube exposure group compared with the control group (48.2±28.1 years versus 67.3±18.0 years, respectively; P=0.003). The proportion of diabetic patients (12.5%) in the tube exposure group was significantly less (P=0.041) compared with the control group (37.5%). Comparisons of the type and position of the drainage implant were not significantly different between the two groups. The average time to tube exposure was 17.2±18.0 months after implantation of the drainage device. In both univariate and multivariate analyses, younger age (P=0.005 and P=0.027) and inflammation prior to tube exposure (P≤0.001 and P=0.004) were significant risk factors. Diabetes was a significant risk factor only in the univariate analysis (P=0.027). Younger age and inflammation were significant risk factors for tube exposure after drainage implant surgery.


Different sites of adenosine formation in the heart.
In an attempt to further define the site of myocardial adenosine formation, isolated guinea pig hearts were perfused with potent inhibitors of 5'-nucleotidase [alpha, beta-methylene adenosine 5'-diphosphate (AOPCP)] and of nucleoside transport [4-nitrobenzyl thioinosine (NBMPR)]. AOPCP (50 microM) inhibited the activity of cardiac ecto-5'-nucleotidase by 85% but did not influence the release of adenosine, inosine, and hypoxanthine formed at an accelerated rate by the heart during hypoxic perfusion (30% O2). In contrast, NBMPR (5 microM) diminished the hypoxia-induced release of adenosine and its degradatives and greatly potentiated the increase of myocardial tissue levels of respective purine compounds. Studies carried out with 5'-deoxyadenosine, an adenosine derivative that is not metabolized, indicate NBMPR to inhibit both uptake and release of adenosine in the isolated heart and in human erythrocytes. Cell fractionation studies on guinea pig ventricular muscle revealed that 5'-nucleotidase, though mainly associated with the membrane fraction, is also found in the cardiac cytosol (200,000-g supernatant), exhibiting a different substrate specificity. Furthermore, S-adenosylhomocysteine hydrolase as well as adenosine kinase and adenosine deaminase proved to be exclusively present in the cytosolic fraction. Our findings suggest that in the hypoxic heart a) ecto-5'-nucleotidase most likely is not involved in the formation of adenosine, b) release of adenosine from the heart requires adenosine to be transported across the sarcolemma membrane, and c) adenosine is predominantly formed intracellularly, a process involving cytosolic 5'-nucleotidase and/or S-adenosylhomocysteine hydrolase.


Intra-articular IL-10 gene transfer regulates the expression of collagen-induced arthritis (CIA) in the knee and ipsilateral paw.
We studied the effects of local IL-10 application, introduced by a recombinant human type 5 adenovirus vector, in the mouse knee joint during the early phase of CIA. One intra-articular injection with the IL-10-expressing virus (Ad5E1mIL-10) caused substantial over-expression of IL-10 in the mouse knee joint, using virus dosages which did not induce distracting inflammation. High expression of IL-10 was noted for a few days, being maximal at day 1. One intra-articular injection of Ad5E1mIL-10 in the knee joints of collagen type II (CII)-immunized mice, before onset of CIA was noted, reduced the incidence of collagen arthritis in that knee. Of high interest, the protective effect of local IL-10 expression by Ad5E1mIL-10 was not restricted to the knee joint alone. The arthritis incidence in the ipsilateral paw was highly suppressed. In contrast, local IL-10 over-expression was not effective when treatment was started after onset of CIA. Further analysis in the acute streptococcal cell wall-induced arthritis model revealed that local IL-10 over-expression markedly suppressed the production of tumour necrosis factor-alpha (TNF-alpha) and IL-1alpha, but had no significant effect on IL-1beta and IL-12 production in the inflamed synovium. These data indicate that local over-expression of IL-10 in the knee joint of mice regulates the expression of collagen arthritis, probably through down-regulation of TNF-alpha.


Classifying Topology in Photonic Heterostructures with Gapless Environments.
Photonic topological insulators exhibit bulk-boundary correspondence, which requires that boundary-localized states appear at the interface formed between topologically distinct insulating materials. However, many topological photonic devices share a boundary with free space, which raises a subtle but critical problem as free space is gapless for photons above the light line. Here, we use a local theory of topological materials to resolve bulk-boundary correspondence in heterostructures containing gapless materials and in radiative environments. In particular, we construct the heterostructure's spectral localizer, a composite operator based on the system's real-space description that provides a local marker for the system's topology and a corresponding local measure of its topological protection; both quantities are independent of the material's bulk band gap (or lack thereof). Moreover, we show that approximating radiative outcoupling as material absorption overestimates a heterostructure's topological protection. As the spectral localizer is applicable to systems in any physical dimension and in any discrete symmetry class (i.e., any Altland-Zirnbauer class), our results show how to calculate topological invariants, quantify topological protection, and locate topological boundary-localized resonances in topological materials that interface with gapless media in general.


Analysis of CRISPR-Cas System in Streptococcus thermophilus and Its Application.
CRISPR-Cas (Clustered regularly interspaced short palindromic repeats-CRISPR associated proteins) loci, which provide a specific immunity against exogenous elements, are hypervariable among distinct prokaryotes. Based on previous researches, this review focuses on concluding systematical genome editing protocols in Streptococcus thermophilus. Firstly, its protocols and optimized conditions in gene editing are introduced. What's more, classification and diversity analyses of S. thermophilus CRISPR-Cas benefit the further understanding of evolution relationship among Streptococcus. Ability of its foreign segment integration and spacer source analyses also indicate a new direction of phage resistance. Above all, all of these point out its potential to be regarded as another model system other than type II CRISPR-Cas in Streptococcus pyogenes.