Epidemiology and determinant factors of neural tube defect: Narrative review.
The epidemiology of neural tube defect (NTD) is face ignorance from the global community. However, the problem is complex and it is a cause for child mortality and morbidity. We provide the latest insights with respect to determinant factors of NTD. Google Scholar and PubMed were systematically searched to identify potential research articles concerning the epidemiology and its determinant factors of NTD. The epidemiology of Neural tube defects increased in some countries. The epidemiology and determinant factors were varies across countries,geographical regions and socioeconomic status of the populations. In general, the determinant factors of NTD were summarized as behavioral, nutrition-related, environmental, medical illness, and health service-related factors. Birth defect is fatal which affects the new generation; specifically, NTD is the problem of middle- and low-income countries. It is a direct cause for neonatal and perinatal mortality rate globally. Even if little factors identified, yet conducting experimental and clinical trial researches are a better approach to slow down the progress.


[Planar molecular arrangements aid the design of MHC class II binding peptides].
The coupling between peptides and MHC-II proteins in the human immune system is not well understood. This work presents an evidence-based hypothesis of a guiding intermolecular force present in every human MHC-II protein (HLA-II). Previously, we examined the spatial positions of the fully conserved residues in all HLA-II protein types. In each one, constant planar patterns were revealed. These molecular planes comprise of amino acid groups of the same chemical species (for example, Gly) distributed across the protein structure. Each amino acid plane has a unique direction and this directional element offers spatial selectivity. Constant within all planes, too, is the presence of an aromatic residue possessing electrons in movement, leading the authors to consider that the planes generate electromagnetic fields that could serve as an attractive force in a single direction. Selection and attraction between HLA-II molecules and antigen peptides would, therefore, be non-random, resulting in a coupling mechanism as effective and rapid as is clearly required in the immune response. On the basis of planar projections onto the HLA-II groove, modifications were made by substituting the key residues in the class II-associated invariant chain peptide-a peptide with a universal binding affinity-resulting in eight different modified peptides with affinities greater than that of the unmodified peptide. Accurate and reliable prediction of MHC class II-binding peptides may facilitate the design of universal vaccine-peptides with greatly enhanced binding affinities. The proposed mechanisms of selection, attraction and coupling between HLA-II and antigen peptides are explained further in the paper.


Hydrogen peroxide-induced cell death in cultured Aplysia sensory neurons.
Widespread neuronal cell death occurs during normal development and as a result of pathological conditions in the nervous system of many organisms. In this study, we investigated the cytotoxicity induced by H(2)O(2) in Aplysia mechanosensory neurons, which serve as a useful model in the study of learning and memory. Treatment with hydrogen peroxide (10(-2)-10 mM) for 3 h produced a nuclear DNA breakage in Aplysia sensory neurons, as revealed by TdT-mediated dUTP nick end labeling (TUNEL) staining, in a dose-dependent manner. Prolonged treatment (6-18 h) of Aplysia sensory neurons with 1 mM hydrogen peroxide produced dramatic morphological changes, such as neurite fragmentation, disintegration of the cell body, and a change in the resting membrane potential. This change in the resting potential was biphasic, and was initially hyperpolarized about 6 h after hydrogen peroxide treatment, but this later shifted to a depolarization some 13-18 h after treatment. Electron microscopic analysis also showed that this hydrogen peroxide-induced cell death was associated with apoptotic nuclear shrinkage, chromatin condensation, and necrotic swelling of organelles. Our results demonstrate that Aplysia sensory neurons show both apoptotic and necrotic characteristics as well as biphasic changes in resting potential during hydrogen peroxide-induced cell death.


Spontaneous resurgence of conditioned fear weeks after successful extinction in brain injured mice.
Mild traumatic brain injury (TBI) is a major risk factor for post-traumatic stress disorder (PTSD), and both disorders share common symptoms and neurobiological defects. Relapse after successful treatment, known as long-term fear resurgence, is common in PTSD patients and a major therapeutic hurdle. We induced a mild focal TBI by controlled cortical impact (CCI) in male C57BL/6 J mice and used fear conditioning to assess PTSD-like behaviors and concomitant alterations in the fear circuitry. We found for the first time that mild TBI, and to a lesser extent sham (craniotomy), mice displayed a spontaneous resurgence of conditioned fear when tested for fear extinction memory recall, despite having effectively acquired and extinguished conditioned fear 6 weeks earlier in the same context. Other characteristic symptoms of PTSD are risk-taking behaviors and cognitive deficits. CCI mice displayed risk-taking behaviors, behavioral inflexibility and reductions in processing speed compared to naïve mice. In conjunction with these changes there were alterations in amygdala morphology 3 months post-trauma, and decreased myelin basic protein density at the primary lesion site and in distant secondary sites such as the hippocampus, thalamus, and amygdala, compared to sham mice. Furthermore, activity-dependent brain-derived neurotrophic factor (BDNF) transcripts were decreased in the prefrontal cortex, a key region for fear extinction consolidation, following fear extinction training in both TBI and, to a lesser extent, sham mice. This study shows for the first time that a mild brain injury can generate a spontaneous resurgence of conditioned fear associated with defective BDNF signalling in the prefrontal cortex, PTSD-like behaviors, and have enduring effects on the brain.


Controlled Pyrazole-Hydrazone Annulation: Regiodivergent Synthesis of 1H- and 2H-Pyrazolo[3,4-d]pyridazinones.
An efficient and controlled site-selective annulation of 3,5-diethoxycarbonyl 4-hydrazonyl pyrazoles is described. The relative proportion of the products is affected by hydrazone intermediate configuration, reaction temperature, and Lewis acid employed. At a temperature of 110-120 °C, the reaction preferentially afforded 1H-pyrazolo[3,4-d]pyridazin-7(6H)-ones, whereas using Yb(OTf)3 in MeCN reflux, 2H-pyrazolo[3,4-d]pyridazin-7(6H)-ones were favored. Computational investigations were performed to clarify the mechanism and the origin of the regiodivergence.


Suicidal ideation in adults aging with HIV: neurological and cognitive considerations.
Because of highly active antiretroviral therapy, people are now aging with HIV. Several stressors associated with aging with HIV may result in increased levels of depression and suicidal ideation. In addition, neurological and cognitive changes that often accompany both aging and HIV must be considered because those aging with HIV are at greater risk of developing such problems. These problems may be reflected in executive functioning deficits and initiation and perseveration difficulties. Adults experiencing such problems may be predisposed to ruminative thoughts that can impair the ability to effectively cope with the stressors associated with aging with HIV. Moreover, other conditions such as posttraumatic stress disorder, chronic drug use, and mitochondrial-damage-related fatigue can predispose these adults to the development of further neurological and cognitive problems. These problems may foster further ruminative thinking and increase the severity of depression and suicidal ideation. Implications for nursing practice, intervention, and research are provided.


Contemporary measures of approach and avoidance goal orientations: similarities and differences.
In response to a resurgence of interest in and demonstrated utility of the approach-avoidance goal distinction, a number of researchers (Elliot & Church, 1997; Midgley et al., 1998; Skaalvik, 1997) have developed instruments to assess individual differences in the tendency to adopt approach-avoidance goals. However, to date there has been no attempt to examine the psychometric properties or conceptual and measurement overlap of these instruments. (i) To determine whether three questionnaires designed to measure approach-avoidance goal orientations are assessing the same or different constructs, and (ii) to examine the psychometric properties of each of the approach-avoidance measures (i.e., internal consistency, convergent, discriminant, factorial, and construct validity). Participants in this study were 475 undergraduate students (N = 228 males; N = 244 females; three missing information) enrolled at two large universities in the United Kingdom. Participants completed a questionnaire which included measures of approach-avoidance goal orientations, effort regulation, test anxiety, perceived ability, and intrinsic motivation, extrinsic motivation, and amotivation. Results revealed a degree of convergence between the three instruments. Each of the instruments demonstrated good psychometric properties although construct validity results were inconsistent across the measures. There is a need for future research to clarify the operational definition and subsequent measurement of the performance avoidance construct, and in particular, to examine the role that effort, impression management, and anxiety/fear of failure play in its conceptualisation.


[FRANCOGYN group: A brief history].
Describing the constitution of the FRANCOGYN group (a national French research group in Oncological and Gynecological Surgery) and present its current and future development. Literature review using PUBMed database with the keyword "FRANCOGYN". Describing the constitution of the FRANCOGYN group (a national French research group in Oncological and Gynecological Surgery) and present its current and future development. The FRANCOGYN group was formed in December 2015, bringing together over the years more than 17 gynecological and oncological surgical department in France. The group carries out clinical research on gynecological pelvic cancers by constituting retrospective cohorts. Its legitimacy allows it to lead or co-lead the drafting of recommendations for clinical practice in the field of gynecological cancers. It now offers prospective randomized research funded by national grants. The FRANCOGYN network allows us to propose a national reflection on the surgical management of pelvic cancers in women, resulting in numerous international reference publications.


Narrowing the focus: Therapeutic cell surface targets for refractory triple-negative breast cancer.
Triple-negative breast cancer (TNBC) is defined as a type of breast cancer with lack of expression of estrogen receptor, progesterone receptor and human epidermal growth factor 2 protein. In comparison to other types of breast cancer, TNBC characterizes for its aggressive behavior, more prone to early recurrence and a disease with poor response to molecular target therapy. Although TNBC is identified in only 25%-30% of American breast cancer cases annually, these tumors continue to be a therapeutic challenge for clinicians for several reasons: Tumor heterogeneity, limited and toxic systemic therapy options, and often resistance to current standard therapy, characterized by progressive disease on treatment, residual tumor after cytotoxic chemotherapy, and early recurrence after complete surgical excision. Cell-surface targeted therapies have been successful for breast cancer in general, however there are currently no approved cell-surface targeted therapies specifically indicated for TNBC. Recently, several cell-surface targets have been identified as candidates for treatment of TNBC and associated targeted therapies are in development. The purpose of this work is to review the current clinical challenges posed by TNBC, the therapeutic approaches currently in use, and provide an overview of developing cell surface targeting approaches to improve outcomes for treatment resistant TNBC.


Open Versus Core Needle Biopsy in Lower-Extremity Sarcoma: Current Practice Patterns and Patient Outcomes.
Historically, open biopsy (OB) was the gold standard for sarcoma diagnosis. Core needle biopsy (CNB) has become increasingly common. There are limited data evaluating how the type of biopsy impacts definitive surgical resection or postoperative outcomes. The aims of this study were to (1) characterize current international biopsy practice patterns, and (2) evaluate how the type of biopsy performed impacts the resection surgery, infection risk, oncological complications, and patient-reported functional outcome scores. This study was a preplanned secondary analysis of the prospective, multicenter PARITY (Prophylactic Antibiotic Regimens in Tumor Surgery) study. Patients with a benign diagnosis, metastatic disease, or no biopsy prior to surgery were excluded. Prospectively collected demographic, biopsy, surgical, and outcome variables were analyzed, and differences between patients undergoing OB and CNB were assessed. Parametric and nonparametric tests were used to compare variables between groups, and the Cox proportional hazards method was used to compare infection-related and oncological outcomes at 1 year. Median functional outcome scores at 1 year were compared. Four hundred and sixty-four patients met the inclusion criteria. Data were collected from 48 sarcoma centers in 12 countries. CNB was the more utilized biopsy modality overall (57.5%). OB was more common in the U.S. and Canada. The median operative time was significantly longer for patients who underwent OB (324 versus 260 minutes; p < 0.001). Significantly more skin (p < 0.001) and fascial tissue (p < 0.001) were excised in the OB group, which also had a lower rate of primary closure (86.3% versus 92.9%; p = 0.03). There were no differences in surgical site infection or oncological outcomes between the groups at 1-year follow-up. CNB was the more common biopsy modality in the PARITY study in most countries. However, OB was more common in the U.S. and Canada. Patients undergoing OB had longer operative times, more excised tissue, and lower rates of primary closure, but this did not translate to differences in infection rates or oncological outcomes, including local recurrence. Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.


Enzymatic synthesis of chitosan-gelatin antimicrobial copolymer and its characterisation.
Schiff bases can be formed by reaction between acylamino and the amino group with microbial transglutaminase (MTGase) as catalyst and used in protein crosslinking in the food industry. A novel chitosan-gelatin copolymer for coating meat products can be synthesised using MTGase as catalyst, with the characteristics of both chitosan and gelatin. The aim of the present study was to synthesise and characterise chitosan-gelatin antimicrobial copolymer. The yield of copolymer increased with increasing gelatin/chitosan ratio, while bacteriostasis of Staphylococcus aureus by the copolymer decreased, showing that its bacteriostatic ability depended on the amino group in chitosan. Under optimal synthesis conditions of 50 degrees C, pH 6 and 40 min reaction time the copolymer yield was 64.5% at a gelatin/chitosan ratio of 0.6. Bacteriostasis of S. aureus by 10 g kg(-1) copolymer solution was 70% of that by chitosan. A novel biological dressing frame material with excellent biocompatibility and antibacterial properties has been successfully prepared. The results of this study provide a background for further investigation of potential applications of chitosan-gelatin copolymer in the areas of agriculture and food.


Presence of diabetes-inhibiting, glutamic acid decarboxylase-specific, IL-10-dependent, regulatory T cells in naive nonobese diabetic mice.
Immunization of NOD mice with autoantigens such as glutamic acid decarboxylase (GAD) 221-235 peptide (p221) can induce Ag-specific CD4(+) T regulatory (Tr) cells. However, it is unclear whether these Tr cells acquire their regulatory capacity due to immunization or whether they are constitutively harbored in unimmunized naive mice. To address this question, we used an I-Ag7 tetramer to isolate p221-specific T cells from naive NOD mice (N221(+) cells) after peptide-specific in vitro expansion. The N221(+) T cells produced IFN-gamma and IL-10, but very little IL-4, in response to p221 stimulation. These T cells could function as regulatory cells and inhibit in vitro proliferation of diabetogenic BDC2.5 cells. This suppressive activity was cell contact-independent and was abrogated by Abs to IL-10 or IL-10R. Interestingly, IL-2 produced by other T cells present in the cell culture induced unactivated N221(+) T cells to exhibit regulatory activities involving production of IL-10. In vivo, N221(+) cells inhibited diabetes development when cotransferred with NOD splenocytes into NOD/scid recipients. Together, these results demonstrate that p221-specific IL-10-dependent Tr cells, including Tr type 1 cells, are present in naive NOD mice. The use of spontaneously arising populations of GAD peptide-specific Tr cells may represent a promising immunotherapeutic approach for preventing type 1 diabetes.


Isochamanetin is a Selective Inhibitor for CyclinD1 in SKOV3 Cell Lines.
The cyclinD1 is an emerging potent therapeutic drug target in the treatment of ovarian cancer. CyclinD1, Cdks phosphorylation regulates cell cycle and controls transcription. For this reason, CyclinD1 have been subject to extensive cell cycle- related research, and consequently various therapeutic inhibitor drugs have been developed to these protein targets. In the present study we identified that the expression levels of Bcl-2, Bax, caspase 8, 9 and cyclinD1 using Q-PCR method in SKOV3 cell lines treated with Isochamanetin. The viability and migratory inhibition ability also studied to know the mode of cell death. Further the expression levels of Bcl-2, caspase8,9, Cytochrome C and CyclinD1 were significantly down regulated in SKOV3 cancer cells treated with isochamanetin, a specific binding molecule to CyclinD1. The therapeutic molecules found by a high through put insilicoscreen of this pocket exhibit cytostatic nature and reduce protein levels of cell cycle. The novel structural site on CyclinD1, which is well conserved and inhibits the SKOV3 cells from G0-G1 to S phase cell cycle progression. The current result suggests that isochamanetin serves as potent binding agent to the cyclinD1.


Empagliflozin (Jardiance). Type 2 diabetes: no rush to use this drug.
* In early 2016, metformin monotherapy remains the treatment of choice for most patients with type 2 diabetes. There are several alternatives for patients in whom metformin is poorly tolerated or ineffective. However, dapagliflozin and canagiflozin have an unfavourable harm-benefit balance and should not be used to enhance the action of metformin. Empagliflozin is the third glifozin to be authorised in the European Union for the treatment of type 2 diabetes. A randomised, double-blind, placebo-controlled trial of empaglifloznin, in combination with other glucose-lowering drugs, involved 7020 patients with type 2 diabetes, an average glycated haemoglobin (HbA1c) concentration of about 8%, and a history of at least one cardiovascular event. After about 3 years of follow-up, overall mortality was lower with empagliflozin (5.7% versus 8.3%, p < 0.001), mainly due to a reduction in cardiovascular mortality, particularly due to heart failure. This benefit does not seem due to efficacy in preventing the cardiovascular complications of diabetes, as there was no difference between the groups in terms of myocardial infarction or stroke. The most likely explanation is an effect in preventing other cardiovascular disorders, such as heart failure, in patients with a history of cardiovascular disorders. This is consistent with the diuretic effect of empagliflozin and its rapid impact on mortality (within a matter of months in the trial), as well as with lower exposure to cardiovascular drugs and reduction in the risk of hospital admission for heart failure. In seven comparative trials, empagliflozin had only a moderate glucose-lowering action: among patients with an average baseline HbA1c of about 8%, the HbA1c fell by about 0.5% more with empagliflozin than with placebo. An even smaller effect was reported in patients with renal impairment. Empagliflozin shares the adverse effects of other gliflozins, including genital infections, kidney failure, and diabetic ketoacidosis. Empagliflozin may also be hepatotoxic. A risk of cancer (especially bladder cancer) cannot be ruled out. Empagliflozin interacts with nephrotoxic drugs, which aggravate its adverse effects and decrease its hypoglycaemic potency. The diuretic action of empagliflozin can lead to volume depletion and a fail in blood pressure, especially during co-administration with other diuretics or antihypertensive drugs. In practice, empagliflozin was found to reduce mortality in a clinical trial involving patients with type 2 diabetes and significant cardiovascular risk factors. This benefit does not seem to be related to the hypoglycaemic effect of empagliflozin or to prevention of the cardiovascular complications of diabetes, but rather to prevention of heart failure in patients with history of cardiovascular disease. In early 2016, it is unclear which patients are most likely to derive a concrete benefit from empagliflozin therapy. Comparative evaluation must continue, especially in patients with heart failure.


Rebamipide increases the amount of mucin-like substances on the conjunctiva and cornea in the N-acetylcysteine-treated in vivo model.
Rebamipide increases the amount of mucin-like substances in the stomach. We aimed to determine the effects of rebamipide on the amount of mucin-like substances in the conjunctiva and cornea of N-acetylcysteine-treated eyes. Furthermore, we attempted to evaluate the effects of rebamipide on the wound healing of N-acetylcysteine-treated eyes. The model was created by instilling 10% N-acetylcysteine solutions into rabbit eyes. Rebamipide was then applied on the day following the completion of N-acetylcysteine treatment. The amount of mucin-like substances on the conjunctiva and cornea was measured using the Alcian-blue binding method. The degree of damage was evaluated using scores based on the areas and densities of the cornea and conjunctival after staining using a rose Bengal solution under blind conditions. Rebamipide increased the level of mucin-like substances on the conjunctiva of N-acetylcysteine-treated eyes when instilled at concentrations of 0.3% or higher, and 1% rebamipide increased the amount of mucin-like substances covering the cornea. Moreover, 1% rebamipide improved the rose Bengal scores of the cornea and conjunctiva in N-acetylcysteine-treated eyes. Rebamipide increased mucin-like substances on the cornea and conjunctiva of N-acetylcysteine-treated eyes. In accordance with the mucin-increasing effects, rebamipide improved the rose Bengal scores for the cornea and conjunctiva of N-acetylcysteine-treated eyes. However, the relevance of these findings to dry eyes is unclear because it is not known whether the change in mucus expression in the N-acetylcysteine model is similar to what occurs in aqueous tear deficiency. Consequently, it may be worth trying on an animal model of keratoconjunctivitis sicca.


An automatic sigh feature for animal ventilators.
A device is described that provides a reliable automatic deep breath to an animal being ventilated with a typical laboratory ventilator. The deep breath is provided by closing a solenoid valve in the expiratory tubing causing the animal to inspire two, three, or four consecutive tidal volumes without expiration. The interval between deep breaths is selected to be every 1, 2, 4, 6, 8, or 10 min. Control of this interval is provided by simple integrated circuits. Total parts cost of this device is approximately $90.


Tbr2 expression in Cajal-Retzius cells and intermediate neuronal progenitors is required for morphogenesis of the dentate gyrus.
The dentate gyrus (DG) is a unique cortical region whose protracted development spans the embryonic and early postnatal periods. DG development involves large-scale reorganization of progenitor cell populations, ultimately leading to the establishment of the subgranular zone neurogenic niche. In the developing DG, the T-box transcription factor Tbr2 is expressed in both Cajal-Retzius cells derived from the cortical hem that guide migration of progenitors and neurons to the DG, and intermediate neuronal progenitors born in the dentate neuroepithelium that give rise to granule neurons. Here we show that in mice Tbr2 is required for proper migration of Cajal-Retzius cells to the DG; and, in the absence of Tbr2, formation of the hippocampal fissure is abnormal, leading to aberrant development of the transhilar radial glial scaffold and impaired migration of progenitors and neuroblasts to the developing DG. Furthermore, loss of Tbr2 results in decreased expression of Cxcr4 in migrating cells, leading to a premature burst of granule neurogenesis during early embryonic development accompanied by increased cell death in mutant animals. Formation of the transient subpial neurogenic zone was abnormal in Tbr2 conditional knock-outs, and the stem cell population in the DG was depleted before proper establishment of the subgranular zone. These studies indicate that Tbr2 is explicitly required for morphogenesis of the DG and participates in multiple aspects of the intricate developmental process of this structure.


Micronutrient Alterations During Continuous Renal Replacement Therapy in Critically Ill Adults: A Retrospective Study.
Continuous renal replacement therapy (CRRT) is commonly used to provide renal replacement therapy in the intensive care unit. Limited published data suggest that CRRT may lead to depletion of water-soluble vitamins and trace elements. The goal of this study was to identify the incidence of trace element and vitamin deficiencies in critically ill patients during CRRT. This study is based on a retrospective chart review of patients who were referred to Emory University Hospital's nutrition support services and had at least 1 serum micronutrient level measured during CRRT (thiamin, pyridoxine, ascorbic acid, folate, zinc, and copper) between April 1, 2009, and June 1, 2012. Seventy-five patients were included in the study. Nine of 56 patients (16%) had below-normal whole blood thiamin concentrations, and 38 of 57 patients (67%) had below-normal serum pyridoxine levels. Serum ascorbic acid and folate deficiencies were identified among 87% (13 of 15) and 33% (3 of 9) of the study patients, respectively. Nine of 24 patients had zinc deficiency (38%), and 41 of 68 patients had copper deficiency (60%). Of the 75 total subjects, 60 patients (80%) had below-normal levels of at least 1 of the micronutrients measured. The incidence of various micronutrient deficiencies in critically ill patients who required CRRT was higher than previously reported. Prospective studies are needed to determine the impact of CRRT on micronutrient status and the potential clinical and metabolic efficacy of supplementation in the intensive care unit setting.


Wire-bow in situ measurements for powerful control of wire-wear during diamond-wire crystalline silicon sawing.
Original instrumental setups embedded in industrial-type multi-diamond-wire sawing equipment are presented for in situ measurements of the apparent wire diameter, the vertical force applied to the wire web, and the wire-web bow during the cutting of crystalline silicon bricks into wafers. The proportionality relationship between the vertical force and the wire bow during the cut of a Czochralski silicon brick is, for the first time, experimentally observed as expected by the theoretical calculations. As a result, the in situ bow measurement is shown to provide a direct control of the cutting efficiency, which is inversely proportional to the vertical force. In addition, the wire-wear evolution during successive cuts is analyzed using the in situ measurement of the apparent wire diameter together with the in situ bow measurements for equivalent cutting conditions using several bow sensors distributed above the wire web. The three-dimensional plot of the cutting efficiency resulting from the bow measurement processing gives access to the distribution of the cutting efficiency along the wire web during the progress of the cut. Given the homogeneous properties of the silicon material used, the cutting efficiency proves to be a representative of the wire-wear. Moreover, the unique capability of the in situ bow measurement to provide a distribution of the measurements on the wire web during the cut allows studying the wire web behavior and the wire cutting efficiency distribution for different cutting conditions. Thanks to the innovative design of the instrumentation coupled with a data analysis based on a deep understanding of the involved physical phenomena, the in situ bow measurement is demonstrated to be a powerful tool to optimize the cutting process in terms of wafer quality and cost efficiency. Moreover, it can provide real-time information opening the door for tuning the parameters during the cutting process.


Inhibition of proteasomal degradation of rpn4 impairs nonhomologous end-joining repair of DNA double-strand breaks.
The proteasome homeostasis in Saccharomyces cerevisiae is regulated by a negative feedback circuit in which the transcription factor Rpn4 induces the proteasome genes and is rapidly degraded by the assembled proteasome. The integrity of the Rpn4-proteasome feedback loop is critical for cell viability under stressed conditions. We have demonstrated that inhibition of Rpn4 degradation sensitizes cells to DNA damage, particularly in response to high doses of DNA damaging agents. The underlying mechanism, however, remains unclear. Using yeast genetics and biochemical approach we show that inhibition of Rpn4 degradation displays a synthetic growth defect with deletion of the MEC1 checkpoint gene and sensitizes several checkpoint mutants to DNA damage. In addition, inhibition of Rpn4 degradation leads to a defect in repair of double-strand breaks (DSBs) by nonhomologous end-joining (NHEJ). The expression levels of several key NHEJ genes are downregulated and the recruitment of Yku70 to a DSB is reduced by inhibition of Rpn4 degradation. We find that Rpn4 and the proteasome are recruited to a DSB, suggesting their direct participation in NHEJ. Inhibition of Rpn4 degradation may result in a concomitant delay of release of Rpn4 and the proteasome from a DSB. This study provides the first evidence for the role of proteasomal degradation of Rpn4 in NHEJ.


MicroRNA-200b Expression in the Vitreous Humor of Patients with Proliferative Diabetic Retinopathy.
The role of microRNA (miRNA)-200b in the pathogenesis of proliferative diabetic retinopathy (PDR) has been studied in diabetic animal models. The aim of this study was to assess miRNA-200b expression in the vitreous of patients with PDR and to determine its correlation with vascular endothelial growth factor (VEGF), one of the pathogenic mechanisms in PDR. Quantitative reverse transcription polymerase chain reaction was used to measure miRNA-200b expression in the vitreous from 29 eyes with PDR and 30 eyes with idiopathic macular holes (IMH; control group). Vitreous VEGF was measured using an enzyme-linked immunosorbent assay. miRNA-200b expression was about 5-fold increased in the vitreous samples from eyes with PDR compared with the controls (p ≤ 0.001). Vitreous VEGF expression was also significantly higher in the PDR group than in the IMH group (p ≤ 0.001), but no significant correlation was found between miRNA-200b and VEGF. Both miRNA-200b and VEGF are increased in the vitreous of patients with PDR but in a noncorrelated pattern. miRNA-200b may be involved in the pathogenesis of PDR but through VEGF-independent mechanisms. Further studies are needed to identify the miRNA-200b-targeted genes involved in the pathogenesis of PDR and to examine the potential role of miRNA-200b as a target for PDR treatment.


Improving the limit of detection in portable luminescent assay readers through smart optical design.
Critical biomarkers of disease are increasingly being detected by point-of-care assays. Chemiluminescence (CL) and electrochemiluminescence (ECL) are often used in such assays due to their convenience and that they do not require light sources or other components that could complicate or add cost to the system. Reports of these assays often include readers built on a cellphone platform or constructed from low-cost components. However, the impact the optical design has on the limit of detection (LOD) in these systems remains unexamined. Here, we report a theoretical rubric to evaluate different optical designs in terms of maximizing the use of photons emitted from a CL or ECL assay to improve the LOD. We demonstrate that the majority of cellphone designs reported in the literature are not optimized, in part due to misunderstandings of the optical tradeoffs in collection systems, and in part due to limitations imposed on the designs arising from the use of a mobile phone with a very small lens aperture. Based on the theoretical rubric, we design a new portable reader built using off-the-shelf condenser optics, and demonstrate a nearly 10× performance enhancement compared to prior reports on an ECL assays running on a portable chip.


Machine Learning Models to Predict Kidney Stone Recurrence Using 24 Hour Urine Testing and Electronic Health Record-Derived Features.
To assess the accuracy of machine learning models in predicting kidney stone recurrence using variables extracted from the electronic health record (EHR). We trained three separate machine learning (ML) models (least absolute shrinkage and selection operator regression [LASSO], random forest [RF], and gradient boosted decision tree [XGBoost] to predict 2-year and 5-year symptomatic kidney stone recurrence from electronic health-record (EHR) derived features and 24H urine data (n = 1231). ML models were compared to logistic regression [LR]. A manual, retrospective review was performed to evaluate for a symptomatic stone event, defined as pain, acute kidney injury or recurrent infections attributed to a kidney stone identified in the clinic or the emergency department, or for any stone requiring surgical treatment. We evaluated performance using area under the receiver operating curve (AUC-ROC) and identified important features for each model. The 2- and 5- year symptomatic stone recurrence rates were 25% and 31%, respectively. The LASSO model performed best for symptomatic stone recurrence prediction (2-yr AUC: 0.62, 5-yr AUC: 0.63). Other models demonstrated modest overall performance at 2- and 5-years: LR (0.585, 0.618), RF (0.570, 0.608), and XGBoost (0.580, 0.621). Patient age was the only feature in the top 5 features of every model. Additionally, the LASSO model prioritized BMI and history of gout for prediction. Throughout our cohorts, ML models demonstrated comparable results to that of LR, with the LASSO model outperforming all other models. Further model testing should evaluate the utility of 24H urine features in model structure.


Missing MRI Pulse Sequence Synthesis Using Multi-Modal Generative Adversarial Network.
Magnetic resonance imaging (MRI) is being increasingly utilized to assess, diagnose, and plan treatment for a variety of diseases. The ability to visualize tissue in varied contrasts in the form of MR pulse sequences in a single scan provides valuable insights to physicians, as well as enabling automated systems performing downstream analysis. However, many issues like prohibitive scan time, image corruption, different acquisition protocols, or allergies to certain contrast materials may hinder the process of acquiring multiple sequences for a patient. This poses challenges to both physicians and automated systems since complementary information provided by the missing sequences is lost. In this paper, we propose a variant of generative adversarial network (GAN) capable of leveraging redundant information contained within multiple available sequences in order to generate one or more missing sequences for a patient scan. The proposed network is designed as a multi-input, multi-output network which combines information from all the available pulse sequences and synthesizes the missing ones in a single forward pass. We demonstrate and validate our method on two brain MRI datasets each with four sequences, and show the applicability of the proposed method in simultaneously synthesizing all missing sequences in any possible scenario where either one, two, or three of the four sequences may be missing. We compare our approach with competing unimodal and multi-modal methods, and show that we outperform both quantitatively and qualitatively.


Carbogenic Nanozyme with Ultrahigh Reactive Nitrogen Species Selectivity for Traumatic Brain Injury.
Reactive oxygen and nitrogen species (RONS), especially reactive nitrogen species (RNS) are intermediate products during incidence of nervous system diseases, showing continuous damage for traumatic brain injury (TBI). Here, we developed a carbogenic nanozyme, which shows an antioxidant activity 12 times higher than ascorbic acid (AA) and behaves as multienzyme mimetics. Importantly, the nanozyme exhibits an ultrahigh scavenging efficiency (∼16 times higher than AA) toward highly active RNS, such as •NO and ONOO- as well as traditional reactive oxygen species (ROS) including O2•-, H2O2, and •OH. In vitro experiments show that neuron cells injured by H2O2 or lipopolysaccharide can be significantly recovered after carbogenic nanozyme treatment via scavenging all kinds of RONS. Moreover, the carbogenic nanozyme can serve as various enzyme mimetics and eliminate the harmful peroxide and glutathione disulfide from injured mice, demonstrating its potential as a therapeutic for acute TBI.


Photothermal bubbles as optical scattering probes for imaging living cells.
We propose and have experimentally studied a new method with improved sensitivity and specificity of imaging of living cells. Intracellular photothermal bubbles generated around gold nanoparticles (NPs) and their clusters were proposed as optical scattering probes for the amplification of scattered light. Microbubbles generated around gold spheres and shells with 10-ns 532-nm laser pulses in individual living cells (leukemia cells, lung and squamous carcinoma cancer cells) have amplified optical side scattering up to 1800-times relative to that of intracellular gold NPs, and without detectable damage to host cells. We explain the discovered optical amplification by the endocytosis-mediated clustering of NPs in cells, and by the selective generation of microbubbles (that do not disrupt the host cell) around these clusters at minimal levels of laser pulse fluence. Photothermal bubbles generated around laser-activated gold NPs may significantly improve the sensitivity and specificity of cell imaging, and can be considered as a new type of optical cellular probes.


Tracking the time course of object categorization using event-related potentials.
Object categorization processes were investigated by measuring event-related potentials while subjects categorized objects at the superordinate (e.g. animal), basic (e.g. dog) and subordinate (e.g. beagle) levels of abstraction. An enhanced negative deflection (N1) was found at posterior recording sites for subordinate level categorizations compared with basic level categorizations and was interpreted as a marker of increased visual analysis. In contrast, superordinate level categorizations produced a larger frontal negativity relative to basic level categorizations and were interpreted as an indicator of increased semantic processing. These results suggest a neurophysiological basis for the separate cognitive processes responsible for subordinate and superordinate object categorizations.


DNA extraction and amplification of leishmania from archived, Giemsa-stained slides, for the diagnosis of cutaneous Leishmaniasis by PCR.
DNA was isolated from 92 Giemsa-stained smears of lesions from suspected cases of cutaneous leishmaniasis and used for PCR-based diagnosis of Leishmania infection. Each smear had been examined under a light microscope at x 1,000 and scored for amastigote numbers. Although the smears had been stored for up to 4 years, all the microscopy-positive slides were also positive by PCR and four of the 14 smears that were negative by microscopy (although of lesions that were clinically consistent with leishmaniasis) were also PCR-positive. PCR-based investigations therefore appear to offer an effective method to confirm suspected cases of cutaneous leishmaniasis using (even archived) samples that have been collected, from humans (and reservoir hosts) in the field, by simple methods.


[Aerobilia: a rare consequence of anaerobic acute cholecystitis: a case report].
Acute acalculous cholecystitis is rare in non critically ill or postoperative patients. We report a case of acute acalculous cholecystitis with secondary bile infection with Clostridium perfringens. Ultrasound and tomodensitometry revealed diffuse aerobilia. The germ in this case report is atypical and contrasts with the very discrete clinical findings. Aerobilia, secondary to the development of bacteria in the biliary tract falsely suggested a bilio-digestive fistula. Treatment included a simple cholecystectomy associated with 7 days of antibiotherapy.


Endoscopic Posterior Cervical Foraminotomy: 2-Dimensional Operative Video.
In the 1940s, the posterior cervical foraminotomy (PCF) was first described. At that time, this technique represented a big step ahead for the treatment of cervical radiculopathy. Rightly, a multitude of studies demonstrated that open microsurgical posterior foraminotomy is an effective treatment for cervical radiculopathy. Open posterior approaches have still the disadvantage of detaching the extensor cervical muscles from the laminae and the spinous processes, which can lead to severe collateral tissue and muscle damage, followed by postoperative complications, such as axial neck pain, shoulder pain, loss of lordosis, or even spinal instability. Minimally invasive techniques have been developed to reduce the approach related trauma. Initially, these techniques have been performed using endoscopic visualization and applied to the lumbar spine with great success. With this in mind, spine surgeons have extended the spectrum of indication and applied endoscopic techniques to treat degenerative cervical spine disorders. Indications for PCF are single-level or multilevel unilateral lateral disc herniation, osseous foraminal stenosis secondary to isolated facet hypertrophy, and persistent radicular symptoms following an anterior cervical spine procedure. Depending on the underlying pathology, clinical success rates from 75% to 96% for the treatment of cervical radiculopathy have been reported. Mainly, there are 2 different endoscopic techniques to perform PCF. The so-called full-endoscopic techniques are performed under continuous irrigation in single-handed technique. The endoscopic tubular assisted technique is performed in bimanual fashion with microsurgical instruments. The purpose of this video is to describe the endoscopic tubular assisted technique in detail. Patient consent was obtained prior to preparation of the video.


Everyday physical activity as a predictor of late-life mortality.
The present study hypothesized that simple, everyday physical activity (EPA) would decline with advancing age; that women would have a more favorable EPA profile than would men; and that EPA would have a survival benefit. Community-dwelling participants (aged 80-98 years, n = 198) wore mechanical actigraphs in order for EPA to be assessed. Individuals were classified as active, inactive, and sedentary based on their level of EPA exhibited over a substantial part of the day. Survival status was available at approximately 2 years. Mean EPA scores decreased with advancing age and, in contrast to men, women in their early eighties appeared to be protected from declining EPA. This partially supported the hypothesis that women would have a more favorable EPA profile. What is most important is that mean EPA scores predicted mortality. Moreover, when compared with their less sedentary counterparts, sedentary adults were more than three times as likely to be deceased 2 years later. Researchers need to conduct new trials to determine whether or how physical activity is associated with mortality.


Search for the Lepton Flavor Violating Decays B^{+}→K^{+}τ^{±}ℓ^{∓} (ℓ=e, μ) at Belle.
We present a search for the lepton flavor violating decays B^{+}→K^{+}τ^{±}ℓ^{∓}, with ℓ=(e,μ), using the full data sample of 772×10^{6} BB[over ¯] pairs recorded by the Belle detector at the KEKB asymmetric-energy e^{+}e^{-} collider. We use events in which one B meson is fully reconstructed in a hadronic decay mode. We find no evidence for B^{±}→K^{±}τℓ decays and set upper limits on their branching fractions at the 90% confidence level in the (1-3)×10^{-5} range. The obtained limits are the world's best results.


Magnetophoresis and ferromagnetic resonance of magnetically labeled cells.
We develop in this paper two methods, based on different physical concepts, to quantify the uptake of magnetic nanoparticles in biological cells. The first one, magnetophoresis, is based on the measurement of the velocity of magnetically labeled cells submitted to a magnetic field gradient. The second one quantitates the particles' electronic spin using an electron paramagnetic resonance experiment. We show a quantitative agreement between both methods for macrophagic cells. The uptake kinetics and uptake capacity are discussed for macrophagic cells and other cell lines.


Thrombophilic gene mutations in children with migraine.
In 35 patients of both sexes (18 boys and 17 girls), mean age 8.9 ± 4.5 years, affected by migraine both with (45.2%) and without an aura (54.9%) (P > 0.05) who had no alteration of brain computerized tomography and/or magnetic resonance imaging, we evaluated possible thrombotic events in the pathogenesis of the disease. In all cases and in 50 random healthy controls clotting tests (prothrombin time, activated partial thromboplastin time, protein C activity (PC), antithrombin III (ATIII), protein S (PS), antiphospholipid antibodies (aPL), and Lupus anticoagulant (LA) were normal. FVIII and FIX activities were increased in seven and five migraine sufferers, respectively. Genetic thrombophilic risk factors - factor V Leiden (FVL) and MTHFR677T - resulted in a significantly increased prevalence in migraine patients when compared with controls but without significant differences for the F2 polymorphism. The examined polymorphisms were associated with an increased risk of developing migraine (odds ratio (OR) > 1). These findings could confirm the key role of a reduced cerebral flow in the pathogenesis of migraine and possible risk of ischaemic stroke (IS) but we feel that these observations need to be confirmed in larger multi-centre studies.


An autopsy case of extraskeletal Ewing's sarcoma followed up for 24 years.
A long-term (24 years) follow-up case of extraskeletal Ewing's sarcoma is reported. The light microscopic examination showed features hardly indistinguishable from Ewing's sarcoma of the bone, that is, the tumor cells were diffusely arranged and uniform in size and shape, and possessed glycogen in the cytoplasm. Homer-Wright rosettes were found only in the autopsy material. An immunohistochemical study using a neural marker (neuron-specific enolase) demonstrated positive staining in most tumor cells. An ultrastructural study revealed intracytoplasmic glycogen particles and incomplete neural characters as follows: the cytoplasmic processes resembled neural processes without neurosecretory granules, microtubules or neurofilaments. These findings suggest that this case finally acquired an incomplete neural character with repeated recurrence. This tumor was diagnosed extraskeletal Ewing's sarcoma, but in future it may be categorized as primitive neuroectodermal tumor (PNET).


Death: The asymmetry mystery.
As the Roman philosopher Lucretius asked, why do we fear and regret death, but do not regret not having been born earlier, when death and prenatal nonexistence are mirror images? Both deprive us of goods we might have had, and this deprivation most plausibly explains the badness of death. This paper first considers and rejects explanations other than the deprivation of goods. It then suggests an explanation in terms of a state of which death deprives us, and which is itself asymmetrical in regard to the future and the past. This sharp asymmetry in this one very important good helps to justify the difference in our attitudes, especially among those for whom death approaches. The paper departs from the usual rigid format in which a philosopher says what she is going to say, then says it, and then repeats it. In matching form to mystery content, the missing clue to the solution will not be revealed until later in the paper.


Translate to divide: сontrol of the cell cycle by protein synthesis.
Protein synthesis underpins much of cell growth and, consequently, cell multiplication. Understanding how proliferating cells commit and progress into the cell cycle requires knowing not only which proteins need to be synthesized, but also what determines their rate of synthesis during cell division.


Improved BLAST searches using longer words for protein seeding.
The blastp and tblastn modules of BLAST are widely used methods for searching protein queries against protein and nucleotide databases, respectively. One heuristic used in BLAST is to consider only database sequences that contain a high-scoring match of length at most 5 to the query. We implemented the capability to use words of length 6 or 7. We demonstrate an improved trade-off between running time and retrieval accuracy, controlled by the score threshold used for short word matches. For example, the running time can be reduced by 20-30% while achieving ROC (receiver operator characteristic) scores similar to those obtained with current default parameters. The option to use long words is in the NCBI C and C++ toolkit code for BLAST, starting with version 2.2.16 of blastall. A Linux executable used to produce the results herein is available at: ftp://ftp.ncbi.nlm.nih.gov/pub/agarwala/protein_longwords


In silico identification of potential drug compound against Peroxisome proliferator-activated receptor-gamma by virtual screening and toxicity studies for the treatment of Diabetic Nephropathy.
Diabetic Nephropathy is a serious complication of diabetes mellitus. Current therapeutic strategies of Diabetic Nephropathy are based on control of modifiable risks like hypertension, glucose levels, and dyslipidemia. Peroxisome proliferator activated receptor-gamma (PPAR-γ) is implicated in several metabolic syndromes including Diabetic Nephropathy, besides obesity, insulin insensitivity, dislipidemia, inflammation, and hypertension. In the present study, virtual screening of 617 compounds from two different public databases was done against PPAR-γ with an objective to find a possible lead compound. Two softwares, PyRx and iGEMDOCK, were used to achieve the docking accuracy in order to avoid loss of candidate compounds. Rosiglitazone (used to treat Diabetic Nephropathy) was taken as the standard compound. A total of 30 compounds with good binding affinity with PPAR-γ were selected for further filtering, on the basis of absorption, distribution, metabolism, excretion, and toxicity (ADMET). The interaction profiling of these 30 compounds, showed a minimum of one and maximum of three interactions with reference to rosiglitazone (SER-289, HIS-449, HIS-323, TYR-473). The fulfilling of ADMET analysis criteria of 30 compounds led to the selection of four compounds (ZINC ID 00181552, 00276456, 00298314, 00448009). Molecular dynamics simulation of these lead compounds in complex with PPAR-γ revealed that three of the four compounds formed a stable complex in the ligand-binding pocket of PPAR-γ during 20-ns simulation. Hence, these three (ZINC ID 00181552, 00276456, 00298314) of the four compounds are potential candidates for experimental validation of biological activity against PPAR-γ in future drug discovery studies.


Nanotechnology in Food and Plant Science: Challenges and Future Prospects.
Globally, food safety and security are receiving a lot of attention to ensure a steady supply of nutrient-rich and safe food. Nanotechnology is used in a wide range of technical processes, including the development of new materials and the enhancement of food safety and security. Nanomaterials are used to improve the protective effects of food and help detect microbial contamination, hazardous chemicals, and pesticides. Nanosensors are used to detect pathogens and allergens in food. Food processing is enhanced further by nanocapsulation, which allows for the delivery of bioactive compounds, increases food bioavailability, and extends food shelf life. Various forms of nanomaterials have been developed to improve food safety and enhance agricultural productivity, including nanometals, nanorods, nanofilms, nanotubes, nanofibers, nanolayers, and nanosheets. Such materials are used for developing nanofertilizers, nanopesticides, and nanomaterials to induce plant growth, genome modification, and transgene expression in plants. Nanomaterials have antimicrobial properties, promote plants' innate immunity, and act as delivery agents for active ingredients. Nanocomposites offer good acid-resistance capabilities, effective recyclability, significant thermostability, and enhanced storage stability. Nanomaterials have been extensively used for the targeted delivery and release of genes and proteins into plant cells. In this review article, we discuss the role of nanotechnology in food safety and security. Furthermore, we include a partial literature survey on the use of nanotechnology in food packaging, food safety, food preservation using smart nanocarriers, the detection of food-borne pathogens and allergens using nanosensors, and crop growth and yield improvement; however, extensive research on nanotechnology is warranted.


How to use the new DSM-5 somatic symptom disorder diagnosis in research and practice: a critical evaluation and a proposal for modifications.
The fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) changed the term "somatoform disorders" to "somatic symptom and related disorders" and further modified diagnostic labels and criteria. We review evidence for the validity of the new criteria, specifically of somatic symptom disorder (SSD), and present a critical discussion of unsolved and new problems. We also provide an update of mechanisms and interventions that have been empirically evaluated in somatoform disorders. For many mechanisms, it is unclear whether their role can be easily transposed to SSD. Therefore more research is needed on the similarities and differences between medically unexplained and medically explained conditions. To overcome the obvious shortcomings of the current classification, we offer a modification of this DSM-5 section as well as a crossover system to apply these criteria for somatic symptom and related disorders. This proposal allows working with DSM-5 but also continuing successful lines of research with concepts such as hypochondriasis/illness anxiety, chronic pain, and medically unexplained versus medically explained syndromes.


Factors associated with newly diagnosed HIV among persons with concomitant sexually transmitted diseases.
We evaluated Illinois and Chicago Departments of Public Health surveillance databases to determine risk factors associated with newly diagnosed HIV among persons with bacterial sexually transmitted diseases (STDs). Test results for Chlamydia, gonorrhea, early syphilis (primary, secondary, and early latent), and HIV from public health clinics in Illinois in 2002 were merged with demographic and behavioral survey data collected during patient visits. STD was defined as any positive non-HIV result. Among 43,517 patient encounters, 5814 (13.4%) had positive STD test results. There were 308 (0.7%) positive new HIV test results, of which 71 (23.1%) had concomitant infection with an STD. Compared with STD-positive, HIV-negative cases, age >30 years (OR = 1.9, 95% CI, 1.0,4.4), men who have sex with men (MSM) (OR = 22.2, 95% CI 11.3-43.7), and bisexual male (OR = 22.4, 95% CI 7.8-64.8) were independently associated with STD and HIV coinfections. Among distinct STDs, syphilis (n = 438) was the least frequent (7.5%), but was reported in the highest proportion (10.1%) of all new HIV infections and conferred the greatest risk (OR = 11.0, 95% CI 7.7-15.8) for newly diagnosed HIV. MSM were at increased risk for newly diagnosed HIV with STD coinfection. Persons with a concomitant STD and HIV were older than US populations that generally constitute the greatest proportion of STD cases. These results highlight the role in particular of syphilis among populations at high risk for HIV transmission. Public health interventions targeting MSM and older adults for effective testing and prevention strategies are critically needed within high-risk networks for cotransmission of STDs and HIV.


Parental smoking in the first two years of a child's life and its associations with breastfeeding.
Exclusive breastfeeding for the first 6 months followed by ongoing breastfeeding to 12 months and beyond is associated with multiple benefits for both mother and child. Maternal smoking is associated with a reduction in breastfeeding. Little is known about the effect of partner smoking on breastfeeding. This study explores the smoking behaviour of mothers and their partners in the first two years of a child's life and its associations with breastfeeding practice. We performed a secondary data analysis using survey data on 1155 mothers from their third trimester of pregnancy and at six, 12 and 24 months after delivery. Survey questions included smoking status of both mother and partner and breastfeeding intention and practice. Logistic regression models were conducted at each time point. Where the mother or both parents smoke, babies were less likely to be breastfed at six months of age (adjusted odds ratio (aOR) 0.29, 95% CI: 0.13-0.66) compared with families where neither parent smoked. Non-smoking mothers with smoking partners were less likely to intend to breastfeed (aOR 0.29, 95% CI: 0.11-0.82) and their babies were less likely to be breastfed at six and 12 months of age (aOR 0.64, 95% CI: 0.42-0.98 and 0.64, 95% CI: 0.43-0.95 respectively). There was no difference in breastfeeding behaviour between smoking and non-smoking parents at 24 months. Smoking parents are less likely to breastfeed their babies at ages six and 12 months. Breastfeeding promotion should target both smoking mothers and smoking partners.


TGF-beta related genes in development.
Embryonic induction is the process by which signals from one cell population change the developmental fate of another. Polypeptides related to growth factors are one group of molecules mediating many inductive events. Recent data on the embryonic expression and function of signaling proteins related to transforming growth factor beta, in both vertebrate and invertebrate systems, have shown that these molecules play important roles in both pattern formation and tissue specification during embryogenesis.


The effects of charge-neutralizing mutation D6.30N on the functions of CB1 and CB2 cannabinoid receptors.
Charge-neutralizing mutation D6.30N of the human cannabinoid receptor subtype 1 (CB1) and cannabinoid receptor subtype 2 (CB2) cannabinoid receptors was made to test two hypotheses: (1) D6.30 may be crucial for the functions of CB1 and CB2 receptors. (2) D6.30 may participate in an ionic lock with R3.50 that keeps the receptors in an inactive conformation. Specific ligand binding and ligand-induced inhibition of forskolin-stimulated cAMP accumulation were observed with human embryonic kidney epithelial cell line (HEK293) cells expressing wild-type CB1 and CB2, as well as CB1D6.30N and CB2D6.30N mutant receptors. There was however a decrease in maximum response of the mutant receptors compared to their wild-type counterparts, suggesting that D6.30 is essential for full activation of both CB1 and CB2 receptors. Both CB1D6.30N and CB2D6.30N demonstrated a level of constitutive activity no greater than that of their wild-type counterparts, indicating that either D6.30 does not participate in a salt bridge with R3.50, or the salt bridge is not critical for keeping cannabinoid receptors in the inactive conformation.


Comparison of DNA adduct formation by aristolochic acids in various in vitro activation systems by 32P-post-labelling: evidence for reductive activation by peroxidases.
Aristolochic acid I (AAI) and aristolochic acid II (AAII), the two major components of the carcinogenic plant extract aristolochic acid (AA), are known to be mutagenic and to form DNA adducts in vivo. According to the structures of the major DNA adducts identified in animals and humans, nitroreduction is the crucial pathway in the metabolic activation of these naturally occurring nitroarenes to their ultimate carcinogenic species. Using the nuclease P1-enhanced version of the 32P-post-labelling assay we investigated the formation of DNA adducts by AAI and AAII in different in vitro activation systems in order to determine the most suitable in vitro system mimicking target tissue activation. Although DNA adducts resulting from oxidative activation of AAs have not yet been identified both reductive and oxidative in vitro systems were employed. In vitro incubations were conducted under standardized conditions (0.3 mM AAs; 4 mM dNp as calf thymus DNA) using rat liver microsomes, xanthine oxidase (a mammalian nitroreductase), horseradish peroxidase, lactoperoxidase and chemical reduction by zinc. Enzymatic incubations were performed under aerobic and anaerobic conditions. A combination of two independent chromatographic systems (ion-exchange chromatography and reversed-phase HPLC) with reference compounds was used for the identification of DNA adducts detected by the 32P-post-labelling assay. The two known major adducts of AAI or AAII found in vivo were generated by all in vitro systems except for incubations with AAII and horseradish peroxidase where two unknown adducts predominated. Irrespective of the in vitro activation system used, the majority of adduct spots obtained were identified as the previously characterized four AA-DNA adducts: dA-AAI, dA-AAII, dG-AAI and dG-AAII. This indicates that both reductive and peroxidative activation of AAI or AAII resulted in chromatographically indistinguishable DNA adducts. Thus, peroxidase mediated activation of AAs led to the formation of the same adducts that had been observed in vivo and upon reductive activation in several in vitro systems. Quantitative analyses of individual adducts formed in the various in vitro systems revealed relative adduct labelling (RAL) values over a 100,000-fold range from 4 in 10(3) for activation of AAII to deoxyadenosine adducts by zinc to only 3 in 10(8) for activation of AAII by lactoperoxidase. The extent of DNA modification by AAI was higher than by AAII in all enzymatic in vitro systems. Only activation by zinc resulted in higher total binding to exogenous DNA by AAII than by AAI. Aerobic incubations with rat liver microsomes generated AAI- and AAII-DNA adduct profiles reproducing profiles in target tissue (forestomach) of rats, thus providing the most appropriate activation among the in vitro systems tested.


[Resistance reversal effect of a novel taxane compound NPB304 and its collaboration with verapamil].
The tumor multidrug resistance reversal effect of NPB304, a novel taxane, was studied. MTT assay was used to determine the IC50 of chemotherapy drugs. Western blotting assay was applied to analyze the expression of P-glycoprotein (P-gp). The effect of compounds on the P-gp function and P-gp ATPase activity was determined by rhodamine 123 (Rh123) accumulation assay and analysis kit, respectively. Molecular docking was employed to predict the binding force between compounds and P-gp. Transmembrane transport of NPB304 was analyzed using MDCK II and MDR1-MDCK II cell model. NPB304 displayed multidrug resistance reversal effect on KBV cells and MCF-7/paclitaxel cells, NPB304 collaborative with P-glycoprotein (P-gp) inhibitors verapamil enhanced the reversal activity, specifically, 10 μmol x L(-1) verapamil in combination with paclitaxel reversed resistance by 56.5-fold, while combined with NPB304 increased the reversal fold; NPB304 synergistically increased Rh123 accumulation in the resistant cells when combined with verapamil, and NPB304 at 0-1 μmol x L(-1) enhanced the ATPase activity activated by verapamil was observed. NPB304 existed the hydrophobic interactions with the TM regions of P-gp, and the binding force between NPB304 and the A chain of the TM region was stronger. P-gp ATPase activity assay demonstrated NPB304 at lower concentrations (0-1.5 μmol x L(-1)) could activate the P-gp ATPase, playing a role on inhibition of P-gp function. However, NPB304 did not have an obvious feature of P-gp substrate. NPB304 exerted itself and synergy with verapamil activity on reversing tumor resistance via inhibiting the P-gp function.


Autologous Induced Stem-Cell-Derived Retinal Cells for Macular Degeneration.
We assessed the feasibility of transplanting a sheet of retinal pigment epithelial (RPE) cells differentiated from induced pluripotent stem cells (iPSCs) in a patient with neovascular age-related macular degeneration. The iPSCs were generated from skin fibroblasts obtained from two patients with advanced neovascular age-related macular degeneration and were differentiated into RPE cells. The RPE cells and the iPSCs from which they were derived were subject to extensive testing. A surgery that included the removal of the neovascular membrane and transplantation of the autologous iPSC-derived RPE cell sheet under the retina was performed in one of the patients. At 1 year after surgery, the transplanted sheet remained intact, best corrected visual acuity had not improved or worsened, and cystoid macular edema was present. (Funded by Highway Program for Realization of Regenerative Medicine and others; University Hospital Medical Information Network Clinical Trials Registry [UMIN-CTR] number, UMIN000011929 .).


[Placental vascular changes in maternal diabetes mellitus].
Uniform pathological changes characteristic for the diabetes mellitus in the placenta were not revealed. In 63 per cent of the 22 cases morphological changes in the small- and middle vessels were observed. The most severe pathological changes were seen in the media in form of concentric fibrosis. It caused narrowing of the lumen, although the intima remained undamaged. It was not possible to detect a correlation between the severity of damage to the placentar vessels and groups described by White.


Breastfeeding initiation: is this influenced by maternal hepatitis B infection?
To elucidate the effect of hepatitis B virus (HBV) infection on breastfeeding uptake in Chinese mothers in an endemic region. A retrospective cohort study on 63 885 consecutive pregnant delivered between January 1997 and June 2008, were extracted from computerized database to examine the relationship between breastfeeding uptake and maternal HBV status, adjusted for demographic factors. A total of 6593 (10.3%) women were hepatitis B surface antigen (HBsAg)-positive, with an annual prevalence of around 10%. In the study period, 29 869 (46.8%) practised breastfeeding, and its prevalence ranged from 35.4 to 54.8% with an increasing trend throughout the years (p < 0.001). HBsAg-positive mothers had a significantly lower rate of breastfeeding (39.2 vs. 47.6% p < 0.001). Multiparas had higher incidence of HBV infection (10.9 vs. 9.8%, p < 0.001) and lower breastfeeding rate (42.2% versus 51.0%, p < 0.001) when compared with primiparas. Among those factors, maternal HBV infection had the strongest negative association with breastfeeding (adjusted odd ratio (aOR) = 0.726, 95% confidence interval (CI): 0.689-0.765). Our results suggested maternal HBV infection was one of the factors for the persistently low breastfeeding rate in Hong Kong over the past decades. To promote breastfeeding, it is necessary to generate definitive data on its safety regarding to mother-to-child transmission (MTCT) of HBV in order to allay the fear and anxiety in HBsAg-positive mothers.


Hypovitaminosis D among newly diagnosed pulmonary TB patients and their household contacts in Uganda.
An estimated one billion people globally live with hypovitaminosis D. Studies have indicated that vitamin D deficiency is a risk factor for active tuberculosis (TB) disease. The aim of this study was to determine the association between vitamin D deficiency and TB status among patients with active TB, latent TB infection (LTBI) and those without TB infection. In a cross-sectional study of active TB patients, LTBI, QuantiFERON GOLD testpositive and (QFN+TST+) household contact and controls QuantiFERON GOLD testnegative (QFN-TST-) samples vitamin D levels were compared. Vitamin D status was determined by measurement of total vitamin D levels with 56 samples of active TB patients, 17 with LTBI, and 22 without TB infection using electrochemiluminescence. The median interquartile range (IQR) age of the study participants was 28 (20-35) years, and the majority (63%) were females. The median (IQR) vitamin D levels were 18 ng/ml (14-24). All groups had vitamin D hypovitaminosis with significantly lower levels among active TB patients (17 ng/ml, 13, 2) than among LTBI individuals (23 ng/ml 16-29) and those without TB infection (22 ng/ml, 17-28).


Blockade of cholinergic receptors by an irreversible antagonist, propylbenzilylcholine mustard (PrBCM), in the rat cerebral cortex causes deficits in passive avoidance learning.
Studies were made on the effects of blockade of muscarinic acetylcholine (mACh) receptors in the rat cerebral cortex on learning and memory assessed by performance of a step-through passive avoidance task. Bilateral injection of propylbenzilylcholine mustard (PrBCM) into both the frontal and parietal cortex at doses of 2.25 X 4 to 22.5 X 4 micrograms decreased mACh receptors dose-dependently, as assessed by [3H]quinuclidinyl benzilate binding studies. When the training trial of a step-through passive avoidance task was performed 24 h after injection of 7.5 X 4 to 22.5 X 4 micrograms PrBCM into the frontal and parietal cortex, and then a retention test was made 24 h after the training trial, the treated rats showed shorter latencies than controls. In contrast, injection of PrBCM into the occipital cortex had no significant effect on performance in the test. These results confirm the notion that cholinergic neurotransmission in the cerebral cortex, especially the frontoparietal cortex, is important in learning and memory. The effects of injection of PrBCM (22.5 X 4 micrograms) into the frontoparietal cortex on 3 postulated phases of the learning and memory process (i.e. registration, retention and recall) were also examined. When PrBCM was injected 24 h before the training trial, no retention of the task was observed 14 days after the training trial. However, when PrBCM was injected 24 h after the training trial, retention of the task 14 days after the training trial was not affected. When PrBCM was injected 3-24 h after the initial training trial, the latencies in the retention test examined 24 h later were shorter than those of control rats.(ABSTRACT TRUNCATED AT 250 WORDS)


Estradiol levels and secretory dynamics in normal girls and boys as determined by an ultrasensitive bioassay: a 10 year experience.
We utilized an ultrasensitive recombinant cell bioassay to measure serum estradiol in 800 normal children from birth through puberty. 105 children had repeat samples every 4 months as they approached puberty. We measured estradiol levels every hour for 24 hours in 55 children. Estradiol increased with age and pubertal stage in girls and boys, and was higher in girls than boys at each stage. Prepubertal girls have estradiol levels of 1.6 +/- 2.6 pg/ml. Prepubertal boys have estradiol levels of 0.4 + 1.1 pg/ml. Estradiol had a diurnal variation in girls and boys, with the trough occurring 08.00-20.00 h in girls, and 12.00-20.00 h in boys. We confirm that estradiol levels are higher in girls than boys even before physical signs of puberty, and that estradiol increases throughout puberty in girls and boys. This 10-year experience in 800 children shows the range and variability of estradiol by an ultrasensitive bioassay.


Katanin, a microtubule-severing protein, is a novel AAA ATPase that targets to the centrosome using a WD40-containing subunit.
Microtubule disassembly at centrosomes is involved in mitotic spindle function. The microtubule-severing protein katanin, a heterodimer of 60 and 80 kDa subunits, was previously purified and shown to localize to centrosomes in vivo. Here we report the sequences and activities of the katanin subunits. p60 is a new member of the AAA family of ATPases, and we show that expressed p60 has microtubule-stimulated ATPase and microtubule-severing activities in the absence of p80. p80 is a novel protein containing WD40 repeats, which are frequently involved in protein-protein interactions. The p80 WD40 domain does not participate in p60 dimerization, but localizes to centrosomes in transfected mammalian cells. These results indicate katanin's activities are segregated into a subunit (p60) that possesses enzymatic activity and a subunit (p80) that targets the enzyme to the centrosome.


Dynamic shifts in brain network activation during supracapacity working memory task performance.
Despite significant advances in understanding how brain networks support working memory (WM) and cognitive control, relatively little is known about how these networks respond when cognitive capabilities are overtaxed. We used a fine-grained manipulation of memory load within a single trial to exceed WM capacity during functional magnetic resonance imaging to investigate how these networks respond to support task performance when WM capacity is exceeded. Analyzing correct trials only, we observed a nonmonotonic (inverted-U) response to WM load throughout the classic WM network (including bilateral dorsolateral prefrontal cortex, posterior parietal cortex, and presupplementary motor areas) that peaked later in individuals with greater WM capacity. We also observed a relative increase in activity in medial anterior prefrontal cortex, posterior cingulate/precuneus, and lateral temporal and parietal regions at the highest WM loads, and a set of predominantly subcortical and prefrontal regions whose activation was greatest at the lowest WM loads. At the individual subject level, the inverted-U pattern was associated with poorer performance while expression of the early and late activating patterns was predictive of better performance. In addition, greater activation in bilateral fusiform gyrus and right occipital lobe at the highest WM loads predicted better performance. These results demonstrate dynamic and behaviorally relevant changes in the level of activation of multiple brain networks in response to increasing WM load that are not well accounted for by present models of how the brain subserves the cognitive ability to hold and manipulate information on-line.


In vivo hepatic adenoviral gene delivery occurs independently of the coxsackievirus-adenovirus receptor.
Systemic administration of adenoviral vectors leads to a widespread distribution of vector. Therefore, targeting of adenoviral vectors to specific tissues or cell types will require methods to ablate the normal tropism of the vector simultaneously with the introduction of new receptor specificities. To inhibit native receptor binding, we mutated residues in the AB loop of the adenovirus type 5 (Ad5) fiber. We genetically incorporated the S408E-P409A mutation, referred to as KO1, into the adenoviral genome alone or in combination with an RGD-targeting ligand in the HI loop of fiber. Transduction experiments confirmed that the KO1 mutation results in a significant reduction in fiber-dependent gene transfer on A549 and primary fibroblast cells that could be restored via the RGD-targeting ligand. Competition transduction experiments verified the receptor-binding properties of each vector on A549 and hepatocytes in vitro. Unexpectedly, in mice systemic delivery of the vector containing the KO1 mutation resulted in efficient liver transduction that was localized specifically to hepatocytes. We confirmed these results in three different mouse strains, indicating that hepatic adenoviral gene transfer may be independent of the coxsackievirus-adenovirus receptor and that in vivo retargeting will require further viral capsid modifications to generate a fully detargeted adenoviral vector upon which to introduce new tropisms.


Expressed emotion research in schizophrenia: theoretical and clinical implications.
The expressed emotion (EE) measure is a robust predictor of relapse in schizophrenia. At least twelve studies from a range of cultures have now shown this, although the authors of one maintain their findings are the result of confounding factors. A thirteenth study which failed to demonstrate a predictive effect was seriously weakened by methodological defects. There is now also evidence for the construct validity of EE, which has been shown to reflect ongoing family interactions. High EE relatives display less effective coping responses, and may adversely affect the patient by creating an unpredictable environment. EE may change with time, and probably reflects the interaction of external stresses, the real problems with the patient, and inappropriate coping responses. The association of high EE with arousal in the patient, as indicated by skin conductance abnormalities, has now been replicated. Although the EE phenomenon can be subsumed under a vulnerability-stress model, the way in which it might mediate relapse has not as yet been specified. Interventions have been successful in reducing relapse, and do so by increasing the tolerance and coping skills of the relatives, and by establishing more realistic expectations. As most have also involved the patient in the process of treatment, they have not fully resolved the question of causal direction. Future studies will clarify these issues, but will not detract from the value that EE has already had in energizing research. It has also provided a framework within which clinicians have begun to recognize and deal with the disabling problems that beset schizophrenic patients and their families.


Double-stranded RNA- and CpG DNA-induced immune responses in Atlantic salmon: comparison and synergies.
Several TLR agonists are shown to activate piscine immunity and are interesting adjuvant candidates in vaccine development. To test the outcome of stimulating Atlantic salmon with CpG DNA and poly I:C, ligands for TLR9 and 3, respectively, we have measured the in vivo expression of different immune molecules in spleen and head kidney. The expression profiles for individual treatments with CpGs or poly I:C not only showed similarities but they also displayed unique profiles. When combining them a synergistic up-regulation of the genes interferon (IFN)-alpha1/alpha2, Mx, CXCL10, IL-1beta, IFN-gamma and CD83 was detected. Interestingly, synergies between two different CpG ODNs classes also resulted in pronounced IFN-alpha1/alpha2 and IFN-gamma transcripts levels. To our knowledge this is the first study showing synergy by combining two different TLR9 ligands. In conclusion, detection of dsRNA and CpG DNA in fish may mimic viral recognition, resulting in an enhanced innate immune response that could be used for vaccination.


Dive into the details of self-supervised learning for medical image analysis.
Self-supervised learning (SSL) has achieved remarkable performance in various medical imaging tasks by dint of priors from massive unlabeled data. However, regarding a specific downstream task, there is still a lack of an instruction book on how to select suitable pretext tasks and implementation details throughout the standard "pretrain-then-finetune" workflow. In this work, we focus on exploiting the capacity of SSL in terms of four realistic and significant issues: (1) the impact of SSL on imbalanced datasets, (2) the network architecture, (3) the applicability of upstream tasks to downstream tasks and (4) the stacking effect of SSL and common policies for deep learning. We provide a large-scale, in-depth and fine-grained study through extensive experiments on predictive, contrastive, generative and multi-SSL algorithms. Based on the results, we have uncovered several insights. Positively, SSL advances class-imbalanced learning mainly by boosting the performance of the rare class, which is of interest to clinical diagnosis. Unfortunately, SSL offers marginal or even negative returns in some cases, including severely imbalanced and relatively balanced data regimes, as well as combinations with common training policies. Our intriguing findings provide practical guidelines for the usage of SSL in the medical context and highlight the need for developing universal pretext tasks to accommodate diverse application scenarios. The code of this paper can be found at https://github.com/EndoluminalSurgicalVision-IMR/Medical-SSL.


A Preliminary Study on the Potential Protective Role of the Antioxidative Stress Markers of Cognitive Impairment: Glutathione and Glutathione Reductase.
: To investigate the relationship between reduced glutathione (GSH), a key molecule of the antioxidant defense system in the blood, and glutathione reductase (GR), which reduces oxidized glutathione (glutathione disulfide [GSSG]) to GSH and maintains the redox balance, with the prevalence of Alzheimer's dementia and cognitive decline. : In all, 20 participants with Alzheimer's dementia who completed the third follow-up clinical evaluation over 6 years were selected, and 20 participants with normal cognition were selected after age and sex matching. The GSH and GR concentrations were the independent variables. Clinical diagnosis and neurocognitive test scores were the dependent variables indicating cognitive status. : The higher the level of GR, the greater the possibility of having normal cognition than of developing Alzheimer's dementia. Additionally, the higher the level of GR, the higher the neurocognitive test scores. However, this association was not significant for GSH. After 6 years, the conversion rate from normal cognition to cognitive impairment was significantly higher in the lower 50th percentile of the GR group than in the upper 50th percentile. : The higher the GR, the lower the prevalence of Alzheimer's dementia and incidence of cognitive impairment and the higher the cognitive test scores. Therefore, GR is a potential protective biomarker against Alzheimer's dementia and cognitive decline.


Fluoresceinated Aminohexanol Tethered Inositol Hexakisphosphate: Studies on Arabidopsis thaliana and Drosophila melanogaster and Docking with 2P1M Receptor.
Inositol hexakisphosphate (InsP6; phytic acid) is considered as the second messenger and plays a very important role in plants, animals, and human beings. It is the principal storage form of phosphorus in many plant tissues, especially in dry fruits, bran, and seeds. The resulting anion is a colorless species that plays a critical role in nutrition and is believed to cure many diseases. A fluoresceinated aminohexanol tethered inositol hexakisphosphate (III) had been synthesized earlier involving many complicated steps. We describe here a simple two-step synthesis of (III) and its characterization using different techniques such as matrix-assisted laser desorption ionization mass spectrometry, tandem mass spectrometry, and Fourier transform infrared, ultraviolet-visible, ultraviolet-fluorescence, 1H nuclear magnetic resonance (NMR), and two-dimensional NMR spectroscopies. The effect of (III) has been investigated in the model systems, Arabidopsis thaliana and Drosophila melanogaster. Using Schrodinger software, computational studies on the binding of (III) with the protein 2P1M (Auxin-receptor TIR1-adaptor ASK1 complex) has revealed strong binding propensity with this compound. These studies on the fluoresceinated tethered phytic acid could have far reaching implications on its efficacy for human health and treatment of diseases (cancer/tumor and glioblastoma) and for understanding phosphorous recycling in the environment, especially for plant systems.


Baroreflex Activation Therapy in Patients With Heart Failure With Reduced Ejection Fraction.
This study demonstrated the safety and effectiveness of baroreflex activation therapy (BAT) in patients with heart failure with reduced ejection fraction (HFrEF). The BeAT-HF (Baroreflex Activation Therapy for Heart Failure) trial was a multicenter, prospective, randomized, controlled trial; subjects were randomized 1:1 to receive either BAT plus optimal medical management (BAT group) or optimal medical management alone (control group). Four patient cohorts were created from 408 randomized patients with HFrEF using the following enrollment criteria: current New York Heart Association (NYHA) functional class III or functional class II (patients who had a recent history of NYHA functional class III); ejection fraction ≤35%; stable medical management for ≥4 weeks; and no Class I indication for cardiac resynchronization therapy. Effectiveness endpoints were the change from baseline to 6 months in 6-min hall walk distance (6MHW), Minnesota Living with HF Questionnaire quality-of-life (QOL) score, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels. The safety endpoint included the major adverse neurological or cardiovascular system or procedure-related event rate (MANCE). Results from, timeline and rationale for, cohorts A, B, and C are presented in detail in the text. Cohort D, which represented the intended use population that reflected the U.S. Food and Drug Administration-approved instructions for use (enrollment criteria plus NT-proBNP <1,600 pg/ml), consisted of 245 patients followed-up for 6 months (120 in the BAT group and 125 in the control group). BAT was safe and significantly improved QOL, 6MHW, and NT-proBNP. In the BAT group versus the control group, QOL score decreased (Δ = -14.1; 95% confidence interval [CI]: -19 to -9; p < 0.001), 6MHW distance increased (Δ = 60 m; 95% CI: 40 to 80 m; p < 0.001), NT-proBNP decreased (Δ = -25%; 95% CI: -38% to -9%; p = 0.004), and the MANCE free rate was 97% (95% CI: 93% to 100%; p < 0.001). BAT was safe and significantly improved QOL, exercise capacity, and NT-proBNP. (Baroreflex Activation Therapy for Heart Failure [BeAT-HF]; NCT02627196).


Seven-year experience with ablation of permanent atrial fibrillation concomitant to mitral valve surgery in 152 patients.
This study analyzed 7 years of results for monopolar endocardial radiofrequency (RF) ablation of permanent atrial fibrillation (pAF) concomitant to mitral valve (MV) surgery. Between 2001 and 2007, 152 patients who had experienced pAF for a median of 4.0 years (interquartile range, 1.5-8.0 years; range, 0.5-33 years) underwent monopolar endocardial RF ablation procedures (pulmonary vein isolation plus a connecting lesion) concomitant to MV surgery. All patients were reexamined to assess survival, conversion rate to stable sinus rhythm (SR), and New York Heart Association (NYHA) class at 8 +/- 1 days after surgery and follow-ups at 3 +/- 1 months and 41 +/- 24 months postoperatively. Data were analyzed exploratatively. The survival rates at the 3 reexamination times were 97%, 95%, and 92%, respectively (6 cardiac and 6 noncardiac deaths), and the corresponding SR rates were 74%, 75%, and 73%. The NYHA class of the patients improved significantly after surgery (P = .006), particularly when a stable SR had been achieved (P = .039). Long-term pAF prior to surgery and a larger left atrium (LA) preoperatively were predictive of the return of postoperative AF (P = .0002, and P = .0003, respectively). Ninety-one percent of the patients with a preoperative pAF duration of <5 years and 88% of the patients with an LA size of <or=55 mm were in stable SR at the late follow-up. The cardiac rhythm at discharge and 3 months after surgery were predictive of a prognosis of long-term rhythm (P = .021, and P = .00002, respectively). Age, sex, and the underlying etiology of MV disease did not have a significant influence on postoperative cardiac rhythm. This study demonstrated that a SR established after combined pAF ablation and MV surgery remains stable over time. Preoperative LA size and pAF duration are useful parameters for evaluating the success rate of pAF ablation concomitant to MV surgery.


A novel cell surface antigen involved in thymocyte and thymic epithelial cell adhesion.
A murine mAb, 7D3, was produced by fusion of spleen cells obtained from mice immunized with a rat thymic epithelial cell line, Tu-D3 and NS/1 myeloma cells. 7D3 antibody reacted with approximately 95% thymocytes, 17% spleen cells, less than 9% of mesenteric lymph node cells and 32% of bone marrow cells of rat origin. 7D3 also reacted with two rat thymic epithelial cell lines but not with a rat fibroblastic cell line. Immunochemical analysis demonstrated that 7D3 antibody recognized a single polypeptide with molecular weight of 80,000 in FTE cells and 80,000 to 96,000 in thymocytes. 7D3 antibody strongly inhibited the thymocyte binding to thymic epithelial cells. In addition, 7D3 antibody inhibited TPA-induced thymocyte aggregation. 7D3 negative rat thymic lymphoma cells bound to 7D3 positive thymic epithelial cells and this binding was inhibited by 7D3 antibody, indicating that a part of thymocyte-thymic epithelial cell binding was mediated by the interaction of 7D3 Ag and undefined ligand to 7D3.


Exploring the Role of Social Support between Discharge Teaching and Readiness for Discharge in Ocular Fundus Disease Patients: A Cross-Sectional Study.
This study aims to evaluate the quality of discharge teaching and readiness for discharge of fundus disease patients treated with day surgery and understand the role of social support between them. This was a cross-sectional descriptive correlational survey. Through convenient sampling, fundus disease patients treated with day surgery from Zhongshan Ophthalmic Center, China, were recruited. Data were collected using demographic and disease-related information, quality of discharge teaching scale, readiness for hospital discharge scale, and social support scale. 255 fundus disease patients treated with day surgery were recruited at last. The mean total score of readiness for discharge, quality of discharge teaching, and social support in patients with fundus disease were 157.91 (SD = 26.68), 122.97 (SD = 21.55), and 36.32 (SD = 7.60), respectively. Participants with stronger social support had better discharge teaching and then had higher readiness for discharge. Social support played a partial mediator role in the relationship between discharge teaching and readiness for discharge. The mediation effect ratio was 5.5%. The quality of discharge teaching and social support among fundus disease patients who underwent day surgery was relatively high, and readiness for discharge was good. Social support is essential for the quality of discharge teaching and the improvement of discharge readiness. Clinical nurses need to provide appropriate guidelines to help patients seek effective support and improve quality of discharge teaching to enhance the readiness for discharge of fundus disease patients treated with day surgery.


End-Organ Damage in Hypertension: An Insight on a Differentiated Outpatient Consultation.
The objective of this study was to determine the prevalence of end-organ damage in hypertensive patients attending an outpatient consultation. Patients were selected from an outpatient consultation at a tertiary hospital care center. All patients who consulted between July 2022 and March 2023 were included. Data on demographic characteristics, blood pressure records, hypertension etiology, medication use, and the presence of target organ damage were collected. A total of 73 patients were included in the study, with 34 patients being male (46.6%) and 39 patients being female (53.4%). The mean age of the patients was 49.8 years. Among the cases of hypertension, 14 (19.2%) were classified as secondary arterial hypertension (AH). The most common cause of secondary AH was obstructive sleep apnea (OSA) (42.9%). Approximately 23.2% of patients had documented end-organ damage potentially related to hypertension, with kidney disease being the most frequent (n = 10, 13.7%). The most commonly prescribed pharmacological classes were angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists (n = 46, 63%). Despite numerous studies and trials on arterial hypertension, it remains a significant contributor to morbidity and mortality, necessitating the continued awareness of its long-term implications.


Two methods for the removal of erythrocytes from buffy coats for the production of human leukocyte interferon.
Two different methods of removing erythrocytes from buffy coats, with the ultimate aim of inducing the white blood cells for the production of leukocyte interferon, i.e., erythrocyte lysis with ammonium chloride, and erythrocyte agglomeration with hydroxyethyl starch, are compared. After two treatments with 0.83% NH4Cl all erythrocytes are lysed and most granulocytes are damaged, although the lymphocytes appear mostly unaffected (as judged by microphotography of Wright-stained smears). Treatment with 3% hydroxyethyl starch causes most erythrocytes to agglomerate and sediment to the bottom of a vessel in less than one hour; the leukocytes (lymphocytes as well as granulocytes), which remain in suspension, are morphologically intact. NH4Cl-treated leukocytes yield, on an average, 3.6 times less interferon than hydroxyethyl starch-treated leukocytes. Leukocyte viability, as judged by trypan blue exclusion does not appear much influenced by either NH4Cl or hydroxyethyl starch treatment. The advantage of hydroxyethyl starch apparently lies in the fact that its use leaves the granulocytes intact and thus obviates the undue release of proteolytic enzymes into the culture medium, with their concomitant deleterious effect on interferon production.


A genomic screen for genes upregulated by demethylation and histone deacetylase inhibition in human colorectal cancer.
Aberrant hypermethylation of gene promoters is a major mechanism associated with inactivation of tumor-suppressor genes in cancer. We previously showed this transcriptional silencing to be mediated by both methylation and histone deacetylase activity, with methylation being dominant. Here, we have used cDNA microarray analysis to screen for genes that are epigenetically silenced in human colorectal cancer. By screening over 10,000 genes, we show that our approach can identify a substantial number of genes with promoter hypermethylation in a given cancer; these are distinct from genes with unmethylated promoters, for which increased expression is produced by histone deacetylase inhibition alone. Many of the hypermethylated genes we identified have high potential for roles in tumorigenesis by virtue of their predicted function and chromosome position. We also identified a group of genes that are preferentially hypermethylated in colorectal cancer and gastric cancer. One of these genes, SFRP1, belongs to a gene family; we show that hypermethylation of four genes in this family occurs very frequently in colorectal cancer, providing for (i) a unique potential mechanism for loss of tumor-suppressor gene function and (ii) construction of a molecular marker panel that could detect virtually all colorectal cancer.


Visual outcome in moderate and severe proliferative diabetic retinopathy.
Four hundred eyes with moderate or severe proliferative diabetic retinopathy, initial good vision, and an average follow-up of 44.3 months were studied. Final visual acuity was 20/40 or better in 33% of these eyes, 20/50 to 5/200 in 32%, and 5/200 or worse in 35%. A poor visual prognosis was correlated with a traction detachment or relatively poor visual acuity at initial examination. No correlation was found between the length of follow-up and final visual prognosis. General guide-lines are available for the management of these patients' conditions.