Intestinal metastasis from choriocarcinoma: a case series and literature review.
Gestational choriocarcinoma is a rare trophoblastic tumor that spreads mainly to the lung, liver, and central nervous system. Fewer than 5% of patients present with metastasis to the gastrointestinal system and have a poor prognosis CASE PRESENTATION: We describe four cases of patients with intestinal metastasis from choriocarcinoma who visited the First Affiliated Hospital of Zhejiang University School of Medicine and the First People's Hospital of Hangzhou between April 2012 and October 2019. Four patients presented with gastrointestinal symptoms or developed gastrointestinal symptoms during treatment for choriocarcinoma. Three patients had these intestinal lesions surgically removed, and the postoperative pathology results suggested choriocarcinoma. All patients received multiple chemotherapy regimens during treatment for suboptimal human chorionic gonadotropin (hCG) levels; one patient died 22 months after a definitive diagnosis was made, and the other three patients are still undergoing regular follow-up. Given the low incidence of intestinal metastases from choriocarcinoma, the metastatic route of intestinal metastases from choriocarcinoma remains to be elucidated, and diagnosis mainly depends on pathology findings. An effective treatment has not been determined, and surgical excision with chemotherapy is generally accepted.


The anti-diarrheal and anti-inflammatory effects of hydroethanol extracts of ripe Annona muricata fruit pulp in Wistar rats using curative method.
The study aimed to determine the anti-diarrheal and anti-inflammatory activities of hydroethanolic extract of ripe Annona muricata fruit pulp (HEAMP) on Wistar rats. Fifty male Wistar rats were divided into five groups, each for the diarrhea and inflammatory phases. Groups A and B 10 mL/kg of distilled water and 2 mL of castor oil, Groups C, D, and E received 2 mL of castor oil + extract (150, 300, and 600 mg/kg). Groups A and B received 10 mL/kg of distilled water and 0.1 mL of egg white. Groups C, D, and E received the (0.1 mL) egg white and extract (150, 300, and 600 mg/kg). Data were analyzed using SPSS (25) using ANOVA followed by post hoc least significant difference, presented as mean ± standard error of the mean, and values considered significant at P < 0.05. The acute toxicity test of HEAMP is above 5000 mg/kg and rich in flavonoids, saponins, and proteins, with carbohydrates and tannins, and glycosides at moderate levels. Steroids, alkaloids, amino acids, and triterpenoids were absent. Furthermore, 30 min after diarrhea induction, the treated groups significantly increased (P = 0.012) in fecal count compared to Group A. Compared to Group B, the treated groups had a significant decrease in the fecal count at 60, 90, 120, and 150 min. At 30-min, there was a significant increase (P = 0.000) in paw-size in the treated groups compared to Group A. The treated groups had significantly lower edematous paw-size levels from 60 to 150 min compared to Group B. The HEAMP had anti-diarrheal and anti-inflammatory properties and is safe for consumption.


Endobronchial brachytherapy provides excellent long-term control of recurrent granulation tissue after tracheal stenosis.
To review the experience of using endobronchial brachytherapy (EBB) as a treatment for recurrent tracheal granulation tissue. Patients referred for EBB at the Rabin Medical Center for benign stenosis were reviewed with institutional review board approval. Patients underwent bronchoscopic resection of granulation tissue followed by insertion of self-expanding metallic stents. After stenting, repeat laser resection was done at least 1 week before brachytherapy. After CT simulation, patients had three-dimensional brachytherapy treatment planning. A single 10-Gy dose was prescribed to 1.0cm from the source and treatment was delivered using high-dose-rate afterloader with (192)Ir source. Patients were followedup with bronchoscopy every 3 months after the completion of therapy. From November 2001 to January 2009, 29 patients were treated with EBB to prevent granulation tissue reformation. Median age was 70 years and 55% of patients were male. Ninety percent of patients were treated to the trachea and the remaining patients had stenoses in the main stem bronchi. The primary cause of stenosis was prolonged mechanical ventilation (76%). The median time from stent placement to brachytherapy was 69 days. Median active length of treatment was 7cm. With a median followup of 36 months, 66% (19 of 29) of patients remained free of granulation tissue. Forty-eight percent of patients have died, with all except 1 patient dying of their underlying condition. A single patient experienced death from tracheoesophageal fistula. EBB is an effective and safe treatment to prevent recurrent granulation tissue formation after endobronchial resection and should be considered in patients who are unable to undergo surgical resection.


Comparison of Valgus Correction Angle between Patients with Developmental Dysplasia Hip and Normal Volunteers Measured by Three-Dimensional Reconstruction and X-Ray.
Bilateral VCA of 50 DDH patients and 56 normal volunteers were measured by Mimics software in the 3D method and X-ray in 2D. Two VCA (the upper VCA and the lower VCA) were measured in both two methods. Every VCA was measured by observer A and observer B for twice separately. The statistical analyses of the differences were calculated among the measurements of the VCA. The mean value of the upper VCA measured in 3D was 4.95° ± 0.76° in DDH group and 5.56° ± 0.62° in the normal group with significant difference (t = -6.457, p < 0.01). The VCA of DDH group and normal group measured by 3D was larger than 2D, both the upper VCA and the lower VCA. The differences indicated statistically significant. The mean value of lower VCA was 0.60° smaller than the mean value of upper VCA in normal volunteers. The mean value of the lower VCA was 0.58° larger than the mean value of the upper VCA in DDH patients. Compared to X-ray, 3D reconstruction technology is more accurate without conventional limitations. The lower VCA of DDH patients should be regarded as the femoral intramedullary guide angle in TKA, especially for patients with femoral deformities.


AKT overactivation can suppress DNA repair via p70S6 kinase-dependent downregulation of MRE11.
Deregulated AKT kinase activity due to PTEN deficiency in cancer cells contributes to oncogenesis by incompletely understood mechanisms. Here, we show that PTEN deletion in HCT116 and DLD1 colon carcinoma cells leads to suppression of CHK1 and CHK2 activation in response to irradiation, impaired G2 checkpoint proficiency and radiosensitization. These defects are associated with reduced expression of MRE11, RAD50 and NBS1, components of the apical MRE11/RAD50/NBS1 (MRN) DNA damage response complex. Consistent with reduced MRN complex function, PTEN-deficient cells fail to resect DNA double-strand breaks efficiently after irradiation and show greatly diminished proficiency for DNA repair via the error-free homologous recombination (HR) repair pathway. MRE11 is highly unstable in PTEN-deficient cells but stability can be significantly restored by inhibiting mTORC1 or p70S6 kinase (p70S6K), downstream kinases whose activities are stimulated by AKT, or by mutating a residue in MRE11 that we show is phosphorylated by p70S6K in vitro. In primary human fibroblasts, activated AKT suppresses MRN complex expression to escalate RAS-induced DNA damage and thereby reinforce oncogene-induced senescence. Taken together, our data demonstrate that deregulation of the PI3K-AKT/ mTORC1/ p70S6K pathways, an event frequently observed in cancer, exert profound effects on genome stability via MRE11 with potential implications for tumour initiation and therapy.


Arthroscopic Modified Elbow Lateral Collateral Ligament Imbrication: An Operative Technique.
When the lateral collateral ligament (LCL) complex fails to support the radiocapitellar and ulnohumeral joints in advanced stages of insufficiency, the patient experiences posterolateral rotatory instability (PLRI). Open lateral ulnar collateral ligament repair with a ligamentous graft has been the standard treatment for PLRI. Despite producing good clinical stability rates, this method is associated with significant lateral soft-tissue dissection and a lengthy recovery period. By fastening the LCL to its humeral insertion, arthroscopic imbrication of the LCL can increase stability. The senior author modified this technique. With the aid of a passer, the LCL complex, lateral capsule, and anconeus may be weaved with a single (doubled) suture, secured with a Nice knot. LCL complex imbrication may be used to restore stability and improve pain and function in patients with grade I and II PLRI.


Further validation that claims data are a useful tool for epidemiologic research on hypertension.
The practice of using medical service claims in epidemiologic research on hypertension is becoming increasingly common, and several published studies have attempted to validate the diagnostic data contained therein. However, very few of those studies have had the benefit of using actual measured blood pressure as the gold standard. The goal of this study is to assess the validity of claims data in identifying hypertension cases and thereby clarify the benefits and limitations of using those data in studies of chronic disease etiology. Disease status was assigned to 19,150 employees at a U.S. manufacturing company where regular physical examinations are performed. We compared the presence of hypertension in the occupational medical charts against diagnoses obtained from administrative claims data. After adjusting for potential confounders, those with measured blood pressure indicating stage 1 hypertension were 3.69 times more likely to have a claim than normotensives (95% CI: 3.12, 4.38) and those indicating stage 2 hypertension were 7.70 times more likely to have a claim than normotensives (95% CI: 6.36, 9.35). Comparing measured blood pressure values identified in the medical charts to the algorithms for diagnosis of hypertension from the claims data yielded sensitivity values of 43-61% and specificity values of 86-94%. The medical service claims data were found to be highly specific, while sensitivity values varied by claims algorithm suggesting the possibility of under-ascertainment. Our analysis further demonstrates that such under-ascertainment is strongly skewed toward those cases that would be considered clinically borderline or mild.


Effect of Stereochemistry on Chirality and Gelation Properties of Supramolecular Self-Assemblies.
Although chiral nanostructures have been fabricated at various structural levels, the transfer and amplification of chirality from molecules to supramolecular self-assemblies are still puzzling, especially for heterochiral molecules. Herein, four series of C2 -symmetrical dipeptide-based derivatives bearing various amino acid sequences and different chiralities are designed and synthesized. The transcription and amplification of molecular chirality to supramolecular assemblies are achieved. The results show that supramolecular chirality is only determined by the amino acid adjacent to the benzene core, irrespective of the absolute configuration of the C-terminal amino acid. In addition, molecular chirality also has a significant influence on the gelation behavior. For the diphenylalanine-based gelators, the homochiral gelators can be gelled through a conventional heating-cooling process, whereas heterochiral gelators form translucent stable gels under sonication. The racemic gels possess higher mechanical properties than those of the pure enantiomers. All of these results contribute to an increasing knowledge over control of the generation of specific chiral supramolecular structures and the development of new optimized strategies to achieve functional supramolecular organogels through heterochiral and racemic systems.


Sensitivity of off-axis performance of aspheric spectacle lenses to tilt and decentration.
Apparatus was modified to measure, and theoretical raytracing was used to predict, off-axis powers of spectacle lenses in the presence of tilt or decentration. In response to poor fitting in the form of tilt or decentration, lenses with aspheric front surfaces were found to have greater off-axis power errors than best-form lenses with spherical surfaces. This is attributable to the aspheric lenses having flatter surfaces than the spherical lenses. The errors are up to twice those occurring for the spherical lenses, and can be quite high, e.g. 0.9 D astigmatism for +6D power with 10 degrees tilt in 20 degrees upgaze. Negative lenses are more sensitive to poor fitting than are positive lenses of the same power. The errors for straight ahead vision associated with tilt are approximately proportional to the square of the angle of tilt, and the errors for straight ahead vision associated with decentration are approximately proportional to the square of decentration. It is most important that aspheric lenses be correctly fitted, which means that each 2 degrees of pantascopic tilt should be accompanied by approximately 1 mm decentration.


Noctuid moths as pollinators of Habenaria sagittifera (Orchidaceae): floral adaptations for the transfer of pollinaria on the thoraxes of moths.
Orchids attach their pollinaria (cohesive masses of pollen) to specific body parts of flower visitors, but usually not to the hairy and scaly body parts of flower-visiting moths, because hairs and scales are easily detached. We demonstrate that pollinaria of Habenaria sagittifera (Orchidaceae) are transferred among flowers on the hairy thoraxes of moths in Japan. Diurnal and nocturnal insects visited the orchid flowers. However, pollinaria were attached only to the hairy thoraxes of plusiine moths (Lepidoptera: Noctuidae). All pollinaria were directly attached to the ventral thorax surfaces at the bases of hairs. Orchid spur lengths matched plusiine proboscis lengths so that nectar-feeding moths contacted the viscidia (sticky pads of pollinaria) and stigma. Other flower visitors did not contact the viscidia or stigmas while feeding on nectar. Habenaria sagittifera appears to have a floral morphology that is adaptive for the transfer of pollinaria on the thoraxes of plusiine moths.


Disruption of the β1L Isoform of GABP Reverses Glioblastoma Replicative Immortality in a TERT Promoter Mutation-Dependent Manner.
TERT promoter mutations reactivate telomerase, allowing for indefinite telomere maintenance and enabling cellular immortalization. These mutations specifically recruit the multimeric ETS factor GABP, which can form two functionally independent transcription factor species: a dimer or a tetramer. We show that genetic disruption of GABPβ1L (β1L), a tetramer-forming isoform of GABP that is dispensable for normal development, results in TERT silencing in a TERT promoter mutation-dependent manner. Reducing TERT expression by disrupting β1L culminates in telomere loss and cell death exclusively in TERT promoter mutant cells. Orthotopic xenografting of β1L-reduced, TERT promoter mutant glioblastoma cells rendered lower tumor burden and longer overall survival in mice. These results highlight the critical role of GABPβ1L in enabling immortality in TERT promoter mutant glioblastoma.


An assessment of Sri Lankan radiographer's knowledge and awareness of radiation protection and imaging parameters related to patient dose and image quality in computed tomography (CT).
As computed tomography (CT) examinations have considerably risen, safe operation is essential to reduce the patients' dose. The main objective of this study was to evaluate the level of knowledge and awareness regarding the CT exposure parameters and radiation protection in CT imaging among Sri Lankan radiographers. An online survey-based study was devised and distributed among the Sri Lankan CT radiographers working in 63 CT units. Questions were divided into three subsections that collected data on the participants' demographic features, knowledge of the radiation protection, and imaging parameters. Eighty-eight radiographers from 32 CT units (out of 63 CT units) distributed across 11 districts (out of 27 districts) participated in this survey.The percentages of correct responses for the questions related to radiation protection, imaging parameters, noise, Diagnostic Reference Level (DRL), and CT dosimetric parameters were 71%, 79%, 87%, 50%, and 66%, respectively. Although the years of experience did not influence any of above aspects, the level of education significantly impacted the knowledge about radiation protection, exposure parameters, and noise. The radiographer's knowledge of radiation protection and most imaging parameters associated with patient safety and image quality is satisfactory. However, findings also show that participants should fill the knowledge gap in radiation-related risks, CT exposure parameters, dosimetric parameters, and DRL. The study suggests the necessity of initiating continuous education programs for radiographers in line with national radiation protection legislation requirements that can be linked with code of practice.


Genetic Variation in VKORC1 and Risk for Osteoporosis.
The vitamin K epoxide reductase complex subunit 1 (VKORC1) plays an important role in bone development and bone metabolism by influencing the vitamin K cycle. The aim of this study was to investigate the association between VKORC1 gene polymorphisms and bone mineral density and the risk of osteoporosis. We determined VKORC1 gene polymorphisms (rs9923231 and rs9934488) by using polymerase chain reaction-restriction and Sanger sequencing method in 606 postmenopausal women including 288 osteoporosis patients and 318 healthy controls. No significant differences were observed in the rs9934488 polymorphisms between the osteoporosis group and controls. Subgroup analyses also indicated no positive result. VKORC1 rs9923231 polymorphism increased the risk of osteoporosis in the homozygous and allelic models. A significant correlation was observed in a subgroup of the elderly (age ≥55 years). Additionally, the genotypes of the rs9923231 polymorphism were significantly associated with low body mass index, and T-score, but not with age, serum calcium, or phosphorus. In conclusion, VKORC1 rs9923231 polymorphism is a genetic contributor to osteoporosis risk and it should be confirmed in large well-designed studies.


Preparation, AIE and ESIPT behaviour, controllable solid-state fluorescence and application of Co2+probe based onα-cyanostilbene.
A simpleα-cyanostilbene-functioned salicylaldehyde-based Schiff-base probe, which exhibited outstanding 'aggregation-induced emission and excited state intramolecular proton transfer (AIE + ESIPT)' emission in solution, aggregation and solid states, was synthesized in high yield of 87%. Its solid-states with different morphologies emitted different fluorescence after crystallization in EtOH/H2O (1/2, v/v) mixtures or pure EtOH solvent. Besides, it exhibited an obvious spectro-photometrical fluorescence quenching for highly selective sensing of Co2+in THF/water system (ƒw= 60%, pH = 7.4), accompanied by an intense green fluorescence turn-off behavior under UV365nmillumination. The binding stochiometry between the ligand and Co2+was found to be 2:1, and the detection limit (DL) was calculated to be 0.41 × 10-8M. In addition, it could be applied to detect Co2+in real water samples and on silica gel testing strip.


The fast oscillation of the EOG in diabetes with and without mild retinopathy.
There is ample evidence that the retinal pigment epithelium (RPE) is affected in diabetes, and that epitheliopathy may be among the early changes. The fast oscillation (FO) of the electro-oculogram (EOG) reflects the activity of the RPE, most notably the mechanisms responsible for pumping fluid and ions in the retina-to-choroid direction. The FO was measured in three groups of subjects: normal controls, eyes of diabetic individuals with no evidence of retinopathy, and eyes of diabetics with mild background retinopathy. FO amplitude, light trough voltage and dark peak voltage in both diabetic groups were all significantly reduced, independent of retinopathy status. The peak to trough ratio was unaffected. These changes, reduced voltages and smaller light-evoked voltage changes, are consistent with a decrease in the resistance of the RPE and may relate to accumulation of fluid in the sub-retinal space.


Innate immunity.
For more than half a century immunological research has been almost exclusively orientated towards the acquired immune response and the mechanisms of immune tolerance. Major discoveries have enabled us to better understand the functioning of the specific immune system: the structure of antibody molecules, the genetic mechanisms leading to the molecular diversity of B (BCR) and T (TCR) lymphocyte antigen receptors, the biological function of major histocompatibility complex (MHC) molecules in the presentation of peptides to alpha/beta receptor bearing T lymphocytes, the processes of positive and negative selection of lymphocytes during the course of their differentiation. The major role of specific or acquired immunity has been shown by the rapidly lethal character of severe combined immune deficiency diseases and various alterations in the mechanisms of tolerance have been proposed to explain the chronic inflammatory illnesses which are considered to be auto-immune. Natural or innate immunity has been known since the first description of an inflammatory reaction attributed to Cornelius Celsus. It entered into the scientific era at the end of the 19th century with the discovery of phagocytes by Metchnikoff and of the properties of the complement system by Bordet [1] but due to the vastness of the field and its lack of clear definition, it failed to excite the interest of researchers. The discovery of cytokines and progress in knowledge of the mechanisms of the inflammatory reaction have certainly helped to banish preconceived ideas about natural immunity, which was wrongly labelled as non-specific. This has led to the proposition of a wider role for immune functions beyond the level of the cell or the organism [2] and to a better understanding of the importance of the immediate defence mechanisms and their role in the later orientation of the acquired response.


Home medication management problems and associated factors among psychiatric patients using home care pharmacy services at government hospitals in western Malaysia.
Proper home medication management plays a role in improving medication adherence, preserving drug efficacy and ensuring safe medication practices, which is crucial to establish positive treatment outcomes. However, no published studies are available on home medication management among psychiatric patients. The study aimed to identify home medication management problems among psychiatric patients in Malaysia and to examine the associations of inappropriate medication storage and lack of a medication administration schedule with sociodemographic factors, disease insight, number of medications and type of home care pharmacy services (HCPS). This multicentre cross-sectional study was conducted among psychiatric patients using HCPS in six government hospitals in western Malaysia. Data were extracted from the HCPS form used for each visit as per the protocol published by the Pharmaceutical Services Division, Ministry of Health Malaysia. A minimum sample size of 169 was needed. Proportional random sampling was applied. The associations of inappropriate medication storage and lack of medication administration schedule with study parameters were analysed using multiple logistic regressions. A total of 205 home visits were conducted with 229 home medication management problems identified; inappropriate medication storage and lack of medication administration schedule topped the list. Inappropriate medication storage was significantly associated with low income [AOR = 4.34 (95% CI 1.17:15.98), p = 0.027], alcohol consumption [AOR = 14.26 (95% CI 1.82:111.38), p = 0.011], poor insight [AOR = 2.34 (95% CI 1.08:5.06), p = 0.030] and part-time HCPS [AOR = 2.60 (95% CI 1.20:5.67), p = 0.016]. Lack of administration schedule was significantly associated with low income [AOR = 6.90 (95% CI 1.46:32.48), p = 0.014], smoking [AOR = 2.43 (95% CI 1.20:4.92), p = 0.013], poor insight [AOR = 5.32 (95% CI 2.45:11.56), p < 0.05] and part-time HCPS [AOR = 2.96 (95% CI 1.42:6.15), p = 0.004]. Inappropriate medication storage and a lack of a medication administration schedule are common among psychiatric patients. The study also highlighted the potential of HCPS to improve disease insight and home medication management among psychiatric patients if the service is utilized fully.


Role of calcium channels in heavy metal toxicity.
The role of voltage-dependent Ca channels (VDCC) in the membrane permeation of two toxic metals, lead (Pb) and cadmium (Cd), was studied in mammalian cells. Both metals interact with Ca-binding sites, but, while Cd influx appears to occur mainly through the same pathways as Ca, Pb is also rapidly taken up by different passive transport systems. Furthermore, I compared the effect of Cd in two Chinese hamster ovary (CHO) cell lines, a wild-type and a modified cell line, which were permanently transfected with an L-type VDCC. When cultures were subjected to a brief (30-60 min) exposure to 50-100 μ M Cd, apoptotic features, metal accumulation, and death were comparable in both cell lines although, in transfected cells, the effect of Cd treatment was partially prevented by nimodipine (VDCC antagonist) and enhanced by BayK8644 (VDCC agonist). Thus, expression of L-type Ca channels is not sufficient to modify Cd accumulation and sensitivity to a toxicological significant extent and while both Cd and Pb can take advantage of VDCC to permeate the membrane, these transport proteins are not the only, and frequently not the most important, pathways of permeation.


Pediatric Rhabdomyosarcomas of the Genitourinary Tract.
Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in the pediatric and adolescent population, with 350 new cases diagnosed each year. While they can develop anywhere in the body, the genitourinary tract is the second most common primary location for an RMS to develop. Overall survival has improved through the increased use of protocols and multidisciplinary approaches. However, the guidelines for management continue to change as systemic and radiation therapeutics advance. Given the relative rarity of this disease compared to other non-solid childhood malignancies, healthcare providers not directly managing RMS may not be familiar with their presentation and updated management. This review aims to provide foundational knowledge of the management of RMSs with an emphasis on specific management paradigms for those arising from the genitourinary tract. The genitourinary tract is the second most common location for an RMS to develop but varies greatly in symptomology and survival depending on the organ of origin. As the clinical understanding of these tumors advances, treatment paradigms have evolved. Herein, we describe the breadth of presentations for genitourinary RMSs with diagnostic and treatment management considerations, incorporating the most recently available guidelines and societal consensus recommendations.


Melatonin ameliorated okadaic-acid induced Alzheimer-like lesions.
To explore the protective effects of melatonin (Mel) on the abnormal phosphorylation of neuronal cytoskeletal proteins. We generated a neuroblastoma (SH-SY5Y) cell system in which cytoskeletal proteins are abnormally phosphorylated resulting in microtubule disruption due to the marked inhibition of protein phosphatase activities by okadaic acid (OA). OA-induced declines in cell viability and mitochondrial metabolic activity were remarkably prevented by Mel. In addition, the hyperphosphorylation/accumulation of neurofilament-(NF-) H/M subunits and the disruption of microtubules, induced by OA, were significantly inhibited by Mel. Our results suggest multiple protective functions of Mel against a series of pathological lesions known to culminate in AD, including abnormal phosphorylation of cytoskeletal proteins, microtubule disassembly and mitochondrion-initiated cell toxicity.


Using functional magnetic resonance imaging to understand the mechanisms of consciousness.
In order to elucidate mental functions that subserve human consciousness, brain activation was investigated in 12 normal, right-handed volunteers who performed tasks of selective attention, working memory, and sensorimotor coordination during the collection of multislice echoplanar functional magnetic resonance images. These functions are located in (and controlled by) distinct anatomical regions that can be identified by functional magnetic resonance imaging techniques. In each subject, 100 10-slice data sets were acquired using a 1.5-T scanner and the blood oxygenation level dependent contrast technique. Time-series regression modeling estimated power in the magnetic resonance signal during the on/off phases of task performance. Comparison between subjects was made possible by the transformation of each data set into standard Talairach space. Activation maps were based on the median value of the fundamental power quotient at each voxel. Results showed the activation of prefrontal and parasagittal cortices in both the selective attention and working memory tasks, but they also revealed activation in both insular cortices and the posterior cingulate gyri. The results provide evidence for structures in the anterior right hemisphere and left medial frontal lobe for attentional tasks, although there appears to be an engagement of a widespread network of anterior brain structures, possibly with the inhibition of some posterior regions, during task performance. The sensorimotor coordination task showed activation regions similar to those seen in selective attention. Once learned, this task probably demands attention rather than overt conscious motor control. Clearly, the functions of attention, working memory, and sensorimotor coordination are not located in single, discrete brain areas. However, interactions and interplay between related areas were demonstrated, giving supporting evidence that complex mental operations rely on the coordinated activity of widely distributed brain regions that contribute to neural networks.


Modeling novelty habituation during exploratory activity in Drosophila.
Habituation is a common form of non-associative learning in which the organism gradually decreases its response to repeated stimuli. The decrease in exploratory activity of many animal species during exposure to a novel open field arena is a widely studied habituation paradigm. However, a theoretical framework to quantify how the novelty of the arena is learned during habituation is currently missing. Drosophila melanogaster display a high mean absolute activity and a high probability for directional persistence when first introduced to a novel arena. Both measures decrease during habituation to the arena. Here, we propose a phenomenological model of habituation for Drosophila exploration based on two principles: Drosophila form a spatial representation of the arena edge as a set of connected local patches, and repeated exposure to these patches is essential for the habituation of the novelty. The level of exposure depends on the number of visitations and is quantified by a variable referred to as "coverage". This model was tested by comparing predictions against the experimentally measured behavior of wild type Drosophila. The novelty habituation of wild type Canton-S depends on coverage and is specifically independent of the arena radius. Our model describes the time dependent locomotor activity, ΔD, of Canton-S using an experimentally established stochastic process Pn(ΔD), which depends on the coverage. The quantitative measures of exploration and habituation were further applied to three mutant genotypes. Consistent with a requirement for vision in novelty habituation, blind no receptor potential A(7) mutants display a failure in the decay of probability for directional persistence and mean absolute activity. The rutabaga(2080) habituation mutant also shows defects in these measures. The kurtz(1) non-visual arrestin mutant demonstrates a rapid decay in these measures, implying reduced motivation. The model and the habituation measures offer a powerful framework for understanding mechanisms associated with open field habituation.


Efficient estimation of the distribution of time to composite endpoint when some endpoints are only partially observed.
Two common features of clinical trials, and other longitudinal studies, are (1) a primary interest in composite endpoints, and (2) the problem of subjects withdrawing prematurely from the study. In some settings, withdrawal may only affect observation of some components of the composite endpoint, for example when another component is death, information on which may be available from a national registry. In this paper, we use the theory of augmented inverse probability weighted estimating equations to show how such partial information on the composite endpoint for subjects who withdraw from the study can be incorporated in a principled way into the estimation of the distribution of time to composite endpoint, typically leading to increased efficiency without relying on additional assumptions above those that would be made by standard approaches. We describe our proposed approach theoretically, and demonstrate its properties in a simulation study.


Electron microscopic detection of the cryptantigen AhumHP (Friedenreich antigen) on human erythrocytes by means of gold-labelled agglutinin from Helix pomatia.
Using the gold-labelled agglutinin anti-AHP from Helix pomatia (edible snail) the ultrastructural site and distribution of the cryptantigen (Friedenreich antigen) AhumHP was revealed on neuraminidase treated human O and B erythrocytes. On A1 and A2 cells the antigen was demonstrated simultaneously with the blood group antigen A by labelling the cells with anti-AHP-ferritin followed by removing the neuraminic acid and labelling with anti-AHP-gold. The cryptantigen is focally distributed on the cell surface.


Bisphenol A induces apoptosis and autophagy in murine osteocytes MLO-Y4: Involvement of ROS-mediated mTOR/ULK1 pathway.
Bisphenol A (BPA) is a widely environmental endocrine disruptor. The accumulated BPA in humans is toxic to osteoblasts and osteoclasts, but few studies focused on the effects of BPA on osteocytes, the most abundant bone cell type, contributing to the development and metabolism of bone. Here, we reported that BPA (50, 100, 200 μmol/L) inhibited the cell viability of osteocytes MLO-Y4, promoted G0/G1 phase arrest and apoptosis in a dose-dependent manner. BPA treatment significantly increased the levels of autophagy-regulated proteins including Beclin-1 and LC3-II along with the decrease of p62, accompanied by the elevation of autophagy flux and the accumulation of acidic vacuoles, which was blocked by the autophagy inhibitor bafilomycin A1 (BafA1). Furthermore, BPA significantly inhibited the mammalian target of rapamycin (mTOR) and activated Unc-51 like autophagy activating kinase 1 (ULK1) signaling, leading to the decreased p-mTOR/mTOR ratio and the increased p-ULK1/ULK1 ratio. The mTOR activator MHY1485 (MHY) or the ULK1 inhibitor SBI-0206965 (SBI) prevented autophagy and enhanced apoptosis caused by BPA, respectively. In addition, BPA increased the levels of intracellular reactive oxygen species (ROS) and malondialdehyde (MDA) and decreased antioxidant enzymes nuclear factor E2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) levels, resulting in oxidative stress. The ROS scavenger N-acetylcysteine (NAC) attenuated BPA-induced the mTOR/ULK1 pathway activation, apoptosis and autophagy. Collectively, ROS-mediated mTOR/ULK1 signaling is involved in BPA-induced apoptosis and autophagy in osteocytes MLO-Y4. Our data first provide in vitro evidence that apoptosis and autophagy as cellular mechanisms for the toxic effect of BPA on osteocytes, thereby advancing our understanding of the potential role of osteocytes in the adverse effect of BPA on bone health.


Generation of a chromosome-level genome assembly for Pacific halibut (Hippoglossus stenolepis) and characterization of its sex-determining genomic region.
The Pacific halibut (Hippoglossus stenolepis) is a key species in the North Pacific Ocean and Bering Sea ecosystems, where it also supports important fisheries. However, the lack of genomic resources limits our understanding of evolutionary, environmental and anthropogenic forces affecting key life history characteristics of Pacific halibut and prevents the application of genomic tools in fisheries management and conservation efforts. In the present study, we report on the first generation of a high-quality chromosome-level assembly of the Pacific halibut genome, with an estimated size of 602 Mb, 24 chromosome-length scaffolds that contain 99.8% of the assembly and a N50 scaffold length of 27.3 Mb. In the first application of this important resource, we conducted genome-wide analyses of sex-specific genetic variation by pool sequencing and characterized a potential sex-determining region in chromosome 9 with a high density of female-specific SNPs. Within this region, we identified the bmpr1ba gene as a potential candidate for master sex-determining (MSD) gene. bmpr1ba is a member of the TGF-β family that in teleosts has provided the largest number of MSD genes, including a paralogue of this gene in Atlantic herring. The genome assembly constitutes an essential resource for future studies on Pacific halibut population structure and dynamics, evolutionary history and responses to environmental and anthropogenic influences. Furthermore, the genomic location of the sex-determining region in Pacific halibut has been identified and a putative candidate MSD gene has been proposed, providing further support for the rapid evolution of sex-determining mechanisms in teleost fish.


dPCR vs. qPCR: The role of Poisson statistics at low concentrations.
The ultimate precision in both dPCR and qPCR experiments is limited by the Poisson statistics in the total number m of template molecules in the sample, giving relative standard deviation 1/m. This means that precision is limited by sample volume at low concentrations. Accordingly qPCR instruments, used in dPCR mode, can give better precision than dPCR instruments in this limit. For example, 13% standard deviation can be achieved with a 96-well plate for number concentrations ~20-5000 mL-1. For fixed m, qPCR loses to dPCR by a factor of ~2 in precision when calibration is needed.


Effect of a calcium-sensitizing agent, levosimendan, on the postcardioplegic inotropic response of the myocardium.
Myocardial contractile function after coronary artery bypass graft surgery is often depressed and may require inotropic support, particularly in patients on treatment with beta-adrenergic and Ca2+ blockers. In view of the increase in cytosolic Ca2+ during early reperfusion, use of Ca2+ sensitizing agents may be preferable to adrenergic agonists for enhancement of contractile function after cardioplegic arrest. The aim of this study was to assess the efficacy of the Ca2+ sensitizer, levosimendan, as an inotrope on the mechanical recovery of hearts after normothermic and hypothermic cardioplegic arrest in the absence and presence of Ca2+ and beta-blockers. Isolated perfused working guinea pig hearts were perfused in the absence or presence of propranolol (10(-6) M) and/or nifedipine (10(-8) M), subjected to 45 minutes of normothermic or 180 minutes of hypothermic cardioplegic arrest, reperfused, and exposed to increasing concentrations of levosimendan (10(-9) to 10(-6) M). Levosimendan (10(-7) to 10(-6) M) has positive inotropic, chronotropic, and vasodilatory effects on normoxic perfused control hearts, as well as during reperfusion after 45 minutes of normothermic cardioplegic arrest. Similar effects were elicited in the presence of the blockers. Levosimendan had no stimulatory effect during reperfusion of hearts subjected to prior hypothermic arrest. Except for the increase in heart rate, the effects of levosimendan on functional performance during reperfusion were comparable with those of adrenaline. Levosimendan elicits a positive inotropic and chronotropic response during reperfusion of hearts after normothermic cardioplegic arrest, both in the absence and presence of Ca2+ and beta-adrenergic blockers.


Use of strontium-90 plesiotherapy for the treatment of a lingual plasmacytoma in a dog.
A 12-year-old, 25 kg, intact male St Bernard crossbreed was presented for treatment of a 538 mm ulcerated tumour on the dorsal tongue. Fine-needle aspiration cytology revealed a plasmacytoma. The dog staged negative for evidence of local metastatic or systemic disease. Histopathology confirmed the diagnosis. Treatment with one 150 Gy dose of radiation delivered with strontium-90 plesiotherapy was performed. Side effects were not noted and there was no visible evidence of tumour remaining at 2 months and 1 year after therapy.


Warm blood cardioplegia reduces the fall in the intracellular concentration of taurine in the ischaemic/reperfused heart of patients undergoing aortic valve surgery.
The effect of cold and warm intermittent antegrade blood cardioplegia, on the intracellular concentration of taurine in the ischaemic/reperfused heart of patients undergoing aortic valve surgery, was investigated. Intracellular taurine was measured in ventricular biopsies taken before institution of cardiopulmonary bypass, at the end of 30 min of ischaemic arrest and 20 min after reperfusion. There was no significant change in the intracellular concentration of taurine in ventricular biopsies taken after the period of myocardial ischaemia in the two groups of patients (from 10.1 +/- 1.0 to 9.6 +/- 0.9 mumol/g wet weight for cold and from 9.3 +/- 1.3 to 10.0 +/- 1.3 mumol/g wet weight for warm cardioplegia, respectively). Upon reperfusion however, there was a fall in taurine in both groups but was only significant (P < 0.05) in the group receiving cold blood cardioplegia (6.9 +/- 0.8 mumol/g wet weight after cold blood cardioplegia versus 8.0 +/- 0.8 mumol/g wet weight following warm blood cardioplegia). Like taurine, there were no significant changes in the intracellular concentration of ATP after ischaemia in the two groups of patients (from 3.2 +/- 0.32 to 2.95 +/- 0.43 mumol/g wet weight for cold and from 2.75 +/- 0.17 to 2.62 +/- 0.21 mumol/g wet weight for warm cardioplegia, respectively). However upon reperfusion there was a significant fall in ATP in both groups with the extent of the fall being less in the group receiving warm cardioplegia (1.79 +/- 0.19 mumol/g wet weight for cold and 1.98 +/- 0.27 mumol/g wet weight for warm cardioplegia, respectively). This work shows that reperfusion following ischaemic arrest with warm cardioplegia reduces the fall in tissue taurine seen after arrest with cold cardioplegia. Accumulation of intracellular sodium provoked by hypothermia and a fall in ATP, may be responsible for the fall in taurine by way of activating the sodium/taurine symport to efflux taurine.


A rapid fluorescence based multiplex polymerase chain reaction--single-strand conformation polymorphism method for p53 mutation detection.
We have developed a fast single-strand conformation polymorphism (SSCP) technique to screen for mutations and polymorphisms in exons 5-8 of the human tumor suppressor gene p53. We use multiplex polymerase chain reaction (PCR) to amplify the four exons in one single PCR reaction and then fluorescent SSCP for screening. p53 fragments are labeled with three different colors and a fourth color is used for an internal size marker calibrating the gel. The method was evaluated in two ways: (i) 16 different cell lines with known mutations were tested blindly for band-shifts with SSCP, and (ii) 32 human urinary bladder cancer samples were screened for mutations using the present technique. After screening for mutations all exons from all samples were sequenced, both sense as well as antisense strands. Evaluating the method with four different gels shows that 21/23 mutations and polymorphism were detected in the cell lines and that 10/10 mutations and polymorphisms were detected in the patient samples. Sensitivity, specificity, positive and negative predictive values were 91/100%, 88/ 97%. 78/77% and 96/100% for cell lines / patient samples, respectively. Sensitivity, using one SSCP gel only, was 87% (20/23) for cell lines and 90% (9/10) for patient samples. We conclude that our modified SSCP technique is efficient and has a sensitivity close to 100% in detecting mutations.


Inferring occurrence of growth checks in pike (Esox lucius) scales by using sequential isotopic analysis of otoliths.
Sequential analysis of otolith oxygen isotope (δ(18) O(oto) ) values was performed by classical mechanical microdrilling and dual inlet mass spectrometry to infer the timing of growth checks in pike (Esox lucius) scales from Lake Annecy (France). It indicated that the first check on scales occurs before the first winter of life of the fish. Eleven fish caught in February and June 2008 were studied. Intra-individual isotopic profiles exhibit cyclic variations that are consistent with that of modeled δ(18) O(oto) values using variations in epilimnion temperature and otolith-specific isotope fractionation equations. The positions of growth checks on scales were compared with the periodic variations of δ(18) O(oto) values on otolith radii using an allometric relationship. All individuals presented at least one check deposited before the first winter. Deposition of some checks might be linked to a shift in fish diet or habitat or to catch-and-release induced stress. Although coupling between sequential analysis of δ(18) O(oto) values and observation of scale growth features has been shown to be useful, there are limitations in the methodology, especially for the growth-attenuated region of otoliths associated with older ages.


Sex, Racial, and Geographic Disparities in Pulmonary Embolism-related Mortality Nationwide.
Rationale: Acute pulmonary embolism is a leading cause of cardiovascular death. There are limited data on the national mortality trends from pulmonary embolism. Understanding these trends is crucial for addressing the mortality and associated disparities associated with pulmonary embolism. Objectives: To analyze the national mortality trends related to acute pulmonary embolism and determine the overall age-adjusted mortality rate (AAMR) per 100,000 population for the study period and assess changes in AAMR among different sexes, races, and geographic locations. Methods: We conducted a retrospective cohort analysis using mortality data of individuals aged ⩾15 years with pulmonary embolism listed as the underlying cause of death in the Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research database from January 2006 to December 2019. These data are produced by the National Center for Health Statistics. Results: A total of 109,992 pulmonary embolism-related deaths were noted in this dataset nationwide between 2006 and 2019. Of these, women constituted 60,113 (54.7%). The AAMR per 100,000 was not significantly changed, from 2.84 in 2006 to 2.81 in 2019 (average annual percentage change [AAPC], 0.2; 95% confidence interval [CI], -0.1 to 0.5; P = 0.15). AAMR increased for men throughout the study period compared with women (AAPC, 0.7 for men; 95% CI, 0.3 to 1.2; P = 0.004 vs. AAPC, -0.4 for women; 95% CI, -1.1 to 0.3; P = 0.23, respectively). Similarly, AAMR for pulmonary embolism increased for Black compared with White individuals, from 5.18 to 5.26 (AAPC, 0.4; 95% CI, 0.0 to 0.7; P = 0.05) and 2.82 to 2.86 (AAPC, 0.0; 95% CI, -0.6 to 0.6; P = 0.99), respectively. Similarly, AAMR for pulmonary embolism was higher in rural areas than in micropolitan and large metropolitan areas during the study period (4.07 [95% CI, 4.02 to 4.12] vs. 3.24 [95% CI, 3.21 to 3.27] vs. 2.32 [95% CI, 2.30-2.34], respectively). Conclusions: Pulmonary embolism mortality remains high and unchanged over the past decade, and enduring sex, racial and socioeconomic disparities persist in pulmonary embolism. Targeted efforts to decrease pulmonary embolism mortality and address such disparities are needed.


An Enhancement of Deep Learning Algorithm for Brain Tumor Segmentation Using Kernel Based CNN with M-SVM.
The brain tumor can be created by uncontrollable increase of abnormal cells in tissue of brain and it has two kinds of tumors: one is benign and another one is malignant tumor. The benign brain tumor does not affect the adjacent normal and healthy tissue but the malignant tumor can affect the neighboring tissues of brain that can lead to the death of person. An early detection of brain tumor can be required to protect the survival of patients. Usually, the brain tumor is detected using MRI scanning method. However, the radiologists are not providing the effective tumor segmentation in MRI image due to the irregular shape of tumors and position of tumor in the brain. Accurate brain tumor segmentation is needed to locate the tumor and it is used to give the correct treatment for a patient and it provides the key to the doctor who must execute the surgery for patient. In this paper, a novel deep learning algorithm (kernel based CNN) with M-SVM is presented to segment the tumor automatically and efficiently. This presented work contains several steps that are preprocessing, feature extraction, image classification and tumor segmentation of brain. The MRI image is smoothed and enhanced by Laplacian of Gaussian filtering method (LoG) with Contrast Limited Adaptive Histrogram Equalization (CLAHE) and feature can be extracted from it based on tumor shape position, shape and surface features in brain. Consequently, the image classification is done using M-SVM depending on the selected features. From MRI image, the tumor is segmented with help of kernel based CNN method.. Experimental results of proposed method can show that this presented technique can executes brain tumor segmentation accurately reaching almost 84% in evaluation with existing algorithms.


Effect of partially purified human somatomedin on human fetal and postnatal cartilage in vitro.
Partly purified somatomedin prepared from adult human plasma stimulated [3H]thymidine and [35S]sulphate uptake into human cartilage. At a final concentration of 0.1 U/ml somatomedin the uptake of [3H]thymidine into fetal cartilage at 18 weeks of gestation was 162 +/- 23% compared with controls. Somatomedin also increased the incorporation of [35S]sulphate into fetal cartilage to 137 +/- 22% at 18 weeks compared to controls. The same concentration of somatomedin (0.1 U/ml) also increased the incorporation of [3H]thymidine into postnatal articular cartilage to 239 +/- 69% and [35S]sulphate to 133 +/- 28% compared to controls. Human somatomedin prepared from adult plasma thus has a mitogenic effect on both fetal and postnatal cartilage. The smaller effect on fetal cartilage may reflect different forms of somatomedin and/or differences in receptors for somatomedins on adult and fetal chondrocytes.


Effect of Ice Slush on Reducing the Oculocardiac Reflex During Strabismus Surgery.
The aim of this study was to explore whether ice slush (IS) causing local hypothermia can effectively inhibit the oculocardiac reflex (OCR) during strabismus surgery. This prospective, randomized, double-blind study included 58 patients with concomitant strabismus scheduled for lateral rectus (LR) recession under general anesthesia. Patients were randomly allocated to receive IS (IS group) or standard treatment (control group) with sterile saline at room temperature before surgery. OCR was defined as a sudden decrease in heart rate (HR) of >15% from baseline. If one incidence of the OCR was found in 1 patient in any stage (0/I/II/III), the patient was defined as an OCR responder, and the incidence of overall OCR was the incidence of OCR responders. The primary outcome was the incidence of overall OCR during all stages of the surgery, which was analyzed by the Z test and computed based on the absolute risk difference with 2-sided 95% confidence intervals (CIs) using the Newcombe method. The overall OCR occurred in 19 of 29 patients (62.5% [95% CI, 45.7-82.1]) in the IS group and 28 of 29 patients (96.6% [95% CI, 82.2-99.9]) in the control group (absolute risk difference, -31.0% [95% CI, -49.4 to -11.0]; Z test, P < .001), which demonstrated that the incidence of overall OCR in IS group was significantly lower than that in the control group. IS on the ocular surface causing local hypothermia is a promising and easily accessible method to reduce the overall OCR, which can improve the safety of strabismus surgery.


Complications and Accuracy of Computed Tomography-guided Transthoracic Needle Biopsy in Patients Over 80 Years of Age.
The purpose of this study was to evaluate the complications and diagnostic accuracy of computed tomography-guided percutaneous transthoracic needle biopsy (PTNB) in patients aged 80 years and older. Consecutive PTNB procedures performed in an academic institution between July 2009 and June 2013 were reviewed. Procedures were performed according to a standard protocol using conscious sedation and rapid on-site pathology evaluation. Patient demographics, lesion characteristics, complications, and final tissue diagnosis were reviewed. Patients below 80 years of age and over 80 years were compared using binary logistic regression. Of 894 biopsies, 141 (16%) were performed on patients over 80 years of age. Comparison of patients over and below 80 years of age did not differ significantly with regard to lesion size and morphology (P=0.663 and 0.453, respectively), and diagnostic accuracy (P=0.268). Pneumothorax rates were 23% versus 24% (P=0.682), and chest tube insertion was required in 2% of both groups (P=0.924). Hemoptysis rates were 3% versus 2% (P=0.376). PTNB is a safe and accurate procedure in patients aged 80 years and older. Complications and diagnostic accuracy are similar to those observed in younger patients.


Targeted temperature management after cardiac arrest is associated with reduced metabolism of pantoprazole - A probe drug of CYP2C19 metabolism.
Targeted temperature management (TTM) is part of standard post-resuscitation care. TTM may downregulate cytochrome enzyme activity and thus impact drug metabolism. This study compared the pharmacokinetics (PK) of pantoprazole, a probe drug of CYP2C19-dependent metabolism, at different stages of TTM following cardiac arrest. This prospective controlled study was performed at the Medical University of Vienna and enrolled 16 patients following cardiac arrest. The patients completed up to three study periods (each lasting 24 h) in which plasma concentrations of pantoprazole were quantified: (P1) hypothermia (33 °C) after admission, (P2) normothermia after rewarming (36 °C, intensive care), and (P3) normothermia during recovery (normal ward, control group). PK was analysed using non-compartmental analysis and nonlinear mixed-effects modelling. 16 patients completed periods P1 and P2; ten completed P3. The median half-life of pantoprazole was 2.4 h (quartiles: 1.8-4.8 h) in P1, 2.8 h (2.1-6.8 h, p = 0.046 vs. P1, p = 0.005 vs. P3) in P2 and 1.2 h (0.9 - 2.3 h, p = 0.007 vs. P1) in P3. A two-compartment model described the PK data best. Typical values for clearance were estimated separately for each study period, indicating 40% and 29% reductions during P1 and P2, respectively, compared to P3. The central volume of distribution was estimated separately for P2, indicating a 64% increase compared to P1 and P3. CYP2C19-dependent drug metabolism is downregulated during TTM following cardiac arrest. These results may influence drug choice and dosing of similarly metabolized drugs and may be helpful for designing studies in similar clinical situations.


Long-term (>5-year) survivors among unresectable or metastatic cancer patients treated with zoledronate-activated killer cells: Seven case reports.
We are conducting an adoptive immunotherapy (AIT) trial using zoledronate-activated killer cells for patients in Japan with incurable cancer. We have encountered seven long-term survivors. Since such long survival may be very rare in cancer treatment, we present the details and a discussion of a possible role of AIT.


An artificial intelligence-accelerated 2-minute multi-shot echo planar imaging protocol for comprehensive high-quality clinical brain imaging.
We introduce and validate an artificial intelligence (AI)-accelerated multi-shot echo-planar imaging (msEPI)-based method that provides T1w, T2w, T2∗ , T2-FLAIR, and DWI images with high SNR, high tissue contrast, low specific absorption rates (SAR), and minimal distortion in 2 minutes. The rapid imaging technique combines a novel machine learning (ML) scheme to limit g-factor noise amplification and improve SNR, a magnetization transfer preparation module to provide clinically desirable contrast, and high per-shot EPI undersampling factors to reduce distortion. The ML training and image reconstruction incorporates a tunable parameter for controlling the level of denoising/smoothness. The performance of the reconstruction method is evaluated across various acceleration factors, contrasts, and SNR conditions. The 2-minute protocol is directly compared to a 10-minute clinical reference protocol through deployment in a clinical setting, where five representative cases with pathology are examined. Optimization of custom msEPI sequences and protocols was performed to balance acquisition efficiency and image quality compared to the five-fold longer clinical reference. Training data from 16 healthy subjects across multiple contrasts and orientations were used to produce ML networks at various acceleration levels. The flexibility of the ML reconstruction was demonstrated across SNR levels, and an optimized regularization was determined through radiological review. Network generalization toward novel pathology, unobserved during training, was illustrated in five clinical case studies with clinical reference images provided for comparison. The rapid 2-minute msEPI-based protocol with tunable ML reconstruction allows for advantageous trade-offs between acquisition speed, SNR, and tissue contrast when compared to the five-fold slower standard clinical reference exam.


Methods for detecting non-randomness in species co-occurrences: a contribution.
Comparison of co-occurrences between species on a group of islands with those expected from a randombased null model could provide evidence on community structure. However, it is difficult to decide on the appropriate null model. Gilpin and Diamond proposed a model and a test for departure from it, but this test is shown to indicate significant structure even when applied to a matrix of random numbers. An alternative method is suggested, using the distribution of Gilpin and Diamond's deviation as test statistic, but determining the expected distribution by Monto Carlo simulation, and using many such simulations as a randomisation test of significance. The null model used accepts the observed totals of occurrences for islands and species; it therefore offers a somewhat conservative test. Applied to the Vanuatu bird data that Gilpin and Diamond used, significant departure from a null model is seen, but with an excess of extreme negative associations, the opposite result from that given by Gilpin and Diamond's method. It is not possible to tell whether the negative associations are due to autecology, biogeography, or to interactions between species.


Defining the contribution of select neuropeptides and their receptors in regulating sesquiterpenoid biosynthesis by Drosophila melanogaster ring gland/corpus allatum through RNAi analysis.
The larval ring gland and adult corpus allatum (CA) of Drosophila melanogaster produce at least three sesquiterpenoid products: methyl farnesoate (MF), juvenile hormone III (JHIII), and JHIII bisepoxide (JHB(3)). Our understanding of neuropeptide regulation of sesquiterpenoid biosynthesis in D. melanogaster has been hampered by uncertainty over the biosynthetic pathway and the sites of action of regulators. As an approach to defining the neuropeptide regulators, we have used in vivo gene-specific silencing (RNAi). D. melanogaster strains containing an inducible UAS-RNAi construct made to either PheGlyLeu-NH(2)-allatostatin (FGLa/AST) and its cognate receptors Dar-1 and Dar-2 or PISCF-allatostatin (PISCF/AST) or its cognate receptors Drostar-1 or Drostar-2 were expressed in vivo. MF, JHIII and JHB(3) production was measured in ring glands of 3rd instars or corpora allata (CA) of adult females using the radiochemical assay. Reduction in FGLa/AST and Dar-1 or Dar-2 mRNA levels had no effect on MF, JHIII, or JHB(3) production in larvae or adults. Inhibition of Drostar-1 expression resulted in a significant decrease in MF and JHB(3) production in 3rd instars with little effect on JHIII biosynthesis. In contrast, inhibition of Drostar-1 in adult females led to a significant increase in MF and JHIII production. Inhibition of Drostar-2 also reduced MF biosynthesis in 3rd instars. In adults, inhibition of Drostar-2 led to a significant increase in MF and JHIII production but showed no effect on JHB(3). PISCF/AST had no effect on sesquiterpenoid biosynthesis when incubated with 3rd instar ring glands but was stimulatory when incubated with adult glands. Inhibition of short neuropeptide F (sNPF) expression by RNAi or application of sNPF to ring glands had no effect on MF, JHIII, or JHB3 biosynthesis in larvae or adults. Reduction in the neuropeptide Y receptor (NepYr) or neuropeptide F receptor (NPF-R) inhibited JHIII and JHB(3) production in 3rd instars but only reduction in NepYr resulted in JHB(3) reduction in adults.


Glutathione peroxidase-1 and neuromodulation: Novel potentials of an old enzyme.
Glutathione peroxidase (GPx) acts in co-ordination with other signaling molecules to exert its own antioxidant role. We have demonstrated the protective effects of GPx,/GPx-1, a selenium-dependent enzyme, on various neurodegenerative disorders (i.e., Parkinson's disease, Alzheimer's disease, cerebral ischemia, and convulsive disorders). In addition, we summarized the recent findings indicating that GPx-1 might play a role as a neuromodulator in neuropsychiatric conditions, such as, stress, bipolar disorder, schizophrenia, and drug intoxication. In this review, we attempted to highlight the mechanistic scenarios mediated by the GPx/GPx-1 gene in impacting these neurodegenerative and neuropsychiatric disorders, and hope to provide new insights on the therapeutic interventions against these disorders.


Utilization and Complications of Catheter Ablation for Atrial Fibrillation in Patients With Hypertrophic Cardiomyopathy.
Background Atrial fibrillation (AF) is common and bears a major clinical impact in patients with hypertrophic cardiomyopathy (HCM). We aimed to investigate the use and real-world safety of catheter ablation for AF in patients with HCM. Methods and Results We drew data from the US National Inpatient Sample to identify cases of AF ablation in HCM patients between 2003 and 2015. Sociodemographic and clinical data were collected, and incidence of catheter ablation complications, mortality, and length of stay were analyzed, including trends between the early (2003-2008) and later (2009-2015) study years. Among a weighted total of 1563 catheter ablation cases in patients with HCM, the median age was 62 (interquartile range, 52-72), 832 (53.2%) were male, and 1150 (73.6%) were white. The average annual volume of AF ablations in patients with HCM doubled between the early and the later study period (79-156). At least 1 complication occurred in 16.1% of cases, and the in-hospital mortality rate was 1%. Cardiac and pericardial complications declined from 8.8% to 2.3% and from 2.8% to 0.9%, respectively, between the early and the later study years (P<0.01). Independent predictors of complications included female sex (odds ratio [OR], 4.81; 95% CI, 2.72-8.51), diabetes mellitus (OR, 6.57; 95% CI, 2.68-16.09) and obesity (OR, 3.82; 95% CI, 1.61-9.06). Conclusions Despite some decline in procedural complications over the years, catheter ablation for AF is still associated with a relatively high periprocedural morbidity and even mortality in patients with HCM. This emphasizes the importance of careful clinical consideration, by an experienced electrophysiologist, in referring patients with HCM for an AF ablation.


Cystadenocarcinoma of the rete testis.
We report a rare case of primary adenocarcinoma of the rete testis. The stage A lesion was managed successfully with orchiectomy and retroperitoneal lymph node dissection. The histopathological features, treatment and prognosis of this unusual malignancy are reviewed.


The effect of subcutaneous administration of delta sleep-inducing peptide (DSIP) on some parameters of sleep in the cat.
Delta sleep inducing peptide (DSIP) significantly increases deep-slow-wave sleep (DSWS) of cats after subcutaneous (SC) injection. Cats (n = 8) were SC injected with DSIP (120 nmol.kg-1) prior to polygraphic recording of EEG combined with electro-oculography, EOG) and electromyography (EMG) for 8 hours. DSIP was found to significantly increase slow-waves (delta sleep) in the sleep EEG. There was a tendency to reduced waking time and a prolongation of slow wave sleep time, and a shortening of sleep onset and REM sleep latencies but the differences from control (Ringer injection) were not statistically significant. There was no change in the amount of REM sleep. These findings support the belief that DSIP can increase sleep wave activity when administered by peripheral route.


Occult nodal metastasis in head and neck carcinoma patients treated with chemoradiotherapy.
Neck lymph node metastasis plays an important role in the prognosis of patients with squamous cell carcinoma of the head and neck. The aim of this study was to evaluate the occult nodal metastasis in patients with head and neck squamous cell carcinoma (HNSCC) treated with chemo radiotherapy. In this 5-year prospective study, patients with recurrent head and neck squamous cell carcinomas (HN-SCC) after primary treatment with chemoradiotherapy or radiotherapy that candidate for surgery were enrolled. In total, 50 patients with squamous cell carcinomas of the head and neck with N0 neck were included in the study. Age, initial location of recurrent tumor, T staging in primary and recurrent tumors, neck condition (N0 or N+), and pathology report for neck metastasis, number of affected lymph nodes and duration of tumor recurrence were examined. Out of 50 patients with mean age of 57.04 ± 14.4 years, 13 were female (26%) and 37 (74%) were male. In terms of primary tumor size, 52% (26 patients) were in T2 stage. The primary and recurrent tumor was located in the oral cavity in 33 patients (66%). Nine 0f 50 patients (18%) had occult metastases. It seems that END surgery is necessary for treatment the occult lymph node neck metastasis of recurrent head and neck cancers with N0 neck. Therefore, it is possible that END surgery has reduced cervical recurrence in these patients.


Audiovisual Presentations on a Handheld PC are Preferred As an Educational Tool by NICU Parents.
Health literacy is critical for understanding complex medical problems and necessary for the well being of the patient. Printed educational materials (PM) have limitations in explaining the dynamics of a disease process. Multimedia formats may be useful for enhancing the educational process. To evaluate whether a printed format or animation with commentary on a handheld personal computer (PC) is preferred as an educational tool by parents of a baby in the NICU. PARENTS EVALUATED TWO FORMATS: A 1-page illustrated document from the American Heart Association explaining patent ductus arteriosus (PDA) and animation with commentary on a handheld PC that explained the physiology of PDA in 1 minute. The reading grade level of the PM was 8.6 versus 18.6 for the audio portion of the animated presentation. Parents viewed each format and completed a four-item questionnaire. Parents rated both formats and indicated their preference as printed, animation, or both. Forty-six parents participated in the survey. Parents preferred animation over PM (50% vs. 17.4%. p = 0.02); 39.1% expressed that the animation was excellent; whereas 4.3% expressed that the PM was excellent (p<0.001). The order of presentation of formats, sex, age, and educational level of parents did not influence the method preferred (p>0.05). Parents preferred animation on a small screen handheld PC despite a much higher language level. Because handheld PCs are portable and inexpensive, they can be used effectively at the bedside with low-cost animation to enhance understanding of complex disease conditions.


Effects of aerobic training on markers of autophagy in the elderly.
Autophagy is a molecular process essential for the maintenance of cellular homeostasis, which appears to (i) decline with age and (ii) respond to physical exercise. In addition, recent evidence suggests a crosstalk between autophagy and toll-like receptor (TLR)-associated inflammatory responses. This study assessed the effects of aerobic exercise training on autophagy and TLR signaling in older subjects. Twenty-nine healthy women and men (age, 69.7 ± 1.0 year) were randomized to a training (TG) or a control (CG) group. TG performed an 8-week aerobic training program, while CG followed their daily routines. Peripheral blood mononuclear cells were isolated from blood samples obtained before and after the intervention, and protein levels of protein 1 light chain 3 (LC3), sequestosome 1 (p62/SQSTM1), beclin-1, phosphorylated unc-51-like kinase (ULK-1), ubiquitin-like autophagy-related (Atg)12, Atg16, and lysosome-associated membrane protein (LAMP)-2 were measured. TLR2 and TLR4 signaling pathways were also analyzed. Peak oxygen uptake increased in TG after the intervention. Protein expression of beclin-1, Atg12, Atg16, and the LC3II/I ratio increased following the training program (p < 0.05), while expression of p62/SQSTM1 and phosphorylation of ULK-1 at Ser(757) were lower (p < 0.05). Protein content of TLR2, TLR4, myeloid differentiation primary response gen 88 (MyD88), and TIR domain-containing adaptor-inducing interferon (TRIF) were not significantly modified by exercise. The current data indicate that aerobic exercise training induces alterations in multiple markers of autophagy, which seem to be unrelated to changes in TLR2 and TLR4 signaling pathways. These results expand knowledge on exercise-induced autophagy adaptations in humans and suggest that the exercise type employed may be a key factor explaining the potential relationship between autophagy and TLR pathways.


Are contrast-enhanced and non-contrast MRI findings reflecting synovial inflammation in knee osteoarthritis: a meta-analysis of observational studies.
To determine the correlation between knee synovitis assessed on contrast-enhanced (CE) and non-contrast enhanced (NCE) magnetic resonance imaging (MRI) with histology in patients with knee osteoarthritis. A comprehensive literature search was performed, and related articles published through July 2018 were extracted. Spearman correlation coefficients of MRI-based scores with histology reports were pooled using random effects model. To evaluate presence of publication bias, Egger test was performed. Of 2377 identified records, eight studies consisting of 246 MRI exams were included. Two studies reported results of dynamic CE (DCE)-MRI examinations (81 knees) and two studies reported results of NCE-MRI. There were moderate positive correlations between CE-MRI scores and macroscopic (r = 0.53 (95% Confidence Interval (CI):0.37-0.66), P < 0.001) as well as microscopic (r = 0.56 (0.39-0.69), P < 0.001) histology. DCE-MRI were strongly correlated (r = 0.71 (0.58-0.80), P-value<0.001), with microscopic histology reports, while the correlation for NCE-MRI was low positive (r = 0.44 (0.20-0.63), P < 0.001). Meta-regression analysis showed that pooled correlation coefficients of DCE-MRI were significantly higher than CE-MRI (Slope = 0.29, SE = 0.13, P-value = 0.02). CE-MRI were also correlated with inflammatory infiltrate (r = 0.42), while the correlations for cell number of synovial lining (r = 0.27) and level of fibrosis (r = 0.29, P < 0.001) were very low. Static and dynamic CE-MRI evaluation of knee synovitis were positively correlated with macroscopic and microscopic features of synovial membrane inflammation. Among the features of synovial tissue inflammation, CE-MRI scores correlated best with the inflammatory infiltrates of synovial tissue. Paucity of current evidence warrants further studies to assess performance of NCE-MRI on determining knee synovitis.


Smad1/Smad5 signaling in limb ectoderm functions redundantly and is required for interdigital programmed cell death.
Bone morphogenetic proteins (BMPs) are secreted signals that regulate apical ectodermal ridge (AER) functions and interdigital programmed cell death (PCD) of developing limb. However the identities of the intracellular mediators of these signals are unknown. To investigate the role of Smad proteins in BMP-regulated AER functions in limb development, we inactivated Smad1 and Smad5 selectively in AER and ventral ectoderm of developing limb, using Smad1 or/and Smad5 floxed alleles and an En1(Cre/+) knock-in allele. Single inactivation of either Smad1 or Smad5 did not result in limb abnormalities. However, the Smad1/Smad5 double mutants exhibited syndactyly due to a reduction in interdigital PCD and an increase in interdigital cell proliferation. Cell tracing experiments in the Smad1/Smad5 double mutants showed that ventral ectoderm became thicker and the descendents of ventral En1(Cre/+) expressing ectodermal cells were located at dorsal interdigital regions. At the molecular level, Fgf8 expression was prolonged in the interdigital ectoderm of embryonic day (E) 13 Smad1/Smad5 double mutants, suggesting that the ectopic Fgf8 expression may serve as a survival signal for interdigital epithelial and mesenchymal cells. Our result suggests that Smad1 and Smad5 are required and function redundantly as intracellular mediators for BMP signaling in the AER and ventral ectoderm. Smad1/Smad5 signaling in the AER and ventral ectoderm regulates interdigital tissue regression of developing limb. Our mutants with defects in interdigital PCD could also serve as a valuable model for investigation of PCD regulation machinery.


Forced expression of the non-coding RNA miR-17∼92 restores activation and function in CD28-deficient CD4+ T cells.
CD28 provides the prototypical costimulatory signal required for productive T-cell activation. Known molecular consequences of CD28 costimulation are mostly based on studies of protein signaling molecules. The microRNA cluster miR-17∼92 is induced by T cell receptor stimulation and further enhanced by combined CD28 costimulation. We demonstrate that transgenic miR-17∼92 cell-intrinsically largely overcomes defects caused by CD28 deficiency. Combining genetics, transcriptomics, bioinformatics, and biochemical miRNA:mRNA interaction maps we empirically validate miR-17∼92 target genes that include several negative regulators of T cell activation. CD28-deficient T cells exhibit derepressed miR-17∼92 target genes during activation. CRISPR/Cas9-mediated ablation of the miR-17∼92 targets Pten and Nrbp1 in naive CD28-/- CD4+ T cells differentially increases proliferation and expression of the activation markers CD25 and CD44, respectively. Thus, we propose that miR-17∼92 constitutes a central mediator for T cell activation, integrating signals by the TCR and CD28 costimulation by dampening multiple brakes that prevent T cell activation.


Remediation of contaminants from wastewater using algal nanoparticles via green chemistry approach: an organized review.
Bio-nanotechnology is one of the new and sound techniques that have various advantages over conventional methods of wastewater treatment. The utilization of nanomaterials like nanoparticles for wastewater treatment is emerging field of research. Both physical and chemical methods can be used for nanoparticle synthesis, but synthesis based on algae (biological method) has numerous advantages over others as it is environmentally friendly and sustainable. Top-down and bottom-up are the two approaches used for nanoparticle synthesis, generally, bio-reduction (bottom-up approach) is used to synthesize nanoparticles. Nanoparticles can be synthesized inside the cell of algae called intracellular synthesis and outside on the surface of the cell called extracellular synthesis. Temperature, pH, and reaction time are some of the factors that can influence the synthesis, size, and properties of nanoparticles. Characterization of nanoparticles is carried out with the help of the techniques like UV-visible spectroscopy (UV-vis), x-ray diffraction, Fourier transfer infrared spectroscopy, etc. Algal nanoparticles are highly efficient in the remediation of contaminants like heavy metals and dyes from wastewater. In the present review, the utilization of algal nanoparticles for wastewater treatment containing contaminants like heavy metals, and dye, and various methods of synthesis of nanoparticles from algae are discussed. Moreover, the challenges and opportunities present in this field are also highlighted. As this field is in its initial stage, therefore, a lot of research gaps are present, which can only be filled by further new research.


Fourier transform infrared (FT-IR) study on cyanide induced biochemical and structural changes in rat sperm.
In the recent years, great attention had been focused on cyanide toxicity because of its widespread use in industries and considered to be a ubiquitous pollutant in the environment. Therefore, the current study aimed to evaluate the toxic effect of cyanide on rat sperms at molecular level by using FT-IR technique. For this purpose, rats were randomly divided into four groups and treated with 0.0, 0.64, 1.2 and 3.2 mg kg-1 body weight (BW) for the period of 90 days. The group treated with lower dose (0.64 mg kg-1 BW) showed an insignificant change in all the peaks, except the peaks assigned to olefinic [bond, double bond]C-H, CH2 asymmetric and CH2 symmetric stretching vibration in the lipids. While, the groups treated with higher doses (1.2 and 3.2 mg kg-1 BW) showed the significant decrease in the area under the peaks corresponds to different bio-molecules. In addition, spectral second derivative analysis showed the significant alteration in α-helix, turns, β-sheet, aggregated β-sheet and random coil structures in the proteins. In conclusion, the selected higher dosage of cyanide had caused significant decrease in the biochemical composition of rat sperms along with structural changes in the proteins. The FT-IR technique is an excellent tool used for the analysis of oxidative damage in the sperms.


Synergistic reinforcing and cross-linking effect of thiol-ene-modified cellulose nanofibrils on natural rubber.
To achieve synergistic reinforcing and cross-linking effect across interface between hydrophilic nanocellulose and hydrophobic rubber, active thiol groups were introduced at reducing end of CNF while retaining hydroxyl groups on the surface, thus forming a percolation network in nanocomposites. The nanocomposites were obtained by casting/evaporating a mixture of dispersed modified CNF and NR in latex form, in which covalent cross-links were formed between thiol groups and double bonds of NR via photochemically initiated thiol-ene reaction. Strong interfacial interaction between NR matrix and end-modified CNF was characterized by Fourier-transform infrared spectroscopy. The structural and mechanical properties of the nanocomposites were evaluated by scanning electron microscopy, dynamic mechanical analysis and tensile tests. Compared to neat NR, the nanocomposite reinforced with 10 wt% modified CNF showed significantly higher values of tensile strength (0.33 to 5.83 MPa), Young's modulus (0.48 to 45.25 MPa) and toughness (2.63 to 22.24 MJ m-3).


Influence of salinity and temperature on the survival and settlement of Heliopora coerulea larvae.
Recurrent thermal stress events and intensified precipitation alter the ocean environment resulting in the decline of coral populations. However, the influence of these changes on larval survival and settlement is not well understood. We examined the effect of salinity (15, 20, 25, 30, 35, and 40 ppt) and temperature (27 °C, 30 °C, and 33 °C) on settlement and survival of larvae of the octocoral, Heliopora coerulea. Larvae settled successfully at salinities from 25 to 30 ppt. On the other hand, larval survival and settlement decreased with increasing temperature. A combination of 25-35 ppt and 27-30 °C resulted in highest survival and settlement. These results indicate that early life stages of H. coerulea are negatively impacted by thermal stress but may be able to survive at reduced salinity. The wider tolerance range of H. coerulea larvae compared to most scleractinian larvae may thus contribute to the success of this coral on disturbed reef ecosystems.


[New oral antidiabetic agents--clinical perspectives].
In recent years new pharmacological agents have emerged, which enable us to widen the spectrum of diabetes management based on clear pathophysiological concepts. One should first of all mention the DPP4-inhibitors and the incretin mimetics, which have the potential of restoring the incretin effect in patients with type 2 diabetes mellitus. Moreover, it has been shown that the agent rimonabant, which was first used in order to achieve weight reduction, also contributed to the significant improvement of metabolic syndrome's parameters. Recent studies have shown that the dual alpha/gamma-PPAR-agonists have serious adverse effects. The thiazolidinediones (glitazones) significantly improve insulin sensitivity, diminish fat accumulation in the liver and increase circulating levels of adiponectin. Various adverse effects of glitazones have been described in recent studies. In the near future one should await the discovery of more oral antidiabetic agents acting through modulation of important enzymes in glucose metabolism and transport pathways.


Synthesis and characterization of conformationally rigid chiral pyridine-N-heterocyclic carbene-based palladacycles with an unexpected Pd-N bond cleavage.
The versatility of a previously developed method for the synthesis of chiral carbene-based palladacycles is demonstrated through the synthesis of two new chiral pyridine-functionalized N-heterocyclic carbene palladacycles with different wingtip groups. The efficiency in their resolution with different counter anions and different chiral amino acid salt auxiliaries has been studied. The absolute stereochemistries of all the chiral compounds were confirmed by single crystal X-ray crystallography. An unexpected Pd-N bond cleavage that resulted in the racemization of the α-carbon center in these complexes has also been investigated.


Integration of databases for radiotherapy outcomes analyses.
The technical nature of radiotherapy requires different data collection strategies for outcomes reporting than those required for most other disciplines in clinical medicine. To correlate advances in radiotherapy technology with treatment outcomes, it is necessary to integrate a given radiotherapy outcomes-study database with the record-and-verify database and with the global hospital database. The authors review the recent development of each of these categories of databases from the vantage point of radiotherapy. Their goal was to integrate these 3 databases for outcomes analyses in radiotherapy at their institution; this process involved (1) the construction of an interface between the record-and-verify database and the outcomes-study database and (2) the use of a bioinformatics database linking the outcomes-study database and the global hospital database. This bioinformatics database was successfully queried in a manner that allowed streamlining data flow of relevance to radiotherapy outcomes studies. Future directions of the application of this integration are discussed.


Effect of insulin analog initiation therapy on LDL/HDL subfraction profile and HDL associated enzymes in type 2 diabetic patients.
Insulin treatment can lead to good glycemic control and result in improvement of lipid parameters in type 2 diabetic patients. This study was designed to evaluate the effect of insulin analog initiation therapy on low-density lipoprotein (LDL)/ high-density lipoprotein (HDL) sub-fractions and HDL associated enzymes in type 2 diabetic patients during early phase. Twenty four type 2 diabetic patients with glycosylated hemoglobin (HbA1c) levels above 10% despite ongoing combination therapy with sulphonylurea and metformin were selected. Former treatment regimen was continued for the first day followed by substitution of sulphonylurea therapy with different insulin analogs (0.4 U/kg/day) plus metformin. Glycemic profiles were determined over 72 hours by continuous glucose monitoring system (CGMS) and blood samples were obtained from all patients at 24 and 72 hours. Plasma levels of cholesteryl ester transfer protein (CETP), lecithin-cholesterol acyltransferase (LCAT), apolipoprotein B (apoB) and apolipoprotein A-1 (apoA-I) were determined by enzyme-linked immunosorbent assay (ELISA). Measurement of CETP and LCAT activity was performed via fluorometric analysis. Paraoxonase (PON1) enzyme activity was assessed from the rate of enzymatic hydrolysis of phenyl acetate to phenol formation. LDL and HDL subfraction analysis was done by continuous disc polyacrylamide gel electrophoresis. Mean blood glucose, total cholesterol (TC), triglyceride (TG) and very low-density lipoprotein cholesterol (VLDL-C) levels were significantly decreased while HDL-C levels were significantly increased after insulin treatment. Although LDL-C levels were not significantly different before and after insulin initiation therapy a significant increase in LDL-1 subgroup and a significant reduction in atherogenic LDL-3 and LDL-4 subgroups were observed. Insulin analog initiation therapy caused a significant increase in HDL-large, HDL- intermediate and a significant reduction in HDL-small subfractions. CETP protein level and activity was significantly increased while apoB levels were significantly decreased following insulin analog initiation therapy. No significant difference was found in LCAT mass, LCAT activity, apoA-I and PON-1 arylesterase levels following insulin initiation therapy. These findings indicate that insulin analog initiation therapy activates lipid metabolism via up-regulating CETP and shows anti-atherogenic effects by increasing HDL-large and decreasing LDL-3 and LDL-4 subfractions in a short time period.


HEY1-mediated cisplatin resistance in lung adenocarcinoma via epithelial-mesenchymal transition.
Lung cancer is one of the most common malignancies and the leading cause of cancer-related death in the world. In patients with advanced lung adenocarcinoma who are negative for driver gene mutations, platinum-based chemotherapy represented by cisplatin remain the standard of care. Therefore, studying the mechanism behind inevitable cisplatin resistance in lung adenocarcinoma is still important. In this study, the potentially related differential expression gene for cisplatin resistance in lung adenocarcinoma was screened in the GEO database. The expression level of HEY1 in cell lines of lung adenocarcinoma was detected and HEY1 expression was up-regulated in cisplatin-resistant lung adenocarcinoma tissues and cell lines A549/DDP. Patients with high HEY1 expression have poor prognosis after cisplatin therapy. Gain and loss function assays uncovered that HEY1 could regulate the cisplatin sensitivity of NSCLC cells. In vivo experiments have confirmed that silence of HEY1 expression can induce cisplatin resistance, and epithelial-mesenchymal transition (EMT) changes occur during this process. Mechanically, HEY1 silencing significantly up-regulated E-cadherin expression and down-regulated Vimentin in A549/DDP cells. While up-regulation of HEY1 resulted in down-regulation of E-cadherin and up-regulation of Vimentin in A549 cells. Immunohistochemical experiments confirmed that E-cadherin was significantly decreased, and Vimentin expression was significantly up-regulated in cisplatin-resistant lung adenocarcinoma tissues. HEY1 can mediate the occurrence of cisplatin-acquired resistance in lung adenocarcinoma, and the possible mechanism is to regulate the EMT. The results of this study can provide a new direction and target for clinical research on the reversal of cisplatin resistance in lung adenocarcinoma.


Loosening of paranodal myelin by repetitive propagation of action potentials.
We have previously shown by X-ray diffraction techniques that the stability of the myelin lattice is decreased by repetitive stimulation of the nerve. We now show that in rat myelinated fibres this structural change is accompanied by the appearance of voltage-sensitive potassium channels which do not normally participate in the generation of the action potential. Since it has previously been shown that structures associated with potassium channels are found in the internodal and paranodal axolemma membrane but are normally concealed under the myelin sheath, we suggest that the acceleration of myelin swelling after repetitive propagation of the action potential may be due to the opening of paranodal axoglial junctions. To our knowledge this is the first demonstration that nerve activity may regulate the structural properties of the paranode.


Troponin Revealed: Uncovering the Structure of the Thin Filament On-Off Switch in Striated Muscle.
Recently, our understanding of the structural basis of troponin-tropomyosin's Ca2+-triggered regulation of striated muscle contraction has advanced greatly, particularly via cryo-electron microscopy data. Compelling atomic models of troponin-tropomyosin-actin were published for both apo- and Ca2+-saturated states of the cardiac thin filament. Subsequent electron microscopy and computational analyses have supported and further elaborated the findings. Per cryo-electron microscopy, each troponin is highly extended and contacts both tropomyosin strands, which lie on opposite sides of the actin filament. In the apo-state characteristic of relaxed muscle, troponin and tropomyosin hinder strong myosin-actin binding in several different ways, apparently barricading the actin more substantially than does tropomyosin alone. The troponin core domain, the C-terminal third of TnI, and tropomyosin under the influence of a 64-residue helix of TnT located at the overlap of adjacent tropomyosins are all in positions that would hinder strong myosin binding to actin. In the Ca2+-saturated state, the TnI C-terminus dissociates from actin and binds in part to TnC; the core domain pivots significantly; the N-lobe of TnC binds specifically to actin and tropomyosin; and tropomyosin rotates partially away from myosin's binding site on actin. At the overlap domain, Ca2+ causes much less tropomyosin movement, so a more inhibitory orientation persists. In the myosin-saturated state of the thin filament, there is a large additional shift in tropomyosin, with molecular interactions now identified between tropomyosin and both actin and myosin. A new era has arrived for investigation of the thin filament and for functional understandings that increasingly accommodate the recent structural results.


Tuberculosis and nature's pharmacy of putative anti-tuberculosis agents.
Due to the growing problem of drug resistant Mycobacterium tuberculosis strains, coupled with the twinning of tuberculosis (TB) to human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS), the burden of TB is now difficult to manage. Therefore, new antimycobacterial agents are being sought from natural sources. This review focuses on natural antimycobacterial agents from endophytes and medicinal plants of Africa, Europe, Asia, South America and Canada. In the countries mentioned in this review, numerous plant species display putative anti-TB activity. Several antimycobacterial chemical compounds have also been isolated, including: ellagitannin punicalagin, allicin, anthraquinone glycosides, iridoids, phenylpropanoids, beta-sitosterol, galanthimine, crinine, friedelin, gallic acid, ellagic acids, anthocyanidin, taraxerol, termilignan B, arjunic acid, glucopyranosides, 1-epicatechol, leucopelargonidol, hydroxybenzoic acids, benzophenanthridine alkaloids, neolignans, and decarine. These compounds may provide leads to novel and more efficacious drugs to lessen the global burden of TB and drug-resistant M. tuberculosis strains. If there is a long-term remedy for TB, it must lie in nature's pharmacy of putative antimycobacterial agents.


Growth and characterisation of a cell culture model of the feline blood-brain barrier.
An in vitro model of the feline blood-brain barrier was developed using primary cultures of brain capillary endothelial cells derived from adult cats. They were grown in the presence of astrocytes obtained from newborn kittens. Feline endothelial cell cultures were characterised by uptake of DiI-acetylated low-density lipoprotein (DiI-Ac-LDL) and expression of von Willebrand factor. Astrocytes were characterised based on their expression of glial fibrillary acidic protein (GFAP). Electron microscopy revealed junctional specialisation between endothelial cells. Occludin and ZO-1 expression by the endothelial cell cultures was detected by Western blot analysis. Barrier function of co-cultured endothelial cells and astrocytes was confirmed by a transendothelial electrical resistance (TEER) value of 30-35 Omegacm2 and apparent permeability coefficients (Papp) for FD-40 (FITC-dextran, 40 kDa) of 4x10(-6) cm/s and for FD-4 (4kDa) of 1.92x10(-5) cm/s. In endothelial cell monolayers grown with astrocyte-conditioned medium, the TEER value was lower (20-25 Omegacm2), and Papp of FD-40 and FD-4 was higher at 6.27x10(-6) and 3.96x10(-5) cm/s, respectively. This model should have useful applications in the examination of events occurring at the BBB early in FIV infection, and may provide knowledge applicable to HIV infection.


Cingulate cortex in the three limbic subsystems.
Broca's (1878) definition of the limbic lobe referred to its being located at the edge of the cerebral cortex, and Papez (1937) and MacLean (1990) welded a series of medial surface structures into what we now know as the limbic system. The last four decades of research have provided a wealth of detailed information on the connectivity and functions of the limbic system and one can only conclude that it is not a uniform and single system. The cingulate cortex itself has three major divisions: anterior primarily for emotion, middle mainly for response selection and feedback-guided decision making, and posterior/retrosplenial cortices for visuospatial orientation and assessing the self-relevance of objects and events. Each of these divisions has a different cytoarchitecture and set of connections. The cingulate observations lead to a new framework of limbic organization: three limbic subsystems that include the amygdala, orbitofrontal cortex, the insula, the hippocampus, and, of course, the cingulate cortex. This concept is expanded in terms of connectivity among them and the underlying functions of each subsystem. The three limbic subsystems considered here are the "anterior emotional subsystem," the "middle sensorimotor subsystem," and the "posterior cognitive spatial map subsystem" for localizing personally relevant objects and episodes. A defining characteristic of the anterior emotional subsystem is its input from the amygdala. Another interesting outcome of this analysis is that the middle hippocampus and anterior midcingulate cortex share a role in approach-avoidance decision making suggesting a potential for connectional synergy. Thus, the concept of "a" limbic system needs radical revision to accommodate a minimum of three limbic subsystems. As this approach was initiated by the three-part composition of the cingulate cortex, a finer-grain analysis of the cingulate region shows that six limbic subsystems may be a more accurate reflection of limbic organization.


Incidence of infectious diseases after earthquakes: a systematic review and meta-analysis.
Evaluation of the incidence of infectious diseases after natural disasters can help develop healthcare policies. This study provides a global review of the most prevalent infectious diseases observed after earthquakes. A systematic review and meta-analysis were performed. A systematic review was performed on electronic databases, including PubMed, Scopus and Web of Science, up to March 2020 (with no time limitations). Studies addressing earthquakes and infectious diseases were collected based on specified inclusion and exclusion criteria. Subsequently, the quality of the studies was assessed by the Newcastle-Ottawa scale (NOS). Data analyses were carried out on six subgroups under five different disease categories using comprehensive meta-analysis software. In total, 24 studies qualified for the systematic review and 18 were included in the meta-analysis. The incidences of gastrointestinal infections, dermal infections, respiratory infections, central nervous system infections and other infectious diseases were as follows: odds ratio (OR) 163.4 (95% confidence interval [CI]: 31.0-858.1), OR 84.5 (95% CI: 27.1-262.8), OR 9.9 (95% CI: 3.5-27.7), OR 0.5 (95% CI: 0.2-1.1) and OR 4.4 (95% CI: 1.9-9.9) cases per 100,000 people, respectively. The association between the incidences of infectious diseases before and after earthquakes was significant, namely, 1.561 (95% CI: 1.244-1.957) with a P-value <0.001. The results show an increase in the prevalence of infectious diseases after earthquakes. Governments should take essential measures to be better prepared for such unpredictable catastrophes.