Reasons behind non-adherence of healthcare practitioners to pediatric asthma guidelines in an emergency department in Saudi Arabia.
The prevalence of childhood bronchial asthma in Saudi Arabia has increased in less than a decade from 8% to 23%. Innovations in the management of asthma led to the development of evidence based clinical practice guidelines and protocols to improve the patients' outcomes. The objectives of this study are to examine the compliance of the healthcare providers in the Pediatrics Emergency Department, in King Khalid University Hospital, with the recommendations of the Pediatrics Asthma Management Protocol (PAMP), and to explore the reasons behind non-adherence. This study is designed in 2 parts, a patients' chart review and a focus group interview. The medical records of all the children who presented to the Pediatric Emergency Department (PED) and were diagnosed as asthmatic, during the period from the 1st of January 2009 to the 31st of March 2009, were reviewed to investigate the compliance of healthcare providers (physicians and nurses) with 8 recommendations of the PAMP which are considered to be frequently encountered evidence-practice gaps, and these are 1) documentation of asthma severity grading by the treating physician and nurse 2) limiting the prescription of Ipratropium for children with severe asthma 3) administration of Salbutamol through an inhaler and a spacer 4) documentation of parental education 5) prescription of systemic corticosteroids to all cases of acute asthma 6) limiting chest x-ray requisition for children with suspected chest infection 7) management of all cases of asthma as outpatients, unless diagnosed as severe or life threatening asthma 8) limiting prescription of antibiotics to children with chest infection. The second part of this study is a focus group interview designed to elicit the reasons behind non-adherence to the recommendations detected by the chart review. Two separate focus group interviews were conducted for 10 physicians and 10 nurses. The focus group interviews were tape-recorded and transcribed verbatim. Theory-based content analysis was used to analyze interviews into themes and sub-themes. A total of 657 charts were reviewed. The percentage of adherence by the healthcare providers to the 8 previously mentioned recommendations was established. There was non-adherence to the first 5 of the 8 aforementioned recommendations. Analysis of the focus group interview revealed 3 main themes as reasons behind non-compliance to the 5 recommendations mentioned above and those are 1) factors related to the organization, 2) factors related to the asthma management protocol 3) factors related to healthcare providers. The organizational barriers and the lack of an implementation strategy for the protocol, in addition to the attitude and beliefs of the healthcare providers, are the main factors behind non-compliance to the PAMP recommendations.


The Hospital Medicine Reengineering Network (HOMERuN): a learning organization focused on improving hospital care.
Converting the health care delivery system into a learning organization is a key strategy for improving health outcomes. Although the collaborative learning organization approach has been successful in neonatal intensive care units and disease-specific collaboratives, there are few examples in general medicine and none in adult medicine that have leveraged the role of hospitalists nationally across multiple institutions to implement improvements. The authors describe the rationale for and early work of the Hospital Medicine Reengineering Network (HOMERuN), a collaborative of hospitals, hospitalists, and multidisciplinary care teams founded in 2011 that seeks to measure, benchmark, and improve the efficiency, quality, and outcomes of care in the hospital and afterwards. Robust and timely evaluation, with learning and refinement of approaches across institutions, should accelerate improvement efforts. The authors review HOMERuN's collaborative model, which focuses on a community-based participatory approach modified to include hospital-based staff as well as the larger community. HOMERuN's initial project is described, focusing on care transition measurement using perspectives from the patient, caregiver, and providers. Next steps and sustainability of the organization are discussed, including benchmarking, collaboration, and effective dissemination of best practices to stakeholders.


Antimicrobial Synergy Testing: Comparing the Tobramycin and Ceftazidime Gradient Diffusion Methodology Used in Assessing Synergy in Cystic Fibrosis-Derived Multidrug-Resistant Pseudomonas aeruginosa.
The need for synergy testing is driven by the necessity to extend the antimicrobial spectrum, reducing drug dosage/toxicity and the development of resistance. Despite the abundance of synergy testing methods, there is the absence of a gold standard and a lack of synergy correlation among methods. The most popular method (checkerboard) is labor-intensive and is not practical for clinical use. Most clinical laboratories use several gradient synergy methods which are quicker/easier to use. This study sought to evaluate three gradient synergy methods (direct overlay, cross, MIC:MIC ratio) with the checkerboard, and compare two interpretative criteria (the fractional inhibitory concentration index (FICI) and susceptibility breakpoint index (SBPI)) regarding these methods. We tested 70 multidrug-resistant Pseudomonas aeruginosa, using a tobramycin and ceftazidime combination. The agreement between the checkerboard and gradient methods was 60 to 77% for FICI, while agreements for SBPI that ranged between 67 and 82.86% were statistically significant (p ≤ 0.001). High kappa agreements were observed using SBPI (Ƙ > 0.356) compared to FICI (Ƙ < 0.291) criteria, and the MIC:MIC method demonstrated the highest, albeit moderate, intraclass correlation coefficient (ICC = 0.542) estimate. Isolate resistance profiles suggest method-dependent synergism for isolates, with ceftazidime susceptibility after increased exposure. The results show that when interpretative criteria are considered, gradient diffusion (especially MIC:MIC) is a valuable and practical method that can inform the treatment of cystic fibrosis patients who are chronically infected with P. aeruginosa.


Microanatomical localization of dopamine receptor protein immunoreactivity in the rat cerebellar cortex.
Dopamine (DA) receptor subtype localization was investigated in rat cerebellar cortex using immunohistochemical techniques with antibodies raised against D1-D5 receptor protein. A faint D1 receptor protein immunoreactivity was developed in molecular and Purkinje neurons layers. D2 receptor protein immunoreactivity was found primarily in cerebellar white matter followed by molecular and granular layers and Purkinje neurons. Antibodies against D2S receptor protein were localized in molecular layer and to a lesser extent, in granular layer. A few Purkinje neurons displayed a faint D2S receptor protein immunoreactivity. D3 receptor protein immunoreactivity was observed primarily in molecular and in Purkinje neurons layers of lobules 9 and 10. A faint D3 receptor protein immunoreactivity was also localized in Purkinje neurons and to a lesser extent, in molecular and granular layers of cerebellar lobules 1-8. D4 receptor protein immunoreactivity was found in cerebellar white matter. A pale immunostaining was also visualized in molecular layer. D5 receptor protein immunoreactivity was localized primarily in molecular and Purkinje neurons layers and to a lesser extent, in granular layer and in white matter. The above results indicate that rat cerebellar cortex expresses the DA receptor subtypes so far identified. Purkinje neurons, which are the only efferent neurons of cerebellum, are richest in DA receptor protein immunoreactivity. This suggests that dopaminergic neurotransmission may modulate efferent inputs from cerebellum. The localization of the majority of D2 and D4 and of a faint D5 protein receptor immunoreactivity in cerebellar white matter suggests that these receptors may be presynaptic and transported axonally.


Phantom gastric mucosa for evaluating computed radiography in double-constrast upper gastrointestinal examinations.
To test the clinical usefulness of computed radiography (CR) with a storage phosphor plate in upper gastrointestinal radiographic examinations, a newly devised phantom gastric mucosa was used. Simulated small elevated and depressed lesions were created on a phantom gastric mucosa made from a styrofoam "plate". Twenty-four sets of each CR and screen-film radiographs (SR) were obtained using phototimed exposures. Receiver operating characteristic (ROC) study and visual ranking using these images were performed. There was no significant difference between the ROC curves of CR and SR. By visual ranking, CR was equal to or better than SR in most cases. In no case was SR definitely superior to CR. CR can be safely applied to upper gastrointestinal roentgenologic examinations.


[Unexplained fever after exposure to rats: rat bite fever or Haverhill fever].
A 24-year old man presented himself to the emergency ward with complaints of fever, nausea, headache, muscle ache and chest pain. Two weeks before presentation he had been bitten by a pet rat. We determined that he had bacteraemia caused by a Streptobacillus moniliformis infection, which led to the development of an illness called rat bite fever. S. moniliformis is a pleomorphic gram-negative rod-shaped bacterium that is considered part of the normal nasopharyngeal flora in rats. It is the cause of two similar illnesses: rat bite fever and Haverhill fever. Clinicians should consider these infections in the work-up of unexplained fever or sepsis, certainly in the presence of known exposure to rats. Treatment consists of antibiotics.


Meteorological effects on adult mosquito (Culex) populations in metropolitan New Jersey.
For two metropolitan New Jersey counties, monthly average adult mosquito (Culex) catch from New Jersey light trap data sets covering multiple decades is related to a number of meteorological factors. From June through August climatological conditions accounted for between 40% and 50% of the variation in average catch. In general, high monthly precipitation totals both in the month corresponding to the catch and the previous month were associated with increased trap catch. However, individual heavy rainfall events tended to reduce catch. Warm temperatures exerted a positive influence on mosquito abundance in June, but were associated with a low catch in August. Linear meteorological relationships explained only a small percentage of the variations in mosquito catch during May and September. During July, and particularly August, antecedent monthly catch also explained a significant portion of the variance in the contemporaneous catch. Over 60% of the variability in August catch could be attributed to the July population.


Peripheral neuroblastic tumors and congenital heart disease. Possible role of hypoxic states in tumor induction.
Peripheral neuroblastic tumors (PNT), including neuroblastomas, pheochromocytomas, ganglioneuromas, and paragangliomas, have been reported in association with congenital heart disease (CHD). If a significant correlation between PNT and CHD could be demonstrated, it would suggest that peripheral neuroblastic tumors might represent reactive, secondary phenomena rather than independent or incidental events. We examined this question by reviewing the autopsy files of The Johns Hopkins Hospital and found that the frequency of congenital cardiovascular problems among patients with PNT was significantly greater than the frequency of CHD in the general autopsy population (p less than 0.001). There was no correlation between CHD and central neuroblastic tumors (CNT), i.e., medulloblastomas, retinoblastomas, or pinealoblastomas, or between CHD and metastatic malignant melanoma. We examined the hypothesis that erythropoietic activity, as might be stimulated by hypoxia, was correlated with the presence of peripheral neuroblastic tumors. We found that most (87%) cardiac malformations associated with PNT produced cyanosis, and histologic assessment of hematopoiesis revealed greater activity in patients with PNT (with or without CHD) compared to those with CNT (p less than 0.05) or malignant melanoma (p less than 0.05). In addition, patients with PNT and CHD had higher frequencies of extramedullary hematopoiesis compared to age-matched controls with similar congenital heart defects (p less than 0.05), and compared to patients with CNT or metastatic malignant melanoma (p less than 0.01). These results suggest that peripheral neuroblastic tumors may arise in a setting of chronic hypoxia produced by congenital heart disease.


Expression levels of elastin and related genes in human varicose veins.
Among the suspected reasons for varicose vein formation are changes in the quantity and content of the elastin protein; however, comprehensive investigations about elastin assembly in varicose vein formation are yet lacking. In this study, we aimed to determine the changes in mRNA levels of elastin and some of its functionally related proteins, fibulin 5, LOXL-1, MMP-2 and MMP-9 in varicose vein formation. We analysed the mRNA levels of elastin, fibulin-5, LOXL1, MMP2 and MMP9 in samples of 35 healthy and 35 varicose great saphenous vein tissues. mRNA levels of these genes were determined by using real-time PCR and normalized with HPRT1. When we compared the patient and control groups, elastin mRNA levels were significantly higher in the patient group than in the control group (P = 0.047), although there were no significant differences in fibulin 5, LOXL1, MMP2 and MMP9 mRNA levels between the patient and control groups. We showed that up-regulation of MMP2 mRNA expression was significantly correlated with hyperlipidaemia (P = 0.029). The up-regulation of elastin expression may play an important role in the pathogenesis of primary varicose veins. Additionally, the up-regulation of MMP2 expression was strongly correlated with hyperlipidaemia in varicose veins.


Neurite, a finite difference large scale parallel program for the simulation of electrical signal propagation in neurites under mechanical loading.
With the growing body of research on traumatic brain injury and spinal cord injury, computational neuroscience has recently focused its modeling efforts on neuronal functional deficits following mechanical loading. However, in most of these efforts, cell damage is generally only characterized by purely mechanistic criteria, functions of quantities such as stress, strain or their corresponding rates. The modeling of functional deficits in neurites as a consequence of macroscopic mechanical insults has been rarely explored. In particular, a quantitative mechanically based model of electrophysiological impairment in neuronal cells, Neurite, has only very recently been proposed. In this paper, we present the implementation details of this model: a finite difference parallel program for simulating electrical signal propagation along neurites under mechanical loading. Following the application of a macroscopic strain at a given strain rate produced by a mechanical insult, Neurite is able to simulate the resulting neuronal electrical signal propagation, and thus the corresponding functional deficits. The simulation of the coupled mechanical and electrophysiological behaviors requires computational expensive calculations that increase in complexity as the network of the simulated cells grows. The solvers implemented in Neurite--explicit and implicit--were therefore parallelized using graphics processing units in order to reduce the burden of the simulation costs of large scale scenarios. Cable Theory and Hodgkin-Huxley models were implemented to account for the electrophysiological passive and active regions of a neurite, respectively, whereas a coupled mechanical model accounting for the neurite mechanical behavior within its surrounding medium was adopted as a link between electrophysiology and mechanics. This paper provides the details of the parallel implementation of Neurite, along with three different application examples: a long myelinated axon, a segmented dendritic tree, and a damaged axon. The capabilities of the program to deal with large scale scenarios, segmented neuronal structures, and functional deficits under mechanical loading are specifically highlighted.


Evaluation of Automated Teleretinal Screening Program for Diabetic Retinopathy.
Diabetic retinopathy is a leading cause of blindness, but its detrimental effects are preventable with early detection and treatment. Screening for diabetic retinopathy has the potential to increase the number of cases treated early, especially in populations with limited access to care. To determine the efficacy of an automated algorithm in interpreting screening ophthalmoscopic photographs from patients with diabetes compared with a reading center interpretation. Retrospective cohort analysis of 15,015 patients with type 1 or 2 diabetes in the Harris Health System in Harris County, Texas, who had undergone a retinal screening examination and nonmydriatic fundus photography via the Intelligent Retinal Imaging System (IRIS) from June 2013 to April 2014 were included. The IRIS-based interpretations were compared with manual interpretation. The IRIS algorithm population statistics were calculated. Sensitivity and false-negative rate of the IRIS computer-based algorithm compared with reading center interpretation of the same images. A total of 15 015 consecutive patients (aged 18-98 years); mean 54.3 years with known type 1 or 2 diabetes underwent nonmydriatic fundus photography for a diabetic retinopathy screening examination. The sensitivity of the IRIS algorithm in detecting sight-threatening diabetic eye disease compared with the reading center interpretation was 66.4% (95% CI, 62.8%-69.9%) with a false-negative rate of 2%. The specificity was 72.8% (95% CI, 72.0%-73.5%). In a population where 15.8% of people with diabetes have sight-threatening diabetic eye disease, the IRIS algorithm positive predictive value was 10.8% (95% CI, 9.6%-11.9%) and the negative predictive value was 97.8% (95% CI, 96.8%-98.6%). In this large urban setting, the IRIS computer algorithm-based screening program had a high sensitivity and a low false-negative rate, suggesting that it may be an effective alternative to conventional reading center image interpretation. The IRIS algorithm shows promise as a screening program, but algorithm refinement is needed to achieve better performance. Further studies of patient safety, cost-effectiveness, and widespread applications of this type of algorithm should be pursued to better understand the role of teleretinal imaging and automated analysis in the global health care system.


The effect of multimorbidity on the gap between global and age-comparative self-rated health scores among the Korean elderly.
Most of the behavior change models regard perceived health status as a motivation for healthy behaviors or chronic disease self-management. The aim of this study was to examine the association between the number of chronic diseases and the difference between global and age-comparative self-rated health scores (GSRH and ASRH). We used national representative survey data pertaining to the elderly in 2011 from the Korea Institute for Health and Social Affairs. In total, 10,003 participants (≥60 years old) were selected from those who had completed the survey in 2008. Multinomial logistic regression was used to estimate relative risk ratios (RRR) with 95% confidence intervals. Demographic factors, socioeconomic status, social connection, and healthy life style were adjusted. Individuals with many chronic diseases were more likely to have a positive gap, resulting in a better ASRH score relative to GSRH (p for trend <0.001): 1-2 diseases (RRR = 1.30, 95% CI = 1.07-1.57), 3-4 diseases (RRR = 1.90, 95% CI = 1.55-2.32), and ≥5 diseases (RRR = 1.75, 95% CI = 1.39-2.20). In addition, the association between the number of chronic diseases and a positive gap varied by sex and living area. Our results suggest that a positive gap between GSRH and ASRH that indicates an overestimated age-comparative health, was associated with the number of chronic diseases. Female or urban-living people had stronger associations. Further research is needed to understand how the gap between GSRH and ASRH could be an alternative measure of SRH and a predictor of major health outcomes.


Actin binding and proteolysis by the baculovirus AcMNPV: the role of virion-associated V-CATH.
Infection of larvae by Autographa californica M nuclear polyhedrosis virus (AcMNPV) results in liquefaction of susceptible hosts, presumably due to the breakdown of cells and extracellular matrices. In Spodoptera frugiperda tissue culture cells, infection leads to dramatic rearrangement and eventual destruction of the actin cytoskeleton. The first of these rearrangements is the formation of actin cables in the cytoplasm of the cell. Cable formation requires release of the budded virus (BV) nucleocapsid from the endosome, but does not require new protein synthesis, suggesting that the nucleocapsid contains the activity necessary to induce cable formation. We have identified two distinct BV-associated actin-targeting activities. The first, a nucleocapsid-associated actin-binding activity, enabled actin copelleting and may also induce actin polymerization and cable formation. The second activity, associated with the nucleocapsid and envelope fractions of BV, was a protease that specifically degraded actin. This protease was identified as V-CATH, a cathepsin L-like protease that is a product of the AcMNPV v-cath gene.


Transfer Learning-based Seizure Detection on Multiple Channels of Paediatric EEGs.
Epilepsy is a common neurological disease characterised by recurring seizures that affect up to 70 million people worldwide. During the first ten years of life, approximately one in every 150 children is diagnosed with epilepsy. EEG is an important tool for diagnosing seizures and other brain disorders. However, expert visual analysis of EEGs is time-consuming. In addition to reducing expert annotation time, the automatic seizure detection method is a powerful tool for assisting experts with the analysis of EEGs. Research on the automated detection of seizures in pediatric EEG has been limited. Deep learning algorithms are typically used in paediatric seizure detection methods; however, they are computationally expensive and take a long time to develop. This problem can be solved using transfer learning. In this study, we developed a transfer learning-based seizure detection method on multiple channels of paediatric EEGs. The publicly available CHB-MIT EEG dataset was used to build our method. The dataset was split into training (n=14), validation (n=4), and testing (n=6). Spectrograms generated from 10 s EEG signals with 5 s overlap were used as the input into three pre-trained transfer learning models (ResNet50, VGG16 and InceptionV3). We took care to separate the children into either the training or test set to ensure that the test set was independent. Based on the EEG test set, the method has 85.41% accuracy, 85.94% recall, and 85.49% precision. This method has the potential to assist researchers and clinicians in the automated analysis of seizures in paediatric EEGs.


Baseline micronuclei frequency in children: estimates from meta- and pooled analyses.
The number of studies evaluating the effect of environmental exposure to genotoxic agents in children has rapidly increased in the last few years. The frequency of micronuclei (MN) in peripheral blood lymphocytes determined with the cytokinesis block assay is among the most popular biomarkers used for this purpose, although large inter- and intralaboratory variability of this end point has been observed in population studies. The availability of reference measures is therefore necessary for laboratories to validate protocols and analytical procedures, and for molecular epidemiologists, as well, to estimate the statistical power of studies and to assess the quality of data. In this article, we provide estimates of the baseline frequency of MN in children, conducting a meta-analysis of MN frequency reported by field studies in children and a pooled analysis of individual data [available from published studies and from the Human Micronucleus International Collaborative Study (HUMN) database]. Thirteen articles were selected for meta-analysis, and individual data included in the pooled analysis were retrieved from the databases of 12 laboratories. Overall means of 4.48 [95% confidence interval (CI), 3.35-5.98] and 5.70 (95% CI, 4.29-7.56) MN per 1,000 binucleated cells were estimated by the meta- and pooled analysis, respectively. A clear effect of age was detected, even within the restricted range of pediatric age considered, with significantly lower frequency values in newborns. No influence of sex was found. The study showed the advantage of using data from large collaborative studies and suggested a synergistic use of meta- and pooled analysis.


Inhomogeneities in the chemical structure of sugarcane bagasse lignin.
Sequential treatments of dewaxed bagasse with distilled water, 0.5 M NaOH, 0.5, 1.0, 1.5, 2.0, and 3.0% H(2)O(2) at pH 11.5, and 2 M NaOH at 55 degrees C for 2 h solubilized 2.8, 52.5, 14.9, 3.3, 5.5, 5.0, 2.8, and 2.2% of the original lignin, respectively. The eight isolated lignin fractions were subjected to a comprehensive structural characterization by UV, FT-IR, and (1)H and (13)C NMR spectroscopies and thermal analysis. The nitrobenzene oxidation method was also applied to the in situ lignins. The seven lignin fractions, isolated successively with alkali and alkaline peroxide, were all SGH-type lignins, with a small amount of esterified p-coumaric acid and mainly etherified ferulic acid. No significant differences were found in the weight-average molecular weights (1680-2220 g/mol) of the seven alkali and alkaline peroxide dissolved lignins. However, the first four lignin fractions, isolated with 0.5 M NaOH and 0.5, 1.0, and 1.5% H(2)O(2) at pH 11.5, were rich in syringyl units and contained large amounts of noncondensed ether structures, whereas the last three lignin fractions, isolated sequentially with 2.0 and 3.0% H(2)O(2) at pH 11.5 and 2 M NaOH at 55 degrees C for 2 h, had a higher degree on condensation and were rich in guaiacyl lignins.


Oxytocin in Huntington's disease and the spectrum of amyotrophic lateral sclerosis-frontotemporal dementia.
Neurodegenerative disorders (NDDs) such as Huntington's disease (HD) and the spectrum of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are characterized by progressive loss of selectively vulnerable populations of neurons. Although often associated with motor impairments, these NDDs share several commonalities in early symptoms and signs that extend beyond motor dysfunction. These include impairments in social cognition and psychiatric symptoms. Oxytocin (OXT) is a neuropeptide known to play a pivotal role in the regulation of social cognition as well as in emotional behaviors such as anxiety and depression. Here, we present an overview of key results implicating OXT in the pathology of HD, ALS and FTD and seek to identify commonalities across these NDDs. OXT is produced in the hypothalamus, a region in the brain that during the past decade has been shown to be affected in HD, ALS, and FTD. Several studies using human post-mortem neuropathological analyses, measurements of cerebrospinal fluid, experimental treatments with OXT as well as genetic animal models have collectively implicated an important role of central OXT in the development of altered social cognition and psychiatric features across these diseases. Understanding central OXT signaling may unveil the underlying mechanisms of early signs of the social cognitive impairment and the psychiatric features in NDDs. It is therefore possible that OXT might have potential therapeutic value for early disease intervention and better symptomatic treatment in NDDs.


Primitive erythropoiesis is regulated by Smad-dependent signaling in postgastrulation mesoderm.
The bone morphogenetic proteins (BMPs) are required for the development of ventral mesoderm, which contributes to the ventral blood island and primitive (yolk sac stage) hematopoiesis. Primitive erythropoiesis is defective when BMP signaling is blocked during gastrulation of Xenopus embryos. This phenotype might be attributed to changes in mesoderm patterning leading indirectly to altered erythropoiesis. We developed an inducible system in order to block BMP signaling in a controlled fashion at later time points in development. For this purpose, an inhibitory Smad, xSmad6, was fused to the estrogen receptor ligand-binding domain. We show that ER-xSmad6 is inactive when expressed in developing embryos, but its activity is induced by estradiol. When induced early in development, ER-xSmad6 causes a dorsalized phenotype, equivalent to overexpression of native xSmad6. When ER-xSmad6 is induced after gastrulation, there is a specific defect in primitive erythropoiesis without any apparent effect on axial patterning. Our results identify an embryonic signal that is Smad-dependent, is required for maintaining expression of GATA-1, and functions within mesoderm and not the overlying ectoderm. Thus, BMP signaling is necessary both during mesoderm patterning and also following early specification events for proper regulation of the primitive erythroid lineage.


Effect of cabergoline on insulin sensitivity, inflammation, and carotid intima media thickness in patients with prolactinoma.
The aim of this study was to evaluate the effect of Cabergoline on insulin sensitivity, inflammatory markers, and carotid intima media thickness in prolactinoma patients. Twenty-one female, newly diagnosed patients with prolactinoma were included in the study. None of the patients were treated previously. Cabergoline was given as treatment, starting with 0.5 mg/day and tapered necessarily. Blood samples were taken for prolactin, highly sensitive C-reactive protein, homocysteine, total cholesterol, low density lipoprotein (LDL) cholesterol, fasting glucose, insulin, and HOMA (homeostasis model assessment of insulin resistance) score was calculated, prior to and 6 months after starting treatment. The body mass index (BMI) was measured and carotid intima media thickness (CIMT) was evaluated for each patient prior to and 6 months after the treatment. The prolactin levels and LDL decreased significantly after cabergoline treatment. Insulin sensitivity improved independently from the decrease in prolactin levels and BMI. The significant decrease in homocysteine and hs-CRP was not related with the decrease in prolactin levels. The significant decrease in CIMT was independent from the decrease in prolactin levels, HOMA score, and BMI. Our data suggest that cabergoline treatment causes an improvement in insulin sensitivity and inflammatory markers and causes a decrease in CIMT independent from the decrease in prolactin, LDL cholesterol, and BMI. We conclude that short term cabergoline treatment can improve endothelial function independently from the changes in metabolic disturbances and inflammatory markers.


Actions to influence the care network of home-dwelling elderly people: A qualitative study.
Positive impact of care networks of home-dwelling elderly people may be based on several network mechanisms: navigation to resources, negotiation between participants and contagion of behaviours. Little is known about actions of participants-elderly people, informal caregivers or formal care providers-to activate such mechanisms and generate support. Aim of this study was to identify actions in relation to these network mechanisms. A cross-sectional qualitative study of 48 interviews with home-dwelling elderly people, informal caregivers and formal care providers in the eastern parts of the Netherlands was conducted between March and September 2016. A framework analysis on network mechanisms categorised actions. Actions were reviewed by network party and compared between networks to explore relations between actions and networks. Results showed that participants navigated through existing relations to seek support. Actions on negotiation were aimed at ameliorating existing relations. Few examples and no actions on contagion of behaviours were found. Actions seemed driven by incidents and existing relations. Elderly people rarely initiated actions, informal caregivers felt hampered by their position in the network. Consistent patterns of relations between actions and network characteristics did not emerge. We concluded that the full potential of network-based support of elderly people is probably underused. Particularly promising seem: navigating the neighbourhood for new informal care, using opposite opinions as a catalyst for change and bringing quality of life and dilemma's into dialogue in the network.


Device-related infection among patients with pacemakers and implantable defibrillators: incidence, risk factors, and consequences.
Device-related infection is a major limitation of device therapy for cardiac arrhythmia. The authors analyzed the incidence and risk factors for cardiac device infection (CDI) among consecutive patients implanted with pacemaker (PM) or implantable cardioverter defibrillator (ICD) (including cardiac resynchronization therapy devices) at a tertiary health center in Hamilton, Ontario, Canada. Most patients with device-related infections were identified by an internal infection control system that reports any positive wound and blood cultures following surgery, between 2005 and the present. A retrospective review of patient records was also performed for all patients who received an ICD or PM between July 1, 2003 and March 20, 2007. A total of 24 infections were identified among 2,417 patients having device surgery (1%). Fifteen of these infections (60%) were diagnosed within 90 days of the last surgical procedure. Univariate analysis showed that patients presenting with CDI were more likely to have had a device replacement, rather than a new implant, had more complex devices (dual/triple chamber vs single), and were more likely to have had a prior lead dislodgement. Multivariate analysis found device replacement (P = 0.02) and cardiac resynchronization therapy (CRT)/dual-chamber devices (P = 0.048) to be independent predictors of infection. One patient developed septic pulmonary emboli after having laser-assisted lead extraction. No patient died and 22 patients received a new device. CDI occurs in about 1% of cases in high volume facilities. Pulse generator replacement surgery and dual- or triple-chamber device implantation were associated with a significantly increased risk of infection.


Evidence of different cell populations in the mouse thymus releasing and responding to mitogenic factor.
The thymocyte population of mice treated with cortisone was examined at various times with respect to its relative capacity to be triggered to DNA synthesis by soluble phytomitogens or mitogenic factors (MF) released by lymph node cells exposed to phytomitogens. The capacity of the thymocyte population to produce MF in response to phytomitogen exposure was also examined. We found that the relative blastogenic activity of both phytomitogens and MF on thymocytes increased as the cell number of the thymus was reduced by the cortisone treatment. However, the reactivity to phytomitogens increased to a higher extent. During the subsequent regeneration of the organ the stimulability of the cells by phytomitogen decreased far below that of MF. The relative capacity of thymocytes to produce MF seemed to parallel their phytomitogen reactivities. One possible explanation of the results is that there exists one subpopulation of cells in the thymus more responsive to phytomitogens than to MF and another more responsive to MF than to phytomitogen. It is possible that the cells that are phytomitogen-responsive are those that can produce MF.


Onset of Kleine-Levin Syndrome in association with isotretinoin treatment.
The synthetic retinoid isotretinoin is an effective treatment option for severe forms of acne vulgaris. However, several reports indicate that some patients experience altered central nervous system functions in association with treatment. We present here the first description of the onset of Kleine-Levin Syndrome (KLS), a rare disorder characterised by periodic hypersomnia and cognitive and behavioural symptoms, in close temporal relation to the start of isotretinoin treatment. We also discuss the biological potential of retinoids to affect sleep. In light of a documented potential of retinoids to modulate sleep-wake regulation, the present case suggests that isotretinoin may rarely trigger the onset of KLS.


Designing and evaluating an interprofessional shared decision-making and goal-setting decision aid for patients with diabetes in clinical care--systematic decision aid development and study protocol.
Care of patients with diabetes often occurs in the context of other chronic illness. Competing disease priorities and competing patient-physician priorities present challenges in the provision of care for the complex patient. Guideline implementation interventions to date do not acknowledge these intricacies of clinical practice. As a result, patients and providers are left overwhelmed and paralyzed by the sheer volume of recommendations and tasks. An individualized approach to the patient with diabetes and multiple comorbid conditions using shared decision-making (SDM) and goal setting has been advocated as a patient-centred approach that may facilitate prioritization of treatment options. Furthermore, incorporating interprofessional integration into practice may overcome barriers to implementation. However, these strategies have not been taken up extensively in clinical practice. To systematically develop and test an interprofessional SDM and goal-setting toolkit for patients with diabetes and other chronic diseases, following the Knowledge to Action framework. 1. Feasibility study: Individual interviews with primary care physicians, nurses, dietitians, pharmacists, and patients with diabetes will be conducted, exploring their experiences with shared decision-making and priority-setting, including facilitators and barriers, the relevance of a decision aid and toolkit for priority-setting, and how best to integrate it into practice.2. Toolkit development: Based on this data, an evidence-based multi-component SDM toolkit will be developed. The toolkit will be reviewed by content experts (primary care, endocrinology, geriatricians, nurses, dietitians, pharmacists, patients) for accuracy and comprehensiveness.3. Heuristic evaluation: A human factors engineer will review the toolkit and identify, list and categorize usability issues by severity.4. Usability testing: This will be done using cognitive task analysis.5. Iterative refinement: Throughout the development process, the toolkit will be refined through several iterative cycles of feedback and redesign. Interprofessional shared decision-making regarding priority-setting with the use of a decision aid toolkit may help prioritize care of individuals with multiple comorbid conditions. Adhering to principles of user-centered design, we will develop and refine a toolkit to assess the feasibility of this approach.


Near-confocal cavity-enhanced Raman spectroscopy for multitrace-gas detection.
Simultaneous detection of multitrace gas is still a challenge. Near-confocal cavity-enhanced Raman spectroscopy is proposed and demonstrated for simultaneous detection of multitrace gas. With a 200 mW incident laser, the excitation power of >9 W forms at two foci of the near-confocal cavity owing to the beam being reflected 50 times. High-power excitation light greatly enhances the detection sensitivity of the Raman system. Using this cavity-enhancing technique, high-sensitivity detection of the mixture of eight gases with same volume ratio has been achieved. This technique may be applied for detecting multitrace gas in many areas.


Health decisions amidst controversy: Prenatal alcohol consumption and the unequal experience of influence and control in networks.
Individuals avoid stigma by looking to members of their networks for guidance on how to behave. Health controversies complicate this process by exposing people to inconsistent norms, influence, and control within their networks. To understand this process, we meld perspectives on networks and social psychology. Using the case of light/moderate drinking during pregnancy, we examine how people make health decisions in the face of controversy. Through in-depth interviews with first-time pregnant individuals and their health care providers, we reveal that individuals' decisions about controversial health behaviors depend on 1) the consistency of the influence and control they encounter, 2) their status relative to enforcers, and 3) the strength of their ties to enforcers. These processes give people from higher social positions more power to resist influence and control. These findings illuminate how medical recommendations and public health interventions should account for the unequal experience of influence and control within networks.


Prevalence and correlates of concussion in children: Data from the Adolescent Brain Cognitive Development study.
Concussions are one of the most common causes for emergency room use in the United States (US) among youth and adolescents; however, prevalence data on concussion in this population are inconsistent. A growing body of literature has explored associations of a range of variables with pediatric concussion, but they have not been explored simultaneously in a well-powered sample in the US. The present study aimed to present lifetime concussion prevalence, evaluate demographic, psychological, and cognitive correlates of concussion, and assess for differences across these variables based on age of first concussion in a large sample of US children. We analyzed the Adolescent Brain Cognitive Development (ABCD) sample, which monitors biopsychosocial development in 11,875 children at 21 sites across the US between ages 9 and 10. Along with presenting rates of concussion, we also evaluated the association of demographics, sleep disturbance, cognitive functioning, and externalizing and internalizing symptoms with concussion history using backwards binary logistic regression. We further conducted univariate comparisons of all variables between those who experienced their first concussion before and after age 5. Significance was based on α = .02, with Benjamini-Hochberg FDR adjustments for multiple comparisons. We found approximately 4% of the sample had experienced a concussion, and significant correlates of experiencing a concussion were male sex, increased family income, and higher somatic symptoms after FDR correction. Symptoms of ADHD were also noted as nominally significant. No differences based on age of first concussion were found. Our analyses provided updated prevalence estimates of pediatric concussion in the US that aligns with many hospital records-based studies. Our findings largely mirrored those in the literature with the exception of somatic symptoms. Limitations of findings and implications of individual findings are discussed.


Molecular basis for the effects of zinc deficiency on spermatogenesis: An experimental study in the Sprague-dawley rat model.
The objective of this study is to investigate the molecular mechanisms underlying the effects of zinc deficiency on spermatogenesis in the Sprague-Dawley (SD) rat. Three groups of eight adult male SD rats were maintained for 4 weeks on a normal diet as control, zinc deficient diet and zinc deficient diet with zinc supplementation of 28 mg zinc/kg body weight respectively. Using standard techniques, the following parameters were compared between the three groups of experimental animals at the end of 4 weeks: (a) Serum zinc, magnesium (Mg), copper (Cu), selenium (Se) and cadmium (Cd), (b) serum sex hormones, malondialdehyde (MDA), superoxide dismutase (SOD) and glutathione peroxidase (GPX), (c) interleukin-4 (IL-4), tumor necrosis factor-alpha (TNF-α), Bcl-2, Bax and caspase-3 expression in the testes, (d) assessment of apoptosis of testicular cells using electron microscopy and (e) testicular volume and histology using the orchidometer and Johnsen score, respectively. The zinc deficient group showed a reduction of testicular volume, serum concentrations of Zn, Cu, Se, Mg, SOD, GPX, IL-4, Bcl-2 and testosterone (P < 0.05), as well as increased levels of serum Cd, MDA and tissue TNF-α, Bax, caspase-3 and apoptosis of the germ cells (P < 0.05) compared with control and zinc supplementation groups. Zinc deficiency is associated with impaired spermatogenesis because of reduced testosterone production, increased oxidative stress and apoptosis. These findings suggest that zinc has a role in male reproduction.


Self-reported health problems and prioritized goals in community-dwelling individuals with spinal cord injury in Sweden.
To explore self-reported health problems and functional goals in community-dwelling individuals with spinal cord injury in Sweden. Cross-sectional descriptive study that used a survey designed by an experienced peer mentor with spinal cord injury. Community-dwelling individuals with spinal cord injury from Sweden. The survey was distributed online by the community peer-based organization RG Active Rehabilitation. A total of 203 individuals (55% males, 90% acquired spinal cord injury) from all regions in Sweden completed the survey. Of these, 33% reported living with > 2 unbearable physical or psychological problems. While some problems (e.g. problems related to bladder and balance) were consistently ranked to be common across all years since injury and type of spinal cord injury, distribution of some other unbearable problems (e.g. type of pain, excessive weight) varied between subgroups. Years since injury, level of acquired spinal cord injury and sex, but not age-group or type of spinal cord injury, explained some of the variation in the goals. The high proportion of reported "unbearable" problems point to the stronger need for systematic, comprehensive, life-long, multi-disciplinary follow-up for people with spinal cord injury. The high rate of goals related to improving strength and fitness across all participants independently of their characteristics highlight the important role of community organizations that offer such lifetime services.


Confocal non-line-of-sight imaging based on the light-cone transform.
How to image objects that are hidden from a camera's view is a problem of fundamental importance to many fields of research, with applications in robotic vision, defence, remote sensing, medical imaging and autonomous vehicles. Non-line-of-sight (NLOS) imaging at macroscopic scales has been demonstrated by scanning a visible surface with a pulsed laser and a time-resolved detector. Whereas light detection and ranging (LIDAR) systems use such measurements to recover the shape of visible objects from direct reflections, NLOS imaging reconstructs the shape and albedo of hidden objects from multiply scattered light. Despite recent advances, NLOS imaging has remained impractical owing to the prohibitive memory and processing requirements of existing reconstruction algorithms, and the extremely weak signal of multiply scattered light. Here we show that a confocal scanning procedure can address these challenges by facilitating the derivation of the light-cone transform to solve the NLOS reconstruction problem. This method requires much smaller computational and memory resources than previous reconstruction methods do and images hidden objects at unprecedented resolution. Confocal scanning also provides a sizeable increase in signal and range when imaging retroreflective objects. We quantify the resolution bounds of NLOS imaging, demonstrate its potential for real-time tracking and derive efficient algorithms that incorporate image priors and a physically accurate noise model. Additionally, we describe successful outdoor experiments of NLOS imaging under indirect sunlight.


Targeting blockage of STAT3 in hepatocellular carcinoma cells augments NK cell functions via reverse hepatocellular carcinoma-induced immune suppression.
STAT3 is an important transcriptional factor for cell growth, differentiation, and apoptosis. Although evidence suggests a positive role for STAT3 in cancer, the inhibitory effects of tumor STAT3 on natural killer (NK) cell functions in human hepatocellular carcinoma are unclear. In this study, we found that blocking STAT3 in hepatocellular carcinoma cells enhanced NK-cell antitumor function. In the case of STAT3-blocked hepatocellular carcinoma cells, NKG2D ligands were upregulated, which promoted recognition by NK cells. Importantly, the cytokine profile of hepatocellular carcinoma cells was altered; in particular, TGF-β and interleukin 10 (IL-10) expression was reduced, and type I interferon (IFN) was induced, thus facilitating NK-cell activation. Indeed, the cytotoxicity of NK cells treated with supernatant from STAT3-blocked hepatocellular carcinoma cells was augmented, with a concomitant elevation of molecules associated with NK cytolysis. Further experiments confirmed that the recovery of NK cells depended on the downregulation of TGF-β and upregulation of type I IFN derived from STAT3-blocked hepatocellular carcinoma cells. These findings demonstrated a pivotal role for STAT3 in hepatocellular carcinoma-mediated NK-cell dysfunction, and highlighted the importance of STAT3 blockade for hepatocellular carcinoma immunotherapy, which could restore NK-cell cytotoxicity in addition to its direct influence on tumor cells.


Measurement of faecal haemoglobin with a faecal immunochemical test can assist in defining which patients attending primary care with rectal bleeding require urgent referral.
Current guidelines document persistent rectal bleeding as an alarm symptom in patients presenting to primary care. We studied whether a faecal immunochemical test could assist in their assessment. From December 2015, faecal immunochemical tests were routinely available to primary care when assessing patients with new-onset bowel symptoms: general practitioners were encouraged to include faecal haemoglobin concentration (f-Hb) within any referral to secondary care. Results with f-Hb ≥10 μg Hb/g faeces were defined as positive. The incidence of significant bowel disease (SBD: colorectal cancer [CRC], higher-risk adenoma [HRA: any ≥1 cm, or three or more] and inflammatory bowel disease [IBD]) at subsequent colonoscopy, referred symptoms and f-Hb were recorded. Of 1447 patients with a faecal immunochemical test result and colonoscopy outcome, SBD was diagnosed in 296 patients (20.5%; 95 with CRC, 133 with HRA, and 68 with IBD). Four hundred and sixty-two patients (31.9%) reported rectal bleeding: 294 had f-Hb ≥10 μg Hb/g faeces. At colonoscopy, 105/294 had SBD versus 14/168 with rectal bleeding and f-Hb <10 μg Hb/g faeces (P < 0.0001), comprising one case of CRC (0.6%), 12 HRA (7.1%) and one new case of IBD (0.6%); further, the single cancer and 8 of the 12 HRA were located in the descending colon. Patients with rectal bleeding and f-Hb <10 μg Hb/g faeces are unlikely to have SBD and could be investigated by sigmoidoscopy alone. Using the faecal immunochemical test to guide investigation of patients with rectal bleeding is a rational and practical way forward.


Characterization of a novel organelle in Toxoplasma gondii with similar composition and function to the plant vacuole.
Toxoplasma gondii belongs to the phylum Apicomplexa and is an important cause of congenital disease and infection in immunocompromised patients. Like most apicomplexans, T. gondii possesses several plant-like features, such as the chloroplast-like organelle, the apicoplast. We describe and characterize a novel organelle in T. gondii tachyzoites, which is visible by light microscopy and possesses a broad similarity to the plant vacuole. Electron tomography shows the interaction of this vacuole with other organelles. The presence of a plant-like vacuolar proton pyrophosphatase (TgVP1), a vacuolar proton ATPase, a cathepsin L-like protease (TgCPL), an aquaporin (TgAQP1), as well as Ca(2+)/H(+) and Na(+)/H(+) exchange activities, supports similarity to the plant vacuole. Biochemical characterization of TgVP1 in enriched fractions shows a functional similarity to the respective plant enzyme. The organelle is a Ca(2+) store and appears to have protective effects against salt stress potentially linked to its sodium transport activity. In intracellular parasites, the organelle fragments, with some markers colocalizing with the late endosomal marker, Rab7, suggesting its involvement with the endocytic pathway. Studies on the characterization of this novel organelle will be relevant to the identification of novel targets for chemotherapy against T. gondii and other apicomplexan parasites as well.


The flight of white-collars: Civil conflict, availability of medical service providers and public health.
Civil conflicts devastate public health both in the short run and in the long run. Analyzing novel data sets that include yearly information on public health and the availability of health professionals across provinces in Turkey in the 1964-2010 period, we provide empirical evidence for our theoretical argument that a major mechanism through which civil conflicts exert their long term negative influences on public health is by discouraging medical personnel to practice in conflict regions. We also assess the effectiveness of certain policy measures that Turkish governments have tried out over the years to counteract this mechanism. Our results reveal that the long running civil conflict in Turkey has been driving away doctors and other highly trained medical personnel from conflict areas and that mandatory service requirements do help counteract this flight.


Reduced innate immunity of Cuban Treefrogs at leading edge of range expansion.
During geographic range expansion, populations of non-indigenous species at the invasion front may benefit from directing resources away from immune defense. To test this hypothesis, we investigated the strength of two innate immune components in populations of invasive Cuban Treefrogs (Osteopilus septentrionalis) in a long-colonized area (core region) and at the invasion front (leading-edge region). First, we compared the region-specific metabolic response of frogs injected with an endotoxin that induces systemic inflammation (lipopolysaccharide, LPS) to sham-injected control frogs pooled from both regions. Males and females were analyzed independently because we detected a sex-related difference in mass-independent metabolism of control frogs, with males exhibiting a significantly higher metabolic rate (F1, 21 = 29.02, P < 0.001) than females. We observed a significantly higher metabolic rate in LPS-injected core frogs compared with control frogs for both males (P = 0.041) and females (P = 0.007). Conversely, in leading-edge populations, there was no significant difference in the metabolic rate of LPS-injected and control frogs (males, P = 0.195; females, P = 0.132). Second, we directly compared bacterial killing ability of frog blood plasma between regions. Bactericidal ability of plasma was significantly greater in frogs from the core region in comparison with those at the leading edge (F1, 26 = 28.67, P < 0.001). For both immune components that we examined, populations from the core exhibited stronger immune responses. Our findings support hypotheses predicting an inverse relationship between immunity and range expansion.


Drug development process and COVID-19 pandemic: Flourishing era of outsourcing.
Traditional drug development is a tedious process with involvement of enormous cost and a high attrition rate. Outsourcing drug development services to contract research organizations (CROs) has become an important strategy for cost and risk reduction, capacity building, and data generation. The therapeutic and operational expertise of these CROs has allowed pharmaceutical industry to reduce in-house infrastructure as well as research capacity. Working with specialized CROs has not only increased the rate of success but also the speed of drug discovery process. Small firms with promising molecules but limited resources and large firms interested in diversifying their dimensions are utilizing the services of efficient CROs. Globally, approximately one-third of the drug development processes are now being outsourced and the data generated by the independent third party are well appreciated during regulatory submissions. In this article, we discuss the international and national trends, outsourcing services and models, key considerations while selecting CRO, and benefits and challenges of outsourcing. Further, we discuss how the technical expertise of competent CROs was utilized when traditional ways of conducting clinical trials were disrupted by the COVID-19 pandemic. Taken together, the increasing health-care demands, COVID-19 pandemic or any other such upcoming health crisis, and recent advances in advanced technologies (machine learning and artificial intelligence, etc.) are likely to fuel global CRO market in the coming years.


Ezetimibe and fenofibrate combination therapy for mixed hyperlipidemia.
The ezetimibe and fenofibrate combination regimen was recently approved by the U.S. Food and Drug Administration for treatment of mixed hyperlipidemia. This powerful lipid-modifying therapy takes advantage of the different mechanisms of action of the two individual components. Ezetimibe selectively inhibits intestinal uptake of dietary and biliary cholesterol, and exerts its effect most notably on the low-density lipoprotein cholesterol (LDL-C). Fenofibrate activates the peroxisome proliferators-activated receptor alpha (PPAR-alpha), thereby increasing the tissue lipoprotein lipase activity and breakdown of triglycerides in very low-density lipoproteins (VLDL). The combination therapy of ezetimibe and fenofibrate has an excellent safety profile and exhibits potent synergistic actions on multiple lipid risk factors and represents another alternative in the clinical management of mixed hyperlipidemia. Further studies are needed to determine the effectiveness and safety of the ezetimibe and fenofibrate combination therapy used in conjunction with other lipid-modifying agents such as statins. Finally, outcome trials are warranted to evaluate if combination therapy would result in additive effects on morbidity and mortality.


Flexibility in data interpretation: effects of representational format.
Graphs and tables differentially support performance on specific tasks. For tasks requiring reading off single data points, tables are as good as or better than graphs, while for tasks involving relationships among data points, graphs often yield better performance. However, the degree to which graphs and tables support flexibility across a range of tasks is not well-understood. In two experiments, participants detected main and interaction effects in line graphs and tables of bivariate data. Graphs led to more efficient performance, but also lower flexibility, as indicated by a larger discrepancy in performance across tasks. In particular, detection of main effects of variables represented in the graph legend was facilitated relative to detection of main effects of variables represented in the x-axis. Graphs may be a preferable representational format when the desired task or analytical perspective is known in advance, but may also induce greater interpretive bias than tables, necessitating greater care in their use and design.


Antioxidant Activity of Myrtus communis L. and Myrtus nivellei Batt. & Trab. Extracts: A Brief Review.
Myrtus communis L. (myrtle) and Myrtus nivellei Batt. & Trab. (Saharan myrtle) have been used in folk medicine for alleviating some ailments. M. communis is largely distributed in the Mediterranean Basin, whereas M. nivellei is confined in specific zones of the central Saharan mountains. The chemical composition and antioxidant activity of berry and leaf extracts isolated from myrtle are deeply documented, whereas those isolated from Saharan myrtle extracts are less studied. In both species, the major groups of constituents include gallic acid derivatives, flavonols, flavonol derivatives, and hydroxybenzoic acids. In coloured berries, anthocyanins are also present. In M. nivellei extracts are reported for some compounds not described in M. communis so far: 2-hydroxy-1,8-cineole-β-d-glucopyranoside, 2-hydroxy-1,8-cineole 2-O-α-l-arabinofuranosyl (1→6)-β-d-glucopyranoside, rugosin A, and rugosin B. Berries and leaves extracts of both species had antioxidant activity. Comparative studies of the antioxidant activity between leaf and berry myrtle extracts revealed that leaf extracts are best antioxidants, which can be assigned to the galloyl derivatives, flavonols, and flavonols derivatives, although the ratio of these groups of compounds might also have an important role in the antioxidant activity. The anthocyanins present in myrtle berries seem to possess weak antioxidant activity. The antioxidant activity of sample extracts depended on various factors: harvesting time, storage, extraction solvent, extraction type, and plant part used, among other factors. Leaf extracts of myrtle revealed to possess anti-inflammatory activity in several models used. This property has been attributed either to the flavonoids and/or hydrolysable tannins, nevertheless nonprenylated acylphloroglucinols (e.g., myrtucommulone and semimyrtucommulone) have also revealed a remarkable role in that activity. The biological activities of myrtle extracts found so far may direct its use towards for stabilizing complex lipid systems, as prebiotic in food formulations, and as novel therapeutic for the management of inflammation.


Detection of Hepatitis E Virus Antibodies in Dogs in the United Kingdom.
Hepatitis E virus (HEV) genotypes 3 and 4 are zoonotic pathogens, with pigs predominantly implicated in disease transmission. The rapid rise in human cases in developed countries over the past decade indicates a change in epidemiology of HEV, and it has been suggested that additional animal species may be involved in transmission of infection. Multiple studies have identified contact with dogs as a risk factor for HEV infection in industrialised nations, and a low seroprevalence to HEV has previously been reported in dogs in low-income countries. In this study we aimed to evaluate the possibility that dogs are susceptible to HEV, and determine the frequency with which this occurs. Serum samples from UK dogs with and without hepatitis were screened for HEV-specific antibodies, and canine liver and stool samples were analysed by qPCR for the presence of HEV RNA. We describe evidence to show HEV infection occurs at low levels in dogs in the UK, but the strain of origin is undetermined. The low seroprevalence level of HEV in dogs implies the risk of zoonotic disease transmission is likely to be limited, but further investigations will be required to determine if HEV-infected dogs can transmit HEV to man.


Human Breast Milk Bacteriome in Health and Disease.
It is well-known that, beyond nutritional components, human breast milk (HBM) contains a wide variety of non-nutritive bio-factors perfectly suited for the growing infant. In the pre-2000 era, HBM was considered sterile and devoid of micro-organisms. Though HBM was not included as part of the human microbiome project launched in 2007, great strides have been made in studying the bacterial diversity of HBM in both a healthy state and diseased state, and in understanding their role in infant health. HBM provides a vast array of beneficial micro-organisms that play a key role in colonizing the infant's mucosal system, including that of the gut. They also have a role in priming the infant's immune system and supporting its maturation. In this review, we provide an in-depth and updated insight into the immunomodulatory, metabolic, and anti-infective role of HBM bacteriome (bacterial community) and its effect on infant health. We also provide key information from the literature by exploring the possible origin of microbial communities in HBM, the bacterial diversity in this niche and the determinants influencing the HBM bacteriome. Lastly, we investigate the role of the HBM bacteriome in maternal infectious disease (human immunodeficiency virus (HIV) and mastitis)), and cancer. Key gaps in HBM bacterial research are also identified.


Fast and accurate computational modeling of adsorption on graphene: a dispersion interaction challenge.
Understanding molecular interactions of graphene is a question of key importance to design new materials and catalytic systems for practical usage. Although for small models good accuracy was demonstrated in theoretical analysis with ab initio and density functional methods, the application to real-size systems with thousands of atoms is currently hardly possible on routine bases due to the high computational cost. In the present study we report that incorporation of dispersion correction led to the principal improvement in the description of graphene systems at a semi-empirical level. The accuracy and the scope of the calculations were explored for a wide range of molecules adsorbed on graphene surfaces (H2, N2, CO, CO2, NH3, CH4, H2O, benzene, naphthalene, coronene, ovalene and cyclohexane). As a challenging parameter, the calculated adsorption energy of aromatic hydrocarbons on graphene Eads = -1.8 ± 0.1 kcal mol(-1) (per one carbon atom) at the PM6-DH2 level was in excellent agreement with the experimentally determined value of Eads = -1.7 ± 0.3 kcal mol(-1). The dispersion corrected semi-empirical method was found to be a remarkable computational tool suitable for everyday laboratory studies of real-size graphene systems. Significant performance improvement (ca. 10(3) times faster) and excellent accuracy were found as compared to the ωB97X-D density functional calculations.


ABO blood groups and risk of covid-19.
Coronavirus pandemic has been the subject of a large number of publications, some of which have shown an increased risk of contracting Covid-19 in carriers of blood group A. In this study we looked at the profile of blood group phenotype of a series of Tunisian patients with covid-19 admitted to Abderrahman Mami hospital in Ariana . Our study included 51 Tunisian patients with SARS-CoV-2 infection admitted to Abderrahmane Mami hospital between late march 2020 and early May 2020. The distribution of blood groups in Covid-19 patients was compared with that of a control group of 1506 patients with no Covid-19 infection as well as with the distribution of blood groups in a population of 63375 voluntary blood donors. Our series, although limited in size, showed a higher prevalence of blood group A among Covid-19 patients, statistically significant compared to ABO blood group distribution among Tunisian blood donors and among a control group of patients without Covid -19. these results are in line with data from the literature, particularly on larger series in China.


Clinical outcome of HCV-related graft cirrhosis and prognostic value of hepatic venous pressure gradient.
Hepatitis C virus (HCV) allograft cirrhosis may progress rapidly requiring re-transplantation but its course is little studied. We evaluated serially biopsied patients who developed HCV-related allograft cirrhosis. We assessed outcome of graft cirrhosis in 55 out of 234 consecutive patients and predictors of decompensation and mortality, including hepatic venous pressure gradient (HVPG) in 38. Allograft cirrhosis (Ishak stage 6, 60%; stage 5, 40%) was diagnosed between 12 and 172 months (median, 52) from transplantation; subsequent follow up was 22 (1-78) months. Faster development (<or=48 months) was associated with tacrolimus and nonuse of azathioprine and prednisolone. Decompensation occurred in 22% with a probability of not developing decompensation reaching 60% at 5 years. Survival among compensated patients was 77% at 5 years, but fell rapidly after decompensation (12% at 1 year). Decompensation and mortality were independently associated with HVPG >or= 10 mmHg, Child-Pugh score >or= 7, and albumin levels <or= 32 g/dl but not with fibrosis stage 5 or 6, HCV genotype (1b, 34%) or immunosuppression used after diagnosis of cirrhosis. In conclusion, Ishak stage 5 and 6 HCV-related cirrhosis have similar prognosis after liver transplantation. An HVPG >or= 10 mmHg, in addition to liver dysfunction, gives independent prognostic information prior to decompensation, allowing early relisting before prognosis becomes extremely poor.


Strange nonchaotic stars.
The unprecedented light curves of the Kepler space telescope document how the brightness of some stars pulsates at primary and secondary frequencies whose ratios are near the golden mean, the most irrational number. A nonlinear dynamical system driven by an irrational ratio of frequencies generically exhibits a strange but nonchaotic attractor. For Kepler's "golden" stars, we present evidence of the first observation of strange nonchaotic dynamics in nature outside the laboratory. This discovery could aid the classification and detailed modeling of variable stars.


Genomic differences among carriage and invasive nontypeable pneumococci circulating in South Africa.
Most pneumococci express a polysaccharide capsule, a key virulence factor and target for pneumococcal vaccines. However, pneumococci showing no serological evidence of capsule expression [nontypeable pneumococci (NTPn)] are more frequently isolated from carriage studies than in invasive disease. Limited data exist about the population structure of carriage NTPn from the African continent. We aimed to characterize carriage NTPn and compare them to previously described invasive NTPn. Carriage and invasive NTPn isolates were obtained from South African cross-sectional studies (2009 and 2012) and laboratory-based surveillance for invasive pneumococcal disease (2003-2013), respectively. Isolates were characterized by capsular locus sequence analysis, multilocus sequence typing, antimicrobial non-susceptibility patterns and phylogenetic analysis. NTPn represented 3.7 % (137/3721) of carriage isolates compared to 0.1 % (39/32 824) of invasive isolates (P<0.001), and 24 % (33/137) of individuals were co-colonized with encapsulated pneumococci. Non-susceptibility to cotrimoxazole [84 % (112/133) vs 44 % (17/39)], penicillin [77 % (102/133) vs 36 % (14/39)], erythromycin [53 % (70/133) vs 31 % (12/39)] and clindamycin [36 % (48/133) vs 18 % (7/39)] was higher (P=0.03) among carriage than invasive NTPn. Ninety-one per cent (124/137) of carriage NTPn had complete deletion of the capsular locus and 9 % (13/137) had capsule genes, compared to 44 % (17/39) and 56 % (22/39) of invasive NTPn, respectively. Carriage NTPn were slightly less diverse [Simpson's diversity index (D)=0.92] compared to invasive NTPn [D=0.97]. Sixty-seven per cent (92/137) of carriage NTPn belonged to a lineage exclusive to NTPn strains compared to 23 % (9/39) of invasive NTPn. We identified 293 and 275 genes that were significantly associated with carriage and invasive NTPn, respectively. NTPn isolates detected in carriage differed from those causing invasive disease, which may explain their success in colonisation or in causing invasive disease.


A grouped ranking model for item preference parameter.
Given a set of rating data for a set of items, determining preference levels of items is a matter of importance. Various probability models have been proposed to solve this task. One such model is the Plackett-Luce model, which parameterizes the preference level of each item by a real value. In this letter, the Plackett-Luce model is generalized to cope with grouped ranking observations such as movie or restaurant ratings. Since it is difficult to maximize the likelihood of the proposed model directly, a feasible approximation is derived, and the em algorithm is adopted to find the model parameter by maximizing the approximate likelihood which is easily evaluated. The proposed model is extended to a mixture model, and two applications are proposed. To show the effectiveness of the proposed model, numerical experiments with real-world data are carried out.


Gamma interferon-activated human macrophages and Toxoplasma gondii, Chlamydia psittaci, and Leishmania donovani: antimicrobial role of limiting intracellular iron.
Iron-saturated transferrin did not reverse the intracellular killing or inhibition of Toxoplasma gondii, Chlamydia psittaci, or Leishmania donovani by gamma interferon-activated human macrophages. Deferoxamine, an iron chelator, also did not impair replication within unstimulated macrophages. Limiting the availability of intracellular iron is an unlikely mechanism in human macrophage activity against these three diverse pathogens.


Impact of periodontal intervention on local inflammation, periodontitis, and HIV outcomes.
The aim of this study was to determine active periodontal disease status in HIV and to determine the impact of periodontal disease resolution on HIV status. In this longitudinal cohort study, 73 HIV-positive subjects received comprehensive dental care. AAP, CDC/AAP, and BGI case definitions determined periodontal classification. Likelihood and frequency of moderate/severe periodontal disease were assessed based on demographic variables. The influence of periodontal intervention was assessed at baseline, 12, and 24 months. IL-6 was measured in a subset of subjects. Of the periodontal classifications, BGI demonstrated the highest percentage category improvement with the intervention (>50%). Moderate/severe periodontitis was positively associated with HIV regardless of race, smoking status, gender, income level, and age, and was associated with increased IL-6. At baseline, the majority of subjects had severe periodontal disease regardless of ART status. Subjects with suppressed viral load at baseline demonstrated a significant improvement in BGI classification (P = 0.026), increased CD4 counts (P = 0.027), and decreased IL-6 levels (P = 0.03). Periodontal inflammation was prevalent regardless of ART status. In virologically suppressed subjects, the intervention decreased periodontitis with a concomitant IL-6 decrease and CD4 increase. These findings suggest a relationship between periodontal inflammation, oral microbial translocation, and HIV status.


Gastric duplication cyst masquerading as a mucinous pancreatic cyst: case report and literature review.
Gastric duplication cysts are rare cystic neoplasms that are often difficult to distinguish from other entities. We describe a healthy 44-year-old woman who presented with acute right lower quadrant abdominal and flank pain as well as chronic nausea and constipation. Her physical examination was unremarkable but contrasted computed tomography revealed a 6 cm cystic lesion between the stomach and body of the pancreas. Endoscopic ultrasonography and fluid analysis were consistent with a mucinous cyst with a markedly elevated fluid carcinoembryonic antigen level. The patient subsequently underwent a laparoscopic distal pancreatectomy, which was converted to an open procedure when the lesion was noted to be adherent to the coeliac axis. Intraoperative endoscopy revealed no abnormality. Final pathology revealed a gastric duplication cyst. The patient recovered well and was asymptomatic on follow-up. In this report, we discuss the incidence, natural history and management of this rare entity.


Is cyberchondria a new transdiagnostic digital compulsive syndrome? A systematic review of the evidence.
Cyberchondria (CYB) has been described relatively recently as a behaviour characterized by excessive online searching for medical information that is associated with increasing levels of health anxiety. Although CYB has received some attention from researchers, there is no consensus about many of its aspects. We describe one of the first reported cases of a treatment-seeking patient with CYB. We review the published literature on the definition of CYB, its assessment, epidemiology, cost and burden, psychological models and mechanisms associated with CYB, relationships between CYB and mental disorders and prevention and treatment strategies. Systematic review of all peer-reviewed papers published within the PubMed, PsycINFO, and Cochrane Library databases. 61 articles were selected. Nearly all the studies were descriptive and cross-sectional recruiting sample mainly from the general/university student population and collecting self-report data via online surveys. Data on epidemiology, clinical features, course, comorbidity and therapeutic interventions were scarce. CYB showed a self-reported association with health anxiety, hypochondriasis and obsessive-compulsive disorder (OCD) as well as other forms of problematic usage of the internet (PUI) The psychological mechanisms associated with CYB include low self-esteem, anxiety sensitivity, intolerance of uncertainty, pain catastrophizing and certain meta-cognitive beliefs. A working definition of CYB includes excessive online health searches that are compulsive and may serve the purpose of seeking reassurance, whilst leading to a worsening of anxiety or distress and further negative consequences. CYB represents a clinically relevant transdiagnostic compulsive behavioural syndrome, closely related to PUI and usually presenting in association with health anxiety, hypochondriasis and/or OCD. CYB is clearly in need of further study and we identify key areas for future research.


DMR1 (CCM1/YGR150C) of Saccharomyces cerevisiae encodes an RNA-binding protein from the pentatricopeptide repeat family required for the maintenance of the mitochondrial 15S ribosomal RNA.
Pentatricopeptide repeat (PPR) proteins form the largest known RNA-binding protein family and are found in all eukaryotes, being particularly abundant in higher plants. PPR proteins localize mostly in mitochondria and chloroplasts, where they modulate organellar genome expression on the post-transcriptional level. The Saccharomyces cerevisiae DMR1 (CCM1, YGR150C) encodes a PPR protein that localizes to mitochondria. Deletion of DMR1 results in a complete and irreversible loss of respiratory capacity and loss of wild-type mtDNA by conversion to rho(-)/rho(0) petites, regardless of the presence of introns in mtDNA. The phenotype of the dmr1Delta mitochondria is characterized by fragmentation of the small subunit mitochondrial rRNA (15S rRNA), that can be reversed by wild-type Dmr1p. Other mitochondrial transcripts, including the large subunit mitochondrial rRNA (21S rRNA), are not affected by the lack of Dmr1p. The purified Dmr1 protein specifically binds to different regions of 15S rRNA in vitro, consistent with the deletion phenotype. Dmr1p is therefore the first yeast PPR protein, which has an rRNA target and is probably involved in the biogenesis of mitochondrial ribosomes and translation.


Relating small airways to asthma control by using impulse oscillometry in children.
Previous reports suggest that the peripheral airways are associated with asthma control. Patient history, although subjective, is used largely to assess asthma control in children because spirometric results are many times normal values. Impulse oscillometry (IOS) is an objective and noninvasive measurement of lung function that has the potential to examine independently both small- and large-airway obstruction. We sought to determine the utility of IOS in assessing asthma control in children. Asthmatic and healthy children (6-17 years) were enrolled in the study. Spirometric and IOS (resistance of the respiratory system at 5 Hz [R5] and 20 Hz [R20], reactance of the respiratory system at 5 Hz [X5], resonant frequency of reactance [Fres], and area under the reactance curve between 5 Hz and Fres [reactance area {AX}]) values were collected in triplicate before and after a bronchodilator was administered. The physicians were blinded to the IOS measurements and assessed asthma control using American Thoracic Society guidelines. Small-airway IOS measurements, including the difference of R5 and R20 [R5-20], X5, Fres, and AX, of children with uncontrolled asthma (n = 44) were significantly different from those of children with controlled asthma (n = 57) and healthy children (n = 14), especially before the administration of a bronchodilator. However, there was no difference in large-airway IOS values (R20). No differences were found between children with controlled asthma and healthy children in any of the end points. Receiver operating characteristic analysis showed cut points for baseline R5-20 (1.5 cm H(2)O · L(-1) · s) and AX (9.5 cm H(2)O · L(-1)) that effectively discriminated controlled versus uncontrolled asthma (area under the curve, 0.86 and 0.84) and correctly classified more than 80% of the population. Uncontrolled asthma is associated with small-airways dysfunction, and IOS might be a reliable and noninvasive method to assess asthma control in children.


Cortical responses to single mechanoreceptive afferent microstimulation revealed with fMRI.
The technique of intraneural microneurography/microstimulation has been used extensively to study contributions of single, physiologically characterized mechanoreceptive afferents (MRAs) to properties of somatosensory experience in awake human subjects. Its power as a tool for sensory neurophysiology can be greatly enhanced, however, by combining it with functional neuroimaging techniques that permit simultaneous measurement of the associated CNS responses. Here we report its successful adaptation to the environment of a high-field MR scanner. Eight median-nerve MRAs were isolated and characterized in three subjects and microstimulated in conjunction with fMRI at 3.0 T. Hemodynamic responses were observed in every case, and these responses were robust, focal, and physiologically orderly. The combination of fMRI with microstimulation will enable more detailed studies of the representation of the body surface in human somatosensory cortex and further studies of the relationship of that organization to short-term plasticity in the human SI cortical response to natural tactile stimuli. It can also be used to study many additional topics in sensory neurophysiology, such as CNS responses to additional classes of afferents and the effects of stimulus patterning and unimodal/crossmodal attentional manipulations. Finally, it presents unique opportunities to investigate the basic physiology of the BOLD effect and to compare the operating characteristics of fMRI and EEG as human functional neuroimaging modalities in an unusually specific and well-characterized neurophysiological setting.


Long-Term Outcomes of Decompression and Grafting in Acute Pathological Proximal Femur Fractures in Children with Unicameral Bone Cysts: A Retrospective Study Utilizing a 120° Fixed-Angle Low-Contact Locking Pediatric Hip Plate.
BACKGROUND Unicameral bone cysts (UBCs) are benign tumor-like lesions that are the most common cause of pathological proximal femur fracture in children. This study aimed to present the outcomes of acute, unstable, pathological proximal femur fractures secondary to UBCs in children. MATERIAL AND METHODS We retrospectively reviewed data on 12 patients with a mean age of 9.3 years (7-12 years) who were initially treated with decompression and grafting, followed by stabilization using a 120° fixed-angle low-contact locking pediatric plate (LCLPP). The Musculoskeletal Tumor Society (MSTS) scores, Capanna classification of cyst repair, time to union, collodiaphyseal angle (CDA), and limb length discrepancy (LLD) were evaluated. RESULTS The mean follow-up was 33.1 months (range, 13-96 months). The mean union time was 9.5 weeks (8-14 weeks). The mean time for reparation of the cyst was 6.9 months (range 3-9 months). Four patients had Dormans type IB, while the remaining had type IIB fractures. According to the Capanna classification, repairs in 10 cases were grade I and in 2 cases grade II. At the last follow-up, the mean 120.8° of preoperative CDA was corrected to 140.9° (P<0.001) and there was no difference compared to the healthy side (P=0.214). The mean postoperative MSTS score was 97.1% (29.1 points). Two patients experienced LLD at the affected extremities, while the other 10 patients healed without any complications. CONCLUSIONS Fixation of acute unstable fractures secondary to UBCs with a 120° fixed-angle LCLPP is a reliable and successful option after decompression and grafting of the lesion.


The natural history of PBC: has it changed?
The prognosis and natural history of primary biliary cirrhosis (PBC) have improved significantly during the last few decades. Patients are diagnosed at earlier stages, are more likely to be asymptomatic at diagnosis, and are more likely to receive medical treatment. The survival of asymptomatic patients is longer than the median survival of symptomatic patients. The natural history of PBC has been assessed in the presence of effective therapy, ursodeoxycholic acid (UDCA). Evidence suggests that UDCA delays histological progression in PBC and decreases the risk of development of esophageal varices. Survival of UDCA-treated patients is better than that of untreated patients and also is better than that predicted by the Mayo model. For patients in early stages of PBC, UDCA treatment may normalize survival. However, patients with stage III and IV PBC do not respond as well to UDCA. Therefore, there is a continued need for additional treatment in patients with advanced disease.


Visual Information Processing in Young and Older Adults.
Decline in information processing with age is well-documented in the scientific literature. However, some discrepancy remains in relation to which cognitive domains are most susceptible to the aging process and which may remain intact. Furthermore, information processing has not been investigated nor considered as a function of affect, familiarity and complexity of tasks in a single experimental study. Thus, the current study investigated rate of visual information processing in 67 young university students (M age = 19.64 years) and 33 educated healthy older adults (M age = 70.33 years), while accounting for depression, anxiety and stress symptoms using the DASS. Rates of visual processing were measured as minimum time of stimulus exposure duration required for correct object recognition on a simple visual task [Inspection Time (IT)], and on a more complex visual cognitive task known as Change Detection (CD)] as well as words per minute on a text reading task (FastaReada). The results demonstrated significantly slower performance by older adults on the IT and CD, but comparable rates of text reading on a semantically more complex, but ecologically valid and familiar visual task that requires organized sequential shifts in attention via eye movements, continuous visual processing, access to working memory and semantic comprehension. The results also demonstrated that affective influences did not play a role in the older adults task performance, and that changes in cognitive domains may begin with older adults being slower to attend to and identify newly appearing familiar objects, as well as slower to encode and embed new information in memory during tasks that require a less practiced/familiar task strategy.


[Renoureteral malformation and lithiasis. Therapeutic approach].
To analyze our results in the treatment of calculi in renoureteral malformations with extracorporeal shock wave lithotripsy (ESWL) alone and the efficacy of ESWL and adjuvant methods in the resolution of calculi in different types of renoureteral malformations. The study comprised 141 cases of renoureteral malformations with urinary calculi; 68 were renal, 69 ureteral and 4 in the Bricker urinary diversion. All patients had been diagnosed by IVP and treated by ESWL. These patients were compared with a control group of 125 patients with calculi and a normal renoureteral system that were treated similarly. The malformations accounted for 2.61% of the 5,400 patients that had been treated in our unit from 1990-1998. The mean number of sessions for the patients with malformations was 1.5 versus 1.2 for the control group. The results of treatment were significantly lower for the group of patients with renal malformations than for the control group (54% vs. 87.2%, respectively). Similar results were obtained for the group of patients with ureteral malformations and the control group (87% vs. 75%). ESWL can be the first treatment option for calculi in patients with renal malformations, although they should be individually evaluated for status of the excretory system, urinary flow dynamics and size of the calculus in order to select the best treatment option. In patients with ureteral malformations, the same criteria utilized for those with a normal excretory system should be applied.


Comparison between measured and calculated length of side branch ostium in coronary bifurcation lesions with intravascular ultrasound.
Accurate evaluation of side branch (SB) ostium could be critical to the treatment of bifurcation lesions. We compared measured and calculated values of side branch ostial length (SBOL) in coronary bifurcation lesions with intravascular ultrasound (IVUS). Pre-intervention and post-intervention IVUS was performed in 113 patients who underwent stent implantation of bifurcation lesions. For the IVUS longitudinal reconstruction of the bifurcation lesions, SBOL, SB diameter, and the angle between the distal portion of the main vessel (MV) and SB were directly measured. In addition, SBOL was calculated as: SB diameter/ sin (angle between distal MV and SB). The relationship between measured and calculated SBOL was then evaluated. The angled between the distal MV and SB were 57.3±12.4° at pre-intervention and 59.4±12.6° at post-intervention. The mean measured and calculated SBOL values were 2.91±0.86 mm and 3.06±0.77 mm at pre-intervention and 2.79±0.82 mm and 2.92±0.69 mm at post-intervention, respectively. Differences between measured and calculated SBOL were 0.15±0.44 mm at pre-intervention and 0.13±0.41 mm at post-intervention. We found that calculated SBOL was correlated with measured SBOL (pre-intervention r=0.863, p<0.001; post-intervention r=0.868, p<0.001). There was a good correlation between measured and calculated SBOLs of the bifurcation lesions in IVUS longitudinal reconstruction. SBOL in the bifurcation lesions can therefore be estimated using the SB diameter and the angle between distal MV and SB.


Lack of interaction of the NMDA receptor antagonists dextromethorphan and dextrorphan with P-glycoprotein.
The anti-N-methyl-D-aspartate (NMDA) effect of dextromethorphan (DEM) seems to be mainly related to the unchanged drug rather than to its more potent metabolite dextrorphan (DOR). The aim of our study was to assess the involvement of P-glycoprotein (P-gp) and pH conditions in the transmembranal transport of these two NMDA antagonists, using a human in vitro Caco-2 cell monolayer model. Transmission electron microscopy, transepithelial electrical resistance, [(3)H]-mannitol permeability, Western blot analysis and the bidirectional transport of the positive controls, rhodamine and digoxine were used to confirm model's integrity and validity. The bidirectional transport of DEM and DOR (1 to 100microM) across the monolayers was investigated in the presence and absence of the P-gp inhibitor cyclosporine A (10microM) at two pH conditions (pH 6.8/7.7-pH 7.4/7.4) and assessed with the specific and more potent P-gp inhibitor GF120918 (4microM). Analytical quantification was achieved using high performance liquid chromatography. At a pH gradient, DEM and DOR were subject to a significant active efflux transport (Papp(B-A) > 2-3x Papp(A-B); p<0.01). However, neither the influx nor the efflux was affected by P-gp inhibitors. At physiological pH, we observed no more efflux of the drugs and no influence of the inhibitors. In conclusion, dextromethorphan and dextrorphan are not P-gp substrates. However, pH-mediated efflux mechanisms seem to be involved in limiting DEM gastrointestinal absorption. The preferential anti-NMDA central effect of DEM appears to be P-gp independent.


The surgical management of pediatric hydrocephalus.
The surgical management of hydrocephalus has undergone incredible changes over the past generation of neurosurgeons, including dramatic improvements in imaging, especially computed tomographic scanning and magnetic resonance imaging, and remarkably innovative advances in cerebrospinal fluid valve technology, complex computer models, and endoscopic equipment and techniques. In terms of overall patient outcomes, however, one could conclude that things are a little better, but "not much." This frustrating yet fascinating dichotomy between technological advancements and clinical outcomes makes hydrocephalus, first described by the ancients, as one of the most understated and complex disorders that neurosurgeons treat. The challenge to the next generation of neurosurgeons is to solve this vexing problem through better understanding of the basic science, improved computer models, additional technological advances, and, most importantly, a broad-based, concerted multidisciplinary attack on this disorder. This review focuses on the evolution of surgery for hydrocephalus over the last 30 years, the current state of the art of hydrocephalus treatment, and what appear to be the most promising future directions.


Minimum cross-entropy pattern classification and cluster analysis.
This paper considers the problem of classifying an input vector of measurements by a nearest neighbor rule applied to a fixed set of vectors. The fixed vectors are sometimes called characteristic feature vectors, codewords, cluster centers, models, reproductions, etc. The nearest neighbor rule considered uses a non-Euclidean information-theoretic distortion measure that is not a metric, but that nevertheless leads to a classification method that is optimal in a well-defined sense and is also computationally attractive. Furthermore, the distortion measure results in a simple method of computing cluster centroids. Our approach is based on the minimization of cross-entropy (also called discrimination information, directed divergence, K-L number), and can be viewed as a refinement of a general classification method due to Kullback. The refinement exploits special properties of cross-entropy that hold when the probability densities involved happen to be minimum cross-entropy densities. The approach is a generalization of a recently developed speech coding technique called speech coding by vector quantization.


Comparison of Helicobacter pylori positive and negative gastric cancer via multi-omics analysis.
Helicobacter pylori (H. pylori) has been regarded as a definite carcinogenic bacterium for gastric cancer (GC). This multi-omics research was designed to investigate the genetic, microbial, and metabolic changes of GC patients when they are infected with H. pylori. We first mined The Cancer Genome Atlas Stomach Adenocarcinoma (STAD) data to identify the key genes and critical pathways in H. pylori-positive individuals with GC compared to H. pylori-negative individuals with GC. Then, fresh stool samples were collected from GC individuals screened for eligibility, and we analyzed the microbial changes and metabolite alterations between H. pylori-positive and H. pylori-negative GC individuals. Finally, we tried to explore the interaction between key gut flora and metabolite changes in GC patients infected with H. pylori. We identified three genes (GCG, APOA1, and IGFBP1) with significant relevance to H. pylori infection, and the survival monogram based on the three H. pylori-related genes showed good predictive ability for overall survival among GC individuals. 16S rRNA sequencing showed that the abundance of Escherichia-Shigella, Bacteroides, Enterococcus, and Lactobacillus was upregulated in GC cases with H. pylori at the level of genus. There exists a great difference in alpha and beta diversity between H. pylori group and non-H. pylori group. The untargeted metabolome analysis identified 295 significant fecal metabolites, and the levels of penitrem E, auberganol, stercobilinogen, and lys thr are upregulated in the H. pylori group. Finally, correlation analysis showed that there exists a significant correlation between the fecal metabolites and gut bacterial strains. This is the first clinical research to investigate the difference between GC patients with H. pylori and GC patients without H. pylori via multi-omics analysis. 16S rRNA sequencing along with untargeted metabolomics demonstrated decreased microbial diversity and metabolic dysregulation in gastric carcinoma individuals with H. pylori infection.IMPORTANCEThis is the first clinical research to systematically expound the difference between gastric cancer (GC) individuals with Helicobacter pylori and GC individuals without H. pylori from the perspective of multi-omics. This clinical study identified significant genes, microbes, and fecal metabolites, which exhibited nice power for differentiating GC individuals with H. pylori infection from GC individuals without H. pylori infection. This study provides a crucial basis for a better understanding of eradication therapy among the GC population.


The protein tyrosine kinase-dependent pathway mediates the effect of K intake on renal K secretion.
Dietary K intake plays an important role in the regulation of K secretion: a decrease stimulates and an increase suppresses kidney expression of protein tyrosine kinase (PTK), which plays a role in regulating Kir1.1 (ROMK), which is responsible for K secretion in the cortical collecting duct (CCD) and K recycling in the thick ascending limb. Tyrosine phosphorylation of ROMK channels increases with low dietary K and decreases with high dietary K. Moreover, stimulation of tyrosine phosphorylation of ROMK1 enhances ROMK1 internalization and reduces the K channel number in the cell surface in the CCD.