Glucocorticoid receptor-like antigen in lymphoma cell membranes: correlation to cell lysis.
S-49 mouse lymphoma cells undergo lysis when treated with glucocorticoids; the mechanism of this effect is not understood. A protein was detected in the plasma membrane of these cells by means of direct immunofluorescent labeling with a monoclonal antibody to the soluble glucocorticoid receptor. Cellular heterogeneity in the content of this glucocorticoid receptor-like molecule was evident. By immunoadsorption to antibody-coated tissue culture plates, the cells were separated into populations positive (100%) and depleted (38%) for this membrane antigen. Gel electrophoresis, specific immunoblot, and autoradiographic (binding of [3H]dexamethasone mesylate) analysis of the membrane proteins from the membrane antigen-positive group revealed multiple protein bands ranging in size from 85 to 145 kilodaltons. Furthermore, comparison of the glucocorticoid sensitivity of these groups of cells showed complete lysis of the membrane antigen-positive cells and only partial lysis of the antigen-deficient group, which suggests that the lysis response of cells to glucocorticoids is mediated by a glucocorticoid receptor-like molecule located in the plasma membrane.


A Retrospective Analysis of Gabapentinoid and Opioids to Opioid Monotherapy for Pain Relief in Patients with Chronic Neck and Low Back Pain.
We compared the reduction in pain and opioid consumption in patients with chronic spinal pain on concomitant gabapentinoids and opioids with patients using opioids only. This was a retrospective chart review of patients with chronic neck or low back pain who were on opioids with at least a 24-month follow-up. Single-center pain clinic in an urban setting. 167 patients with chronic spinal pain lasting at least six months. Patients on gabapentin or pregabalin were included in the gabapentinoid group, while the other patients were included in the non-gabapentinoid group. Primary outcome was assessment of pain scores measured via a numeric rating scale (NRS), and secondary outcomes were response to the treatment (>2 point reduction on NRS) and daily opioid use measured in morphine milliequivalents. Pain scores were reduced in the first six months and plateaued after that in both groups. At the end of 24 months, the average pain score was 6.71 in the gabapentinoid group, while the average pain score was 7.18 in the non-gabapentinoid group. There was no statistical significance between the groups (p = 0.28). There was no difference in response to treatment in gabapentinoid group (33.3%) when compared with non-gabapentinoid group (32.7%). We also failed to find any significant difference in daily opioid usage between the two groups. Gabapentinoids may not lead to reduction in pain or opioid consumption in patients with chronic spinal pain. A careful approach must be adopted while prescribing gabapentinoids in the chronic spinal pain patient population.


[Clinical characteristics and geriatric evaluation of elderly patients with pneumonia in a hospital in Buenos Aires, Argentina].
In order to determine the clinical and geriatric characteristics of elderly adults with pneumonia in a hospital in Buenos Aires, Argentina, a cross-sectional study was carried out in 2010, included 66 patients hospitalized for pneumonia. The mean age of the study subjects was 82, 54.5% of whom were men. 47.0% of the hospitalizations were due to community-acquired pneumonia. As for the functional evaluation, 31.8% showed dependence in performing basic activities of daily living and 69.4% presented dependence in instrumental activities of daily living. The most frequent clinical characteristics observed were fever, cough, dyspnea and expectoration. The causative agent of pneumonia was identified in 34.8% of the cases, 18 of which were bacterial (27.2%) and 5 viral (7.5%). The crude mortality rate was 28.8%, but was close to 50% in those patients having confusional syndrome. We conclude that pneumonia in elderly patients has special characteristics, which can be observed with a proper diagnostic and geriatric evaluation.


Genome-scale network analysis of imprinted human metabolic genes.
System analysis of metabolic network reconstructions can be used to calculate functional states or phenotypes. This provides tools to study the metabolic effects of genetic and epigenetic properties, such as dosage sensitivity. We used the genome-scale reconstruction of human metabolism (Recon 1) to analyze the effect of nine known or predicted imprinted genes on metabolic phenotypes. Simulations of maternal deletion of ATP10A indicated an anabolic metabolism consistent with the known clinical phenotypes of obesity. The abnormal expression of the other genes affected fewer subsections of metabolism consistent with a lack of established clinical phenotypes. We found that four of nine genes had metabolic effect as predicted by the Haig's parental conflict theory.


The Effects of Nursing Case Management on Self-Care Behaviors, Clinical Outcomes, and Quality of Life Among Community-Dwelling Older Adults with Poorly Controlled Type 2 Diabetes in Thailand.
This study evaluated the effectiveness of nursing case management on self-care, clinical outcomes, and quality of life in community-dwelling older adults with poorly controlled type 2 diabetes in Thailand. The research employed a quasi-experimental, single-group, pretest - posttest design. Methods: Twenty-three participants participated in a 12-week nursing case management program, which was tailored to the individual's needs and abilities, as well as their family, community, and healthcare context. Self-care behaviors increased significantly (p = .000) after implementation of the case management program, while waist circumference, fasting capillary blood glucose, and hemoglobin A1c decreased significantly (p = .001, p = .000, p = .003, respectively) from pre-intervention values. Quality of life was significantly better after the program (p = .000) than before. Results suggest that implementing tailored nursing case management could increase self-care behaviors and quality of life while decreasing waist circumference, fasting capillary blood glucose, and hemoglobin A1c in community-dwelling older adults with poorly controlled type 2 diabetes. The effectiveness of nursing case management depends on the healthcare context, the training and expertise of case managers, as well as the patient's needs and preferences. Furthermore, the availability of families and communities can influence the nursing case management outcomes.


Updated meta-analysis of classical fear conditioning in the anxiety disorders.
The aim of the current study was twofold: (1) to systematically examine differences in fear conditioning between anxiety patients and healthy controls using meta-analytic methods, and (2) to examine the extent to which study characteristics may account for the variability in findings across studies. Forty-four studies (published between 1920 and 2013) with data on 963 anxiety disordered patients and 1,222 control subjects were obtained through PubMed and PsycINFO, as well as from a previous meta-analysis on fear conditioning (Lissek et al.). Results demonstrated robustly increased fear responses to conditioned safety cues (CS-) in anxiety patients compared to controls during acquisition. This effect may represent an impaired ability to inhibit fear in the presence of safety cues (CS-) and/or may signify an increased tendency in anxiety disordered patients to generalize fear responses to safe stimuli resembling the conditioned danger cue (CS+). In contrast, during extinction, patients show stronger fear responses to the CS+ and a trend toward increased discrimination learning (differentiation between the CS+ and CS-) compared to controls, indicating delayed and/or reduced extinction of fear in anxiety patients. Finally, none of the included study characteristics, such as the type of fear measure (subjective vs. psychophysiological index of fear), could account significantly for the variance in effect sizes across studies. Further research is needed to investigate the predictive value of fear extinction on treatment outcome, as extinction processes are thought to underlie the beneficial effects of exposure treatment in anxiety disorders.


Student health policies of U.S. medical schools.
Medical students are at risk of exposure to bloodborne pathogens, yet few data are available about U.S. medical schools' policies to protect students. A cross-sectional survey of the student affairs deans at the 126 U.S. medical schools was conducted in May 1994. A confidential questionnaire inquired about policies regarding vaccination for hepatitis B virus (HBV), blood and body-fluid exposures, universal precautions training, and health and disability insurance for students. A total of 108 (86%) of the schools participated in the survey. Most (99, 92%) required either HBV vaccination, evidence of immunity, or a signed waiver refusing vaccination. Nearly all (94, 87%) required health insurance, and almost all (101, 94%) offered a plan (at a mean cost of $690 annually), but fewer schools (69, 64%) offered disability insurance. The schools frequently held students responsible for the costs of HBV vaccination (73, 68%), postexposure serologic testing (22, 20%), and treatment of training-related medical problems (43, 40%). Most medical schools comply with current recommendations for preventing training-related exposures to bloodborne pathogens, illness, and injury, but students face a substantial financial responsibility for these services at a time when many have large debts. Many schools do not have disability insurance readily available for students. Medical schools should review their student health policies to protect students adequately.


Arrested development: the effects of incarceration on the development of psychosocial maturity.
Improvements in temperance, perspective, and responsibility are a part of typical development of psychosocial maturity during adolescence. The existing literature suggests that the developmental course of psychosocial maturity is influenced by normative variations in social context, but little is known about how atypical contexts, such as incarceration, influence its development. The study investigates how the development of psychosocial maturity is affected by incarceration, using data from a 7-year longitudinal study of 1,171 adolescent males. We compared the effects of confinement in juvenile facilities with varying degrees of focus on incarceration versus rehabilitation (i.e., secure vs. residential treatment facilities) and tested whether facility quality and age at incarceration moderate the effect of incarceration on psychosocial maturity. The results indicate that incarceration in a secure setting, but not a residential treatment facility, is associated with a short-term decline in temperance and responsibility. The total amount of time incarcerated in a residential treatment facility, but not a secure setting, had a negative effect on the developmental trajectory of psychosocial maturity. Age at incarceration, but not the facility quality, moderated the effect of recent incarceration: older youths were more susceptible to short-term negative effects of recent incarceration in a secure setting, but they also benefited more than younger participants from short-term positive effects of incarceration in a residential treatment setting. Furthermore, youths who perceived their incarceration setting as unsafe evinced a decline in temperance. Future research and policy implications are discussed.


Secondary Metabolites in Ramalina terebrata Detected by UHPLC/ESI/MS/MS and Identification of Parietin as Tau Protein Inhibitor.
Liquid chromatography coupled with mass spectrometry is an outstanding methodology for fast analysis of phenolic compounds in biological samples. Twenty two compounds were quickly and accurately identified in the methanolic extract of the Antarctic lichen Ramalina terebrata for the first time using ultra high pressure liquid chromatography coupled with photodiode array detector and high resolution mass spectrometry (UHPLC-PDA-Q/Orbitrap/MS/MS). In addition, the extract and the four compounds isolated from this species were tested for the inhibitory activity of tau protein aggregation, which is a protein involved in Alzheimer's disease (AD). All compounds showed null activity with the exception of parietin, which it was able to inhibit aggregation process of tau in a concentration range between 3 µg/mL (10 µM) to 28 µg/mL (100 µM). In addition, we show how parietin interact with tau (306)VQIVYK(311) hexapeptide inside of the microtubule binding domain (4R) with the help of molecular docking experiments. Finally, the constituents present in the methanolic extract could possibly contribute to the established anti-aggregation activity for this extract and this in-depth analysis of the chemical composition of R. terebrata could guide further research into its medicinal properties and potential uses.


Identification of anti-virulence compounds that disrupt quorum-sensing regulated acute and persistent pathogenicity.
Etiological agents of acute, persistent, or relapsing clinical infections are often refractory to antibiotics due to multidrug resistance and/or antibiotic tolerance. Pseudomonas aeruginosa is an opportunistic Gram-negative bacterial pathogen that causes recalcitrant and severe acute chronic and persistent human infections. Here, we target the MvfR-regulated P. aeruginosa quorum sensing (QS) virulence pathway to isolate robust molecules that specifically inhibit infection without affecting bacterial growth or viability to mitigate selective resistance. Using a whole-cell high-throughput screen (HTS) and structure-activity relationship (SAR) analysis, we identify compounds that block the synthesis of both pro-persistence and pro-acute MvfR-dependent signaling molecules. These compounds, which share a benzamide-benzimidazole backbone and are unrelated to previous MvfR-regulon inhibitors, bind the global virulence QS transcriptional regulator, MvfR (PqsR); inhibit the MvfR regulon in multi-drug resistant isolates; are active against P. aeruginosa acute and persistent murine infections; and do not perturb bacterial growth. In addition, they are the first compounds identified to reduce the formation of antibiotic-tolerant persister cells. As such, these molecules provide for the development of next-generation clinical therapeutics to more effectively treat refractory and deleterious bacterial-human infections.


Diabetes and Quality of Life: Initial Approach to Depression, Physical Activity, and Sexual Dysfunction.
The different aspects that contribute to quality of life in patients with diabetes mellitus, such as mood, are of great importance for the treatment of this disease. These aspects not only influence the well-being of patients but also influence treatment adherence, therefore affecting the course of the disease. A panel of experts from Argentina, Chile, and Uruguay performed a review of the main aspects affecting quality of life in patients with diabetes: physical activity, mood disorders, and sexual activity. The consensus of the panel was that physical activity is important in the treatment of patients with diabetes because it reduces morbidity, mortality, and disease complications, and it should be performed on a regular basis, bearing in mind the patient's characteristics. Increased physical activity is associated with better glycemic control, and in individuals with glucose intolerance, it delays progression toward diabetes. In patients with diabetes, there is a high prevalence of depression, which can influence treatment adherence. Therefore, early detection of depression is essential to improve the course of diabetes. Regarding sexual activity, erectile dysfunction may be a significant sign in the case of suspected diabetes and the early diagnosis of vasculopathy in patients with diabetes. In conclusion, greater emphasis should be placed on improving patient knowledge, early detection, and multidisciplinary approaches to deal with the aspects of diabetes that affect patients' quality of life.


Using Machine Learning to Assess Physician Competence: A Systematic Review.
To identify the different machine learning (ML) techniques that have been applied to automate physician competence assessment and evaluate how these techniques can be used to assess different competence domains in several medical specialties. In May 2017, MEDLINE, EMBASE, PsycINFO, Web of Science, ACM Digital Library, IEEE Xplore Digital Library, PROSPERO, and Cochrane Database of Systematic Reviews were searched for articles published from inception to April 30, 2017. Studies were included if they applied at least one ML technique to assess medical students', residents', fellows', or attending physicians' competence. Information on sample size, participants, study setting and design, medical specialty, ML techniques, competence domains, outcomes, and methodological quality was extracted. MERSQI was used to evaluate quality, and a qualitative narrative synthesis of the medical specialties, ML techniques, and competence domains was conducted. Of 4,953 initial articles, 69 met inclusion criteria. General surgery (24; 34.8%) and radiology (15; 21.7%) were the most studied specialties; natural language processing (24; 34.8%), support vector machine (15; 21.7%), and hidden Markov models (14; 20.3%) were the ML techniques most often applied; and patient care (63; 91.3%) and medical knowledge (45; 65.2%) were the most assessed competence domains. A growing number of studies have attempted to apply ML techniques to physician competence assessment. Although many studies have investigated the feasibility of certain techniques, more validation research is needed. The use of ML techniques may have the potential to integrate and analyze pragmatic information that could be used in real-time assessments and interventions.


Albumin helps mediate removal of taurocholate by rat liver.
Perfused rat liver removes 97% of the taurocholate from the afferent circulation when the perfusate albumin concentration is 0.5 g/dl. Increasing the albumin concentration 10-fold reduces the concentration of free taurocholate by a factor of five but produces only a 50% reduction in the apparent uptake coefficient. A similar discrepancy is evident from a model-independent analysis of the extraction fractions. From these observations we argue that uptake is not driven solely, or even predominantly, by the plasma concentration of free taurocholate but also depends on interaction between albumin and the cell surface. Nonequilibrium binding, saturation kinetics, and an inhomogeneous population of liver cells are considered as alternative explanations and excluded. The possibility that albumin exerts its effect by enhancing the diffusion of taurocholate across an unstirred layer in the Disse space appears improbable but cannot be eliminated.


Immunoregulation of a viral model of multiple sclerosis using the synthetic cannabinoid R+WIN55,212.
Theiler murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD) is a mouse model of chronic-progressive multiple sclerosis (MS) characterized by Th1-mediated CNS demyelination and spastic hindlimb paralysis. Existing MS therapies reduce relapse rates in 30% of relapsing-remitting MS patients, but are ineffective in chronic-progressive disease, and their effects on disability progression are unclear. Experimental studies demonstrate cannabinoids are useful for symptomatic treatment of spasticity and tremor in chronic-relapsing experimental autoimmune encephalomyelitis. Cannabinoids, however, have reported immunosuppressive properties. We show that the cannabinoid receptor agonist, R+WIN55,212, ameliorates progression of clinical disease symptoms in mice with preexisting TMEV-IDD. Amelioration of clinical disease is associated with downregulation of both virus and myelin epitope-specific Th1 effector functions (delayed-type hypersensitivity and IFN-gamma production) and the inhibition of CNS mRNA expression coding for the proinflammatory cytokines, TNF-alpha, IL1-beta, and IL-6. Clinical trials investigating the therapeutic potential of cannabinoids for the symptomatic treatment of MS are ongoing, and this study demonstrates that they may also have potent immunoregulatory properties.


The oxysterol-binding protein superfamily: new concepts and old proteins.
The Kes1 OSBP (oxysterol-binding protein) is a key regulator of membrane trafficking through the TGN (trans-Golgi network) and endosomal membranes. We demonstrated recently that Kes1 acts as a sterol-regulated rheostat for TGN/endosomal phosphatidylinositol 4-phosphate signalling. Kes1 utilizes its dual lipid-binding activities to integrate endosomal lipid metabolism with TORC1 (target of rapamycin complex 1)-dependent proliferative pathways and transcriptional control of nutrient signalling.


Protein-Embedded Metalloporphyrin Arrays Templated by Circularly Permuted Tobacco Mosaic Virus Coat Proteins.
Bioenergetic processes in nature have relied on networks of cofactors for harvesting, storing, and transforming the energy from sunlight into chemical bonds. Models mimicking the structural arrangement and functional crosstalk of the cofactor arrays are important tools to understand the basic science of natural systems and to provide guidance for non-natural functional biomaterials. Here, we report an artificial multiheme system based on a circular permutant of the tobacco mosaic virus coat protein (cpTMV). The double disk assembly of cpTMV presents a gap region sandwiched by the two C2-symmetrically related disks. Non-native bis-his coordination sites formed by the mutation of the residues in this gap region were computationally screened and experimentally tested. A cpTMV mutant Q101H was identified to create a circular assembly of 17 protein-embedded hemes. Biophysical characterization using X-ray crystallography, cyclic voltammetry, and electron paramagnetic resonance (EPR) suggested both structural and functional similarity to natural multiheme cytochrome c proteins. This protein framework offers many further engineering opportunities for tuning the redox properties of the cofactors and incorporating non-native components bearing varied porphyrin structures and metal centers. Emulating the electron transfer pathways in nature using a tunable artificial system can contribute to the development of photocatalytic materials and bioelectronics.


Transcriptional consequences of genomic structural aberrations in breast cancer.
Using a long-span, paired-end deep sequencing strategy, we have comprehensively identified cancer genome rearrangements in eight breast cancer genomes. Herein, we show that 40%-54% of these structural genomic rearrangements result in different forms of fusion transcripts and that 44% are potentially translated. We find that single segmental tandem duplication spanning several genes is a major source of the fusion gene transcripts in both cell lines and primary tumors involving adjacent genes placed in the reverse-order position by the duplication event. Certain other structural mutations, however, tend to attenuate gene expression. From these candidate gene fusions, we have found a fusion transcript (RPS6KB1-VMP1) recurrently expressed in ∼30% of breast cancers associated with potential clinical consequences. This gene fusion is caused by tandem duplication on 17q23 and appears to be an indicator of local genomic instability altering the expression of oncogenic components such as MIR21 and RPS6KB1.


Cumulative Lactation and Onset of Hypertension in African-American Women.
Hypertension affects nearly 1 of 3 women and contributes to cardiovascular disease, the leading cause of death in the United States. Breastfeeding leads to metabolic changes that could reduce risks of hypertension. Hypertension disproportionately affects black women, but rates of breastfeeding among black women lag behind those in the general population. In the Black Women's Health Study (n = 59,001), we conducted a nested case-control analysis using unconditional logistic regression to estimate the association between breastfeeding and incident hypertension at ages 40-65 years using data collected from 1995 to 2011. Controls were frequency-matched 2:1 to 12,513 hypertensive women by age and questionnaire cycle. Overall, there was little evidence of association between ever breastfeeding and incident hypertension (odds ratio = 0.97, 95% confidence interval: 0.92, 1.02). However, age modified the relationship (P = 0.02): Breastfeeding was associated with reduced risk of hypertension at ages 40-49 years (odds ratio = 0.92, 95% confidence interval: 0.85, 0.99) but not at older ages. In addition, risk of hypertension at ages 40-49 years decreased with increasing duration of breastfeeding (P for trend = 0.08). Our results suggest that long-duration breastfeeding may reduce the risk of incident hypertension in middle age. Addressing breastfeeding as a potential preventative health behavior is particularly compelling because it is required for only a discrete period of time.


Reliability and validity of the English (Singapore) and Chinese (Singapore) versions of the Short-Form 36 version 2 in a multi-ethnic urban Asian population in Singapore.
We aimed to evaluate the measurement properties of the Singapore English and Chinese versions of the Short-Form 36 version 2 (SF-36v2) Questionnaire, an improved version of the widely used SF-36, for assessing health-related quality of life (HRQoL) in a multi-ethnic urban Asian population in Singapore. SF-36v2 scores and data on medical history, demographic and lifestyle factors from the Singapore Prospective Study Programme were analyzed. Convergent and divergent validity, internal consistency, floor and ceiling effects, known group validity and factor structure of the SF-36v2 were assessed for the English and Chinese versions, respectively. Complete data for 4,917 participants (45.8 %) out of 10,747 eligible individuals were analyzed (survey language: 4,115 English and 802 Chinese). Item-scale correlations exceeded 0.4 for all items of the English SF-36v2 and for all except one item of the Chinese SF-36v2 (bathe and dress: item-scale correlation: 0.36). In the English SF-36v2, Cronbach's alpha exceeded 0.70 for all scales. In the Chinese SF-36v2, Cronbach's alpha exceeded 0.7 on all scales except social functioning (Cronbach's alpha: 0.68). For known groups validity, respondents with chronic medical conditions expectedly reported lower SF-36v2 score on most English and Chinese SF-36v2 scales. In confirmatory factor analysis, the Singapore three-component model was favored over the United States two-component and Japan three-component models. The English and Chinese SF-36v2 are valid and reliable for assessing HRQoL among English and Chinese-speaking Singaporeans. Test-retest reliability and responsiveness of the English and Chinese SF-36v2 in Singapore remain to be evaluated.


DeSanctis-Cacchione syndrome. A case report with autopsy findings.
One of the first patients studied by Cleaver on the DNA repair defect to ultraviolet light damage in xeroderma pigmentosum has been subjected to autopsy examination. This patient had the DeSanctis-Cacchione syndrome (microcephaly, dwarfism, mental deficiency, and choreoathetosis). Her autopsy findings were similar to those of the other three patients with this syndrome, emphasizing olivopontocerebellar atrophy, who underwent autopsy. The patient apparently could not tolerate psoralens because of increased incidence of carcinoma formation.


Distinct substance P and calcitonin gene-related peptide immunoreactive nerves in the guinea pig eye.
Using a double labeling indirect immunofluorescent technique, we studied the guinea pig trigeminal ganglion and eye for co-localization of substance P and calcitonin gene-related peptide. In the trigeminal ganglion, the number of neurons immunoreactive for calcitonin gene-related peptide significantly outnumber those immunoreactive for substance P, but virtually all substance P positive neurons are immunoreactive for calcitonin gene-related peptide. In the eye, a complex pattern of co-localization is present; both peptides co-localize in most immunoreactive nerve fibers. Nerve fibers immunoreactive only for calcitonin gene-related peptide tend to be concentrated in the cornea and posterior ciliary body. Nerve fibers immunoreactive only for substance P are present in relation to both iris muscles. Sensory denervation by intracranial transection of the ophthalmic and maxillary nerves fails to eliminate these substance P positive but CGRP negative iris nerve fibers. These findings indicate an alternative origin for substance P immunoreactive nerves supplying the iris muscles in this species.


Blood urea nitrogen in the early assessment of acute pancreatitis: an international validation study.
Objective assessment of acute pancreatitis (AP) is critical to help guide resuscitation efforts. Herein we (1) validate serial blood urea nitrogen (BUN) measurement for early prediction of mortality and (2) develop an objective BUN-based approach to early assessment in AP. We performed a secondary analysis of 3 prospective AP cohort studies: Brigham and Women's Hospital (BWH), June 2005 through May 2009; the Dutch Pancreatitis Study Group (DPSG), March 2004 through March 2007; and the University of Pittsburgh Medical Center (UPMC), June 2003 through September 2007. Meta-analysis and stratified multivariate logistic regression adjusted for age, sex, and creatinine levels were calculated to determine risk of mortality associated with elevated BUN level at admission and rise in BUN level at 24 hours. The accuracy of the BUN measurements was determined by area under the receiver operating characteristic curve (AUC) analysis compared with serum creatinine measurement and APACHE II score. A BUN-based assessment algorithm was derived on BWH data and validated on the DPSG and UPMC cohorts. A total of 1043 AP cases were included in analysis. In pooled analysis, a BUN level of 20 mg/dL or higher was associated with an odds ratio (OR) of 4.6 (95% confidence interval [CI], 2.5-8.3) for mortality. Any rise in BUN level at 24 hours was associated with an OR of 4.3 (95% CI, 2.3-7.9) for death. Accuracy of serial BUN measurement (AUC, 0.82-0.91) was comparable to that of the APACHE II score (AUC, 0.72-0.92) in each of the cohorts. A BUN-based assessment algorithm identified patients at increased risk for mortality during the initial 24 hours of hospitalization. We have confirmed the accuracy of BUN measurement for early prediction of mortality in AP and developed an algorithm that may assist physicians in their early resuscitation efforts.


Three-element optical system with a given fixed position of optical center.
Our paper presents a detailed theoretical analysis of the three-element optical system with zero separation of principal planes and approximately corrected Petzval sum, which has the required value of the axial position of its optical center for a given value of focal length and a given value of axial distance of the image focal point from the last element of the system. Formulas that make it possible to calculate paraxial parameters of such types of optical systems are derived, and the application of the derived formulas is presented in several examples. Such optical systems represent a subset of the new family of optical systems with the constant position of the optical center. The optical center of such an optical system is at a given required axial position, and this position does not change with the object distance, which could be advantageous for certain applications.


Prediction of cytotoxicity of heavy metals adsorbed on nano-TiO2 with periodic table descriptors using machine learning approaches.
Nanoparticles with their unique features have attracted researchers over the past decades. Heavy metals, upon release and emission, may interact with different environmental components, which may lead to co-exposure to living organisms. Nanoscale titanium dioxide (nano-TiO2) can adsorb heavy metals. The current idea is that nanoparticles (NPs) may act as carriers and facilitate the entry of heavy metals into organisms. Thus, the present study reports nanoscale quantitative structure-activity relationship (nano-QSAR) models, which are based on an ensemble learning approach, for predicting the cytotoxicity of heavy metals adsorbed on nano-TiO2 to human renal cortex proximal tubule epithelial (HK-2) cells. The ensemble learning approach implements gradient boosting and bagging algorithms; that is, random forest, AdaBoost, Gradient Boost, and Extreme Gradient Boost were constructed and utilized to establish statistically significant relationships between the structural properties of NPs and the cause of cytotoxicity. To demonstrate the predictive ability of the developed nano-QSAR models, simple periodic table descriptors requiring low computational resources were utilized. The nano-QSAR models generated good R2 values (0.99-0.89), Q2 values (0.64-0.77), and Q2F1 values (0.99-0.71). Thus, the present work manifests that ML in conjunction with periodic table descriptors can be used to explore the features and predict unknown compounds with similar properties.


Nonoperative management of unusual blunt traumatic rupture of the thoracic aorta.
A conservative nonoperative method of management was utilized in an atypical case of blunt traumatic rupture of the thoracic aorta. In unusual or complicated tears of the aortic arch, as described here, a delayed or expectant method of management may be justified.


Rapid Lewis Acid Screening and Reaction Optimization Using 3D-Printed Catalyst-Impregnated Stirrer Devices in the Synthesis of Heterocycles.
We describe the development of Lewis acid (LA) catalyst-impregnated 3D-printed stirrer devices and demonstrate their ability to facilitate the rapid screening of reaction conditions to synthesize heterocycles. The stereolithography 3D-printed stirrer devices were designed to fit round-bottomed flasks and Radleys carousel tubes using our recently reported solvent-resistant resin, and using CFD modeling studies and experimental data, we demonstrated that the device design leads to rapid mixing and rapid throughput over the device surface. Using a range of LA 3D-printed stirrers, the reaction between a diamine and an aldehyde was optimized for the catalyst and solvent, and we demonstrated that use of the 3D-printed catalyst-embedded devices led to higher yields and reduced reaction times. A library of benzimidazole and benzothiazole compounds were synthesized, and the use of devices led to efficient formation of the product as well as low levels of the catalyst in the resultant crude mixture. The use of these devices makes the process of setting up multiple reactions simpler by avoiding weighing out of catalysts, and the devices, once used, can be simply removed from the reaction, making the process of compound library synthesis more facile.


[Current combination chemotherapy containing paclitaxel for advanced, recurrent gastric cancer].
5-FU has been a key chemotherapeutic agent in the treatment of advanced or recurrent gastric cancer. In order to enhance the effect of 5-FU, biochemical modulation or combination chemotherapy has been developed. Although several phase III studies were reported in the 1990s, a standard chemotherapeutic regimen has not been established worldwide. Recently, a newly developed anticancer agent, Paclitaxel, can be clinically used for advanced gastric cancer either as a single agent or in combination with such as 5-FU, cisplatin, and TS-1. It may well further improve the quality of life and prolong the survival of patients with gastric cancer. Further assessment for the well design phase III clinical trials will be necessary to establish the availability of such combination modalities for the treatment of advanced, recurrent gastric cancer.


miR-186 regulates glycolysis through Glut1 during the formation of cancer-associated fibroblasts.
Emerging evidence has suggested that glycolysis is enhanced in cancer-associated fibroblasts (CAF), and miR-186 is downregulated during the CAF formation. However, it is not clear whether miR-186 is involved in the regulation of glycolysis and what the role of miR-186 plays during the CAF formation. In this study, quantitative PCR analysises show miR-186 is downregulated during the CAF formation. Moreover, miR-186 targets the 3' UTR of Glut1, and its overexpression results in the degradation of Glut1 mRNA, which eventually reduces the level of Glut1 protein. On the other hand, knockdown of miR-186 increased the expression of Glut1. Both time course and dose response experiments also demonstrated that the protein and mRNA levels of Glut1 increase during CAF formation, according to Western blot and quantitative PCR analyses, respectively. Most importantly, besides the regulation on cell cycle progression, miR-186 regulates glucose uptake and lactate production which is mediated by Glut1. These observations suggest that miR-186 plays important roles in glycolysis regulation as well as cell cycle checkpoint activation.


Anemia among pregnant women in Cambodia: A descriptive analysis of temporal and geospatial trends and logistic regression-based examination of factors associated with anemia in pregnant women.
Anemia is a major public health problem for thirty-two million pregnant women worldwide. Anemia during pregnancy is a leading cause of child low birth weight, preterm birth, and perinatal/neonatal mortality. Pregnant women are at higher risk of anemia due to micronutrient deficiencies, hemoglobinopathies, infections, socio-demographic and behavioral factors. This study aimed to: 1) assess temporal and geospatial trends of anemia in Cambodia and 2) identify factors associated with anemia among pregnant women aged 15-49 years old in Cambodia. We analyzed data from the Cambodia Demographic and Health Survey (CDHS) for 2005, 2010, and 2014. Data were pooled across the three survey years for all pregnant women aged 15-49 years. Survey weights were applied to account for the complex survey design of the CDHS. Descriptive statistics were estimated for key sociodemographic characteristics of the study population. We used logistic regressions to assess factors associated with anemia among pregnant women aged 15-49 years old. Anemia in pregnant women aged 15-49 in Cambodia decreased from 56% in 2005 to 53% in 2014. With the highest in Preah Vihear and Stung Treng provinces (74.3%), in Kratie province (73%), and in Prey Veng (65.4%) in 2005, 2010, and 2014 respectively. Compared to pregnant women from the wealthiest households, women from poorest households were more likely to have anemia (AOR = 2.8; 95% CI: 1.6-4.9). Pregnant women from coastal regions were almost twice as likely of having anemia (AOR = 1.9; 95% CI: 1.2-3.0). Pregnant women were more likely anemic if they were in their 2nd trimester (AOR = 2.6; 95% CI: 1.9-3.6) or 3rd trimester (AOR = 1.6 95% CI: 1.1-2.3). Anemia remains highly prevalent among pregnant women in Cambodia. Public health interventions and policies to alleviate anemia should be prioritized and shaped to address these factors.


Ultrasound-guided ilioinguinal/iliohypogastric nerve blocks versus caudal block for postoperative analgesia in children undergoing unilateral groin surgery.
Ultrasound (US) guidance is strongly recommended when performing peripheral nerve blocks in infants and children. To assess whether US-guided ilioinguinal/iliohypogastric (II/IH) nerve blocks with local anesthetic (LA) would provide comparable postoperative analgesia to blind technique caudal block with LA following pediatric unilateral groin surgery. Secondary endpoints included analgesic consumption, parental satisfaction, and postoperative complications. Prospective, crossover randomized controlled trial performed on children undergoing unilateral groin surgery. Fifty children aged 1-6 years scheduled for unilateral groin surgery were included in the study. After induction of general anesthesia and prior to surgical incision, patients were prospectively randomized into one of two groups: Group B received US-guided II/IH nerve blocks with 0.1 ml.kg(-1) of 0.25% bupivacaine and Group C received a caudal blockade with 0.7 ml.kg(-1) of 0.25% bupivacaine. Patients were assessed in the recovery room, the day-stay unit and for 24 h at home for pain score, analgesic consumption, and parental satisfaction. Arithmetic mean and standard deviation values were calculated and statistical analyses were performed for each group. Independent sample t-test was used to compare continuous variables exhibiting normal distribution, and Chi-squared test or Fisher exact test for non-continuous variables. P<0.05 was considered significant. The average pain scores during hospital stay were 1.82±1.71and 1.52±1.41 for group C and group B respectively (P>0.05). The average time to first rescue analgesia was longer in group B 253±102.6 min as compared to 219.6±48.4 min in group C. In recovery room, four patients in group C required pain rescue medication compared to five patients in group B (P>0.05). Similarly eight patients in the group C and six patients in group B required pain rescue medication at day-stay unit or at home (P>0.05). Group C received 0.74 pain rescue medication doses (range 0-8), while group B received 0.65 pain rescue medication doses (range 0-6) at hospital and at home (P>0.05). US-guided II/IH nerve blocks is an ideal postoperative analgesic for unilateral groin surgery in children, particularly hernia repairs and is as effective as caudal block, with a lower volume of local anesthetics.


Plasmodesmata-located protein overexpression negatively impacts the manifestation of systemic acquired resistance and the long-distance movement of Defective in Induced Resistance1 in Arabidopsis.
Systemic acquired resistance (SAR) is a plant defence response that provides immunity to distant uninfected leaves after an initial localised infection. The lipid transfer protein (LTP) Defective in Induced Resistance1 (DIR1) is an essential component of SAR that moves from induced to distant leaves following a SAR-inducing local infection. To understand how DIR1 is transported to distant leaves during SAR, we analysed DIR1 movement in transgenic Arabidopsis lines with reduced cell-to-cell movement caused by the overexpression of Plasmodesmata-Located Proteins PDLP1 and PDLP5. These PDLP-overexpressing lines were defective for SAR, and DIR1 antibody signals were not observed in phloem sap-enriched petiole exudates collected from distant leaves. Our data support the idea that cell-to-cell movement of DIR1 through plasmodesmata is important during long-distance SAR signalling in Arabidopsis.


[Diagnosis and conservative treatment of tubal pregnancy using pelviscopy in comparison with laparotomy].
Operative pelviscopy substitutes at the Department of Obstetrics and Gynecology, University of Kiel, laparotomy for the treatment of tubal pregnancy in ruptured and non-ruptured tubes. Tubectomy, as well as tubal incision with the extraction of the pregnancy product and consecutive suture of the tubes is possible by pelviscopy. All patients with conservative treated tubal pregnancy by pelviscopy are explained that remnants can remain; careful beta-hCG-measurements over a time of at least 14 days post operatively have to be performed. Pregnancy rates in patients with the desire to have children after the pelviscopic treatment reach the same level of success as after a treatment by laparotomy. The operation technique is for the patient less physically stress-full and leads to a faster healing process. The hospitalization time with this treatment is shortened to a maximum of 2-3 days.


Quadricuspid aortic valve with centrally fenestrated leaflets causing aortic insufficiency.
The occurrence of a quadricuspid aortic valve with single, central leaflet fenestrations causing aortic insufficiency has not previously been reported. We recently encountered these features during aortic valve replacement for severe aortic regurgitation in a 20-year-old man who had had a history of aortic insufficiency since age 2 years. The patient's late increase in symptoms was probably due to the fact that 1 of the 4 leaflets was somewhat flail, allowing incomplete coaptation and producing regurgitation over and above that caused by the central fenestrations.


Prevalence and influence of tibial tunnel widening after isolated anterior cruciate ligament reconstruction using patella-bone-tendon-bone-graft: long-term follow-up.
The aim of the present study was to evaluate incidence, degree and impact of tibial tunnel widening (TW) on patient-reported long-term clinical outcome, knee joint stability and prevalence of osteoarthritis (OA) after isolated anterior cruciate ligament (ACL) reconstruction. On average, 13.5 years after ACL reconstruction via patella-bone-tendon-bone autograft, 73 patients have been re-evaluated. Inclusion criteria consisted of an isolated anterior cruciate ligament rupture and reconstruction, a minimum of 10-year follow-up and no previous anterior cruciate ligament repair or associated intra-articular lesions. Clinical evaluation was performed via the International Knee Documentation Committee (IKDC) score and the Tegner and Lysholm scores. Instrumental anterior laxity testing was carried out with the KT-1000™ arthrometer. The degree of degenerative changes and the prevalence of osteoarthritis were assessed with the Kellgren-Lawrence score. Tibial tunnel enlargement was radiographically evaluated on both antero-posterior and lateral views under establishment of 4 degrees of tibial tunnel widening by measuring the actual tunnel diameters in mm on the sclerotic margins of the inserted tunnels on 3 different points (T1-T3). Afterwards, a conversion of the absolute values in mm into a 4 staged ratio, based on the comparison to the results of the initial drill-width, should provide a better quantification and statistical analysis. Evaluation was performed postoperatively as well as on 2 year follow-up and 13 years after ACL reconstruction. Minimum follow-up was 10 years. 75% of patients were graded A or B according to IKDC score. The mean Lysholm score was 90.2±4.8 (25-100). Radiological assessment on long-term follow-up showed in 45% a grade I, in 24% a grade II, in 17% a grade III and in additional 12% a grade IV enlargement of the tibial tunnel. No evident progression of TW was found in comparison to the 2 year results. Radiological evaluation revealed degenerative changes in sense of a grade II OA in 54% of patients. Prevalence of a grade III or grade IV OA was found in 20%. Correlation analysis showed no significant relationship between the amount of tibial tunnel enlargement (P>0.05), long-term clinical results, anterior joint laxity or prevalence of osteoarthritis. Tunnel widening remains a radiological phenomenon which is most commonly observed within the short to midterm intervals after anterior cruciate ligament reconstruction and subsequently stabilises on mid and long- term follow-up. It does not adversely affect long-term clinical outcome and stability. Furthermore, tunnel widening doesn't constitute an increasing prevalence of osteoarthritis.


Association between pediatric traumatic brain injury and epilepsy at later ages in Finland: A nationwide register-based cohort study.
This study was undertaken to examine how pediatric traumatic brain injury (pTBI) correlates with incidence of epilepsy at later ages in Finland. This nationwide retrospective register-based cohort study extended from 1998 to 2018. The study group consisted of 71 969 pediatric (<18 years old) patients hospitalized with TBI and a control group consisting of 64 856 pediatric patients with distal extremity fracture. Epilepsy diagnoses were gathered from the Finnish Social Insurance Institution. Kaplan-Meier and multivariable Cox regression models were conducted to analyze the probability of epilepsy with 95% confidence intervals (CIs). Cumulative incidence rates (CIRs) for the first 2 years were .5% in the pTBI group and .1% in the control group. The corresponding rates after 15 years of follow-up were 1.5% in the pTBI group and .7% in the control group. Due to proportional hazard violations, the study population was split to the first 2 years and in subgroup analysis 4 years. During the first 2 years of surveillance, the hazard ratio (HR) for the pTBI group was 4.38 (95% CI = 3.39-5.66). However, between years 2 and 20, the HR for the pTBI group was 2.02 (95% CI = 1.71-2.38). A total of 337 patients (.47%) underwent neurosurgery, and 36 (10.7%) patients subsequently developed epilepsy. The CIR for the first year after TBI was 4.5% (95% CI = 2.3-6.7) in operatively managed patients and .3% (95% CI = .3-.4) in nonoperatively managed patients. Corresponding figures after 15 years were 12.0% (95% CI = 8.2-15.8) and 1.5% (95% CI = 1.4-1.6). During the first 4 years of surveillance, the HR for the operative pTBI group was 14.37 (95% CI = 9.29-20.80) and 3.67 (95% CI = 1.63-8.22) between years 4 and 20. pTBI exposes patients to a higher risk for posttraumatic epilepsy for many years after initial trauma. Children who undergo operative management for TBI have a high risk for epilepsy, and this risk was highest during the first 4 years after injury.


Management of alcoholic hepatitis.
About 5,000 people die each year from chronic liver disease in England and Wales alone. In many patients, the liver injury is due to chronic excessive alcohol consumption and manifests as alcoholic hepatitis (an acute inflammation of the liver), cirrhosis, or alcoholic hepatitis superimposed on a background of cirrhosis. Mild alcoholic hepatitis may be asymptomatic and reversible, but where the hepatitis is more severe, up to 65% of those affected die from it. The incidence of alcoholic hepatitis in the UK seems set to increase with the rise in heavy drinking, particularly among women. Here we review how patients with alcoholic hepatitis should be managed.


Increased oxidative stress and damage in patients with chronic bacterial prostatitis.
To investigate whether chronic bacterial prostatitis (CBP) increases oxidative stress and damage in patients with CBP, and to explore its possible mechanism. Eighty patients with CBP and 80 healthy adults as controls were enrolled in a case-control study, in which levels of nitric oxide (NO), vitamin C (VC), and vitamin E (VE) in plasma, as well as malondialdehyde (MDA), activities of superoxide dismutase (SOD), and catalase (CAT) in erythrocytes were determined by spectrophotometry. Compared with the average values of NO, VC, VE, MDA, SOD, and CAT in the healthy control group, those of plasma NO and erythrocyte MDA in the CBP group were significantly increased (P < 0.001), and those of plasma VC and VE as well as erythrocyte SOD and CAT in the CBP group were significantly decreased (P < 0.001). Findings from partial correlation analysis for course of the disease and NO, VC, VE, MDA, SOD, and CAT in 80 patients with CBP, adjusted for age, suggested that with prolonged course of the disease, values of NO and MDA were gradually increased (P < 0.001), and those of VC, VE, SOD, and CAT were gradually decreased (P < 0.05-0.001). The findings from stepwise regression analysis for course of the disease and NO, VC, VE, MDA, SOD, and CAT in CBP group suggested that the model of stepwise regression was Y = -19.1160 + 0.3112MDA + 0.0337NO, F = 22.1734, P < 0.001, r = 0.6045, P < 0.001. The findings from the reliability analysis for VC, VE, SOD, CAT, NO, and MDA in the CBP group showed that the reliability coefficients' alpha (6 items) was 0.7195, P < 0.0001, and the standardized item alpha was 0.9307, P < 0.0001. There exist increased oxidative stress and damage induced by chronic bacterial prostatitis in patients, and such a phenomenon is closely related to the course of disease.


Genome-wide features of neuroendocrine regulation in Drosophila by the basic helix-loop-helix transcription factor DIMMED.
Neuroendocrine (NE) cells use large dense core vesicles (LDCVs) to traffic, process, store and secrete neuropeptide hormones through the regulated secretory pathway. The dimmed (DIMM) basic helix-loop-helix transcription factor of Drosophila controls the level of regulated secretory activity in NE cells. To pursue its mechanisms, we have performed two independent genome-wide analyses of DIMM's activities: (i) in vivo chromatin immunoprecipitation (ChIP) to define genomic sites of DIMM occupancy and (ii) deep sequencing of purified DIMM neurons to characterize their transcriptional profile. By this combined approach, we showed that DIMM binds to conserved E-boxes in enhancers of 212 genes whose expression is enriched in DIMM-expressing NE cells. DIMM binds preferentially to certain E-boxes within first introns of specific gene isoforms. Statistical machine learning revealed that flanking regions of putative DIMM binding sites contribute to its DNA binding specificity. DIMM's transcriptional repertoire features at least 20 LDCV constituents. In addition, DIMM notably targets the pro-secretory transcription factor, creb-A, but significantly, DIMM does not target any neuropeptide genes. DIMM therefore prescribes the scale of secretory activity in NE neurons, by a systematic control of both proximal and distal points in the regulated secretory pathway.


Bullying Victimization in Medically Hospitalized Patients With Somatic Symptom and Related Disorders: Prevalence and Associated Factors.
The purpose of this study is to describe the prevalence of bullying victimization among medically admitted patients with somatic symptom and related disorders (SSDs) and to compare demographic, diagnostic, and psychosocial characteristics of bullied versus nonbullied patients. Medically admitted patients at a tertiary pediatric facility referred to the Psychiatry Consultation Service with somatic concerns were assessed via a quality improvement (QI) initiative, the SSD Standardized Clinical Assessment and Management Plan (SSD-SCAMP). Retrospective chart and QI data on adolescent and young adult patients assessed via SSD-SCAMP from May 2012 - December 2014 were reviewed. Medical records of 282 patients (aged 12-22 years) diagnosed with SSDs were reviewed. Approximately 37% had a history of bullying victimization. Compared with nonbullied patients, bullied patients had higher somatization scores, more functional neurologic symptoms, and longer admissions. Bullied patients also had higher rates of comorbid anxiety, suicidal histories, and family psychiatric histories. Furthermore, bullied patients also had higher rates of learning disabilities and school accommodations and endorsed more significant life events within the year before hospitalization. This study describes the unique health and psychosocial challenges experienced by medically hospitalized bullied adolescents and young adults with SSDs. The findings highlight the importance of a multidisciplinary approach to assessment and management. By implementing QI initiatives such as the SSD-SCAMP, providers can bridge the gap between the clinical needs and long-term management of patients with SSDs.


Guidelines to Classify Female Subject Groups in Sport-Science Research.
To review current cycling-related sport-science literature to formulate guidelines to classify female subject groups and to compare this classification system for female subject groups with the classification system for male subject groups. A database of 82 papers that described female subject groups containing information on preexperimental maximal cycle-protocol designs, terminology, biometrical and physiological parameters, and cycling experience was analyzed. Subject groups were divided into performance levels (PLs), according to the nomenclature. Body mass, body-mass index, maximal oxygen consumption (VO2max), peak power output (PPO), and training status were compared between PLs and between female and male PLs. Five female PLs were defined, representing untrained, active, trained, well-trained, and professional female subjects. VO2max and PPO significantly increased with PL, except for PL3 and PL4 (P < .01). For each PL, significant differences were observed in absolute and relative VO2max and PPO between male and female subject groups. Relative VO2max is the most cited parameter for female subject groups and is proposed as the principal parameter to classify the groups. This systematic review shows the large variety in the description of female subject groups in the existing literature. The authors propose a standardized preexperimental testing protocol and guidelines to classify female subject groups into 5 PLs based on relative VO2max, relative PPO, training status, absolute VO2max, and absolute PPO.


Molecular packing in 1-hexanol-DMPC bilayers studied by molecular dynamics simulation.
The structure and molecular packing density of a "mismatched" solute, 1-hexanol, in lipid membranes of dimyristoyl phosphatidylcholine (DMPC) was studied by molecular dynamics simulations. We found that the average location and orientation of the hexanol molecules matched earlier experimental data on comparable systems. The local density or molecular packing in DMPC-hexanol was elucidated through the average Voronoi volumes of all heavy (non-hydrogen) atoms. Analogous analysis was conducted on trajectories from simulations of pure 1-hexanol and pure (hydrated) DMPC bilayers. The results suggested a positive volume change, DeltaV(m), of 4 cm(3) mol(-1) hexanol partitioned at 310 K in good accordance with experimental values. Analysis of the apparent volumes of each component in the pure and mixed states further showed that DeltaV(m) reflects a balance between a substantial increase in the packing density of the alcohol upon partitioning and an even stronger loosening in the packing of the lipid. Furthermore, analysis of Voronoi volumes along the membrane normal identifies a distinctive depth dependence of the changes in molecular packing. The outer (interfacial) part of the lipid acyl chains (up to C8) is stretched by about 4%. Concomitantly, the average lateral area per chain decreases and these two effects compensate so that the overall packing density in the outer region, where the hexanol molecules are located, remains practically constant. The core of the bilayer (C9-C13) is slightly thinned. The average lateral area per chain in this region expands, resulting in a looser packing density. The net effect in the core is a 2-3% decrease in density corresponding to a total volume increase of approximately 14 cm(3) mol(-1) hexanol partitioned.


Immunotherapy for autoimmune and inflammatory renal diseases.
New treatments for autoimmune renal disease are required, and a developing knowledge of its underlying immunopathogenesis has identified sites where immunotherapy is likely to be effective. Experience with intravenous immunoglobulin and lymphocyte depletion by monoclonal antibodies in systemic vasculitis and systemic lupus erythematosus is awaiting confirmation by randomized trials. Treatments at or near clinical testing include monoclonal antibody blockade of leucocyte-endothelial interactions and CD40 mediated B-cell activation, and immunoablation with autologous stem-cell transplantation for more severe multisystem autoimmune disease.


Anatomy and relationships of the suprascapular nerve: anatomical constraints to mobilization of the supraspinatus and infraspinatus muscles in the management of massive rotator-cuff tears.
Thirty-one shoulders in eighteen cadavera were dissected to allow study of the neurovascular anatomy of the rotator cuff and to help determine the limits of mobilization of the cuff for the repair of chronic massive retracted tears. The dissection demonstrated the diameter, length, and relationships of the suprascapular nerve and its branches and made clear the dangers of extensive mobilization and advancement of the supraspinatus and infraspinatus muscles. The suprascapular nerve ran an oblique course across the supraspinatus fossa, was relatively fixed on the floor of the fossa, and was tethered underneath the transverse scapular ligament. In twenty-six (84 per cent) of the thirty-one shoulders, there were no more than two motor branches to the supraspinatus muscle, and the first was always the larger of the two. In twenty-six (84 per cent) of the thirty-one shoulders, the first motor branch originated underneath the transverse scapular ligament or just distal to it. In one shoulder (3 per cent), the first motor branch passed over the ligament. The average distance from the origin of the long tendon of the biceps to the motor branches of the supraspinatus was three centimeters. In fifteen (48 per cent) of the thirty-one shoulders, the infraspinatus muscle had three or four motor branches of the same size. The average distance from the posterior rim of the glenoid to the motor branches of the infraspinatus muscle was two centimeters. The motor branches to the supraspinatus muscle were fewer, usually smaller, and significantly shorter than those to the infraspinatus muscle. The standard anterosuperior approach allowed only one centimeter of lateral advancement of either tendon and limited the ability of the surgeon to dissect safely beyond the neurovascular pedicle. The advancement technique of Debeyre et al., or a modification of that technique, permitted lateral advancement of each muscle of as much as three centimeters and was limited by tension in the motor branches of the suprascapular nerve. In some situations, the safe limit of advancement may be even less. We concluded that lateral advancement of the rotator cuff is limited anatomically and may place the neurovascular structures at risk.


Comparison between different cell kinetic variables in human breast cancer.
Cell kinetics holds a prominent role among biological factors in predicting clinical outcome and response to treatment in neoplastic patients. Different cell kinetic variables are often considered as valid alternatives to each other, but the limited size of case series analysed in several studies and the lack of simultaneous determinations of all the variables on the same tumours do not justify this conclusion. In the present study, the correlation between [3H]thymidine labelling index ([3H]dT LI), flow cytometric S phase cell fraction (FCM-S) and Ki-67 immunoreactivity (Ki-67/MIB-1) was verified and the type of correlation with the most important clinical, pathological and biological patient and tumour characteristics was investigated in a very large series of breast cancer patients. Ki-67/MIB-1, FCM-S and [3H]dT LI were determined in 609, 526 and 485 patients, respectively, and all three cell proliferation indices were evaluated in parallel on the same tumour in a series of 330 breast cancer patients. All the cell kinetic determinations were performed within the context of National Quality Control Programmes. Very poor correlation coefficients (ranging from 0.37 to 0.18) were observed between the different cell kinetic variables determined in parallel on the same series of breast cancers. Moreover, Ki-67/MIB-1 and FCM-S showed a significant relationship with histological type, grade and tumour size, whereas statistically significant correlations were not observed for [3H]dT LI. In conclusion, the results show that the different cell kinetic variables provide different biological information and cannot be considered as alternatives to each other.


Effects of voluntary running on plasma levels of neurotrophins, hippocampal cell proliferation and learning and memory in stressed rats.
Previous studies have shown that a 2-week treatment with 40 mg/kg corticosterone (CORT) in rats suppresses hippocampal neurogenesis and decreases hippocampal brain-derived neurotrophic factor (BDNF) levels and impairs spatial learning, all of which could be counteracted by voluntary wheel running. BDNF and insulin-like growth factor (IGF-1) have been suggested to mediate physical exercise-enhanced hippocampal neurogenesis and cognition. Here we examined whether such running-elicited benefits were accompanied by corresponding changes of peripheral BDNF and IGF-1 levels in a rat model of stress. We examined the effects of acute (5 days) and chronic (4 weeks) treatment with CORT and/or wheel running on (1) hippocampal cell proliferation, (2) spatial learning and memory and (3) plasma levels of BDNF and IGF-1. Acute CORT treatment improved spatial learning without altered cell proliferation compared to vehicle treatment. Acute CORT-treated non-runners showed an increased trend in plasma BDNF levels together with a significant increase in hippocampal BDNF levels. Acute running showed no effect on cognition, cell proliferation and peripheral BDNF and IGF-1 levels. Conversely, chronic CORT treatment in non-runners significantly impaired spatial learning and suppressed cell proliferation in association with a decreased trend in plasma BDNF level and a significant increase in hippocampal BDNF levels. Running counteracted cognitive deficit and restored hippocampal cell proliferation following chronic CORT treatment; but without corresponding changes in plasma BDNF and IGF-1 levels. The results suggest that the beneficial effects of acute stress on cognitive improvement may be mediated by BDNF-enhanced synaptic plasticity that is hippocampal cell proliferation-independent, whereas chronic stress may impair cognition by decreasing hippocampal cell proliferation and BDNF levels. Furthermore, the results indicate a trend in changes of plasma BDNF levels associated with a significant alteration in hippocampal levels, suggesting that treatment with running/CORT for 4 weeks may induce a change in central levels of hippocampal BDNF level, which may not lead to a significant change in peripheral levels.


Apolipoprotein E-deficient mice develop an anti-Chlamydophila pneumoniae T helper 2 response and resist vascular infection.
Hypercholesterolemia could inhibit the immune response against various pathogens. No information is available about its impact on the immune response toward Chlamydophila pneumoniae. Apolipoprotein E (apoE)-deficient and wild-type mice fed a normal diet were infected with a single intranasal inoculation of viable C. pneumoniae. Whereas interferon gamma concentrations (T helper 1 response) were similar in the lungs and spleen of apoE-deficient and wild-type mice, increased concentrations of interleukin 10, interleukin 6, and interleukin 4 (T helper 2 response) were found in the lungs of apoE-deficient mice. The spleen B lymphocyte percentage and interleukin 4 levels and serum specific antibody titers were higher in apoE-deficient mice. C. pneumoniae infection was facilitated neither in the lungs nor in the aorta of these mice. On the contrary, the number of apoE-deficient mice with detectable levels of bacterial DNA in the aorta was clearly decreased. When low-density lipoprotein receptor-deficient mice fed a normal diet were similarly infected, no difference in the interleukin 4 concentration and infection level was observed in the lungs and no protection was found in the aorta. Mild hypercholesterolemia in mice does not facilitate C. pneumoniae persistence in the vascular wall. ApoE deficiency, rather than mild hypercholesterolemia, probably favors the development of an unusual anti-C. pneumoniae T helper 2 response and protects against vascular infection.


The Transmembrane Helix Tilt May Be Determined by the Balance between Precession Entropy and Lipid Perturbation.
Hydrophobic helical peptides interact with lipid bilayers in various modes, determined by the match between the length of the helix's hydrophobic core and the thickness of the hydrocarbon region of the bilayer. For example, long helices may tilt with respect to the membrane normal to bury their hydrophobic cores in the membrane, and the lipid bilayer may stretch to match the helix length. Recent molecular dynamics simulations and potential of mean force calculations have shown that some TM helices whose lengths are equal to, or even shorter than, the bilayer thickness may also tilt. The tilt is driven by a gain in the helix precession entropy, which compensates for the free energy penalty resulting from membrane deformation. Using this free energy balance, we derived theoretically an equation of state, describing the dependence of the tilt on the helix length and membrane thickness. To this end, we conducted coarse-grained Monte Carlo simulations of the interaction of helices of various lengths with lipid bilayers of various thicknesses, reproducing and expanding the previous molecular dynamics simulations. Insight from the simulations facilitated the derivation of the theoretical model. The tilt angles calculated using the theoretical model agree well with our simulations and with previous calculations and measurements.


Population structure and antimicrobial resistance patterns of Salmonella Typhi isolates in urban Dhaka, Bangladesh from 2004 to 2016.
Multi-drug resistant typhoid fever remains an enormous public health threat in low and middle-income countries. However, we still lack a detailed understanding of the epidemiology and genomics of S. Typhi in many regions. Here we have undertaken a detailed genomic analysis of typhoid in urban Dhaka, Bangladesh to unravel the population structure and antimicrobial resistance patterns in S. Typhi isolated between 2004-2016. Whole genome sequencing of 202 S. Typhi isolates obtained from three study locations in urban Dhaka revealed a diverse range of S. Typhi genotypes and AMR profiles. The bacterial population within Dhaka were relatively homogenous with little stratification between different healthcare facilities or age groups. We also observed evidence of exchange of Bangladeshi genotypes with neighboring South Asian countries (India, Pakistan and Nepal) suggesting these are circulating throughout the region. This analysis revealed a decline in H58 (genotype 4.3.1) isolates from 2011 onwards, coinciding with a rise in a diverse range of non-H58 genotypes and a simultaneous rise in isolates with reduced susceptibility to fluoroquinolones, potentially reflecting a change in treatment practices. We identified a novel S. Typhi genotype, subclade 3.3.2 (previously defined only to clade level, 3.3), which formed two localized clusters (3.3.2.Bd1 and 3.3.2.Bd2) associated with different mutations in the Quinolone Resistance Determining Region (QRDR) of gene gyrA. Our analysis of S. Typhi isolates from urban Dhaka, Bangladesh isolated over a twelve year period identified a diverse range of AMR profiles and genotypes. The observed increase in non-H58 genotypes associated with reduced fluoroquinolone susceptibility may reflect a change in treatment practice in this region and highlights the importance of continued molecular surveillance to monitor the ongoing evolution of AMR in Dhaka. We have defined new genotypes and lineages of Bangladeshi S. Typhi which will facilitate the identification of these emerging AMR clones in future surveillance efforts.


From community of practice to epistemic community - law, discipline and security in the battle for the legalisation of medical cannabis in Poland.
Although public debates on cannabis are ongoing in many countries, there are currently no EU-wide rules for either medical or recreational use of cannabis. Numerous studies have illustrated that creating such rules is a complex challenge. The battle over the legalisation of medical use of cannabis in Poland is a good example for analysing the mutual impact of the social practices that various actors perform through and by the discourses in the field of health care: how they discursively create their own roles and take positions and how they shape the coalitions and opposition in trying to achieve their strategic goals. This article aims to reconstruct and explain how different types of knowledge are discursively used to sustain or question power relations in the healthcare field. The dispersed knowledge-power influences social actors, who try to define or redefine social practices and aspire to guide them in the healthcare field. The presented approach allows authors to go beyond the social actors' perception vs institutional regulations and to analyse discursive actions as elements of the complex networks of meanings activating various type of resources. Those dynamic networks, involving the different (and sometimes the same) actors in the different actions, open the new fields of rationality. Starting by identifying the crucial actors and their discursive actions visible in the mainstream press discourse, we will reconstruct three types of groups related to medical cannabis. We will then investigate three types of dispositives - law, discipline and security - to investigate the relations between discursive and non-discursive elements. The proposed analysis belongs to the Critical Discourse Analysis (CDA) paradigm and includes investigation of the media discourses and in-depth interviews with the identified actors.


Allergic bronchopulmonary aspergillosis: review of literature and proposal of new diagnostic and classification criteria.
Allergic bronchopulmonary aspergillosis (ABPA) is an immunological pulmonary disorder caused by hypersensitivity to Aspergillus fumigatus, manifesting with poorly controlled asthma, recurrent pulmonary infiltrates and bronchiectasis. There are estimated to be in excess of four million patients affected world-wide. The importance of recognizing ABPA relates to the improvement of patient symptoms, and delay in development or prevention of bronchiectasis, one manifestation of permanent lung damage in ABPA. Environmental factors may not be the only pathogenetic factors because not all asthmatics develop ABPA despite being exposed to the same environment. Allergic bronchopulmonary aspergillosis is probably a polygenic disorder, which does not remit completely once expressed, although long-term remissions do occur. In a genetically predisposed individual, inhaled conidia of A. fumigatus germinate into hyphae with release of antigens that activate the innate and adaptive immune responses (Th2 CD4(+) T cell responses) of the lung. The International Society for Human and Animal Mycology (ISHAM) has constituted a working group on ABPA complicating asthma (www.abpaworkinggroup.org), which convened an international conference to summarize the current state of knowledge, and formulate consensus-based guidelines for diagnosis and therapy. New diagnosis and staging criteria for ABPA are proposed. Although a small number of randomized controlled trials have been conducted, long-term management remains poorly studied. Primary therapy consists of oral corticosteroids to control exacerbations, itraconazole as a steroid-sparing agent and optimized asthma therapy. Uncertainties surround the prevention and management of bronchiectasis, chronic pulmonary aspergillosis and aspergilloma as complications, concurrent rhinosinusitis and environmental control. There is need for new oral antifungal agents and immunomodulatory therapy.


Glyoxalase II, a detoxifying enzyme of glycolysis byproduct methylglyoxal and a target of p63 and p73, is a pro-survival factor of the p53 family.
The p53 family proteins are transcription factors and have both common and distinct functions. p53 is a classic tumor suppressor, whereas p63 and p73 have fundamental functions in development. To gain an insight into the functional diversities among the p53 family, target genes specifically regulated by p63 and p73 were examined. Here, we found that the GLX2 gene, which encodes glyoxalase II enzyme, is up-regulated by p63 and p73. Accordingly, a specific responsive element was found in intron 1 of the GLX2 gene, which can be activated and bound by p63 and p73. We also found that, upon overexpression, the cytosolic, but not the mitochondrial, GLX2 inhibits the apoptotic response of a cell to methylglyoxal, a by-product of glycolysis. Likewise, we showed that cells deficient in GLX2 are hypersensitive to methylglyoxal-induced apoptosis. Interestingly, a deficiency in GLX2 also enhances the susceptibility of a cell to DNA damage-induced apoptosis in a p53-dependent manner. These observations reveal a novel link between the p53 family and the glyoxalase system. Given that methylglyoxal is frequently generated under both physiological and pathological conditions, we postulate that GLX2 serves as a pro-survival factor of the p53 family and plays a critical role in the normal development and in the pathogenesis of various human diseases, including cancer, diabetes, and neurodegenerative diseases.


Timeline of changes in appetite during weight loss with a ketogenic diet.
Diet-induced weight loss (WL) leads to increased hunger and reduced fullness feelings, increased ghrelin and reduced satiety peptides concentration (glucagon-like peptide-1 (GLP-1), cholecystokinin (CCK) and peptide YY (PYY)). Ketogenic diets seem to minimise or supress some of these responses. The aim of this study was to determine the timeline over which changes in appetite occur during progressive WL with a ketogenic very-low-energy diet (VLED). Thirty-one sedentary adults (18 men), with obesity (body mass index: 37±4.5 kg m-2) underwent 8 weeks (wks) of a VLED followed by 4 wks of weight maintenance. Body weight and composition, subjective feelings of appetite and appetite-related hormones (insulin, active ghrelin (AG), active GLP-1, total PYY and CCK) were measured in fasting and postprandially, at baseline, on day 3 of the diet, 5 and 10% WL, and at wks 9 and 13. Data are shown as mean±s.d. A significant increase in fasting hunger was observed by day 3 (2±1% WL), (P<0.01), 5% WL (12±8 days) (P<0.05) and wk 13 (17±2% WL) (P<0.05). Increased desire to eat was observed by day 3 (P<0.01) and 5% WL (P<0.05). Postprandial prospective food consumption was significantly reduced at wk 9 (16±2% WL) (P<0.01). Basal total PYY was significantly reduced at 10% WL (32±8 days) (P<0.05). Postprandial active GLP-1 was increased at 5% WL (P<0.01) and CCK reduced at 5 and 10% WL (P<0.01, for both) and wk 9 (P<0.001). Basal and postprandial AG were significantly increased at wk 13 (P<0.001, both). WL with a ketogenic VLED transiently increases the drive to eat up to 3 weeks (5% WL). After that, and while participants are ketotic, a 10-17% WL is not associated with increased appetite. However, hunger feelings and AG concentrations increase significantly from baseline, once refeeding occurs.


Facilitated Asynchronous Online Learning to Build Public Health Strategic Skills.
The COVID-19 pandemic spurred significant government investments for hiring public health workers. There are clear opportunities to help build capacities among both current and incoming public health workers, closing well-elucidated skill gaps. To report on the development process, methods used, and outcomes seen from a point-in-time public health workforce capacity-building initiative, Public Health Essentials (PHE) . Capacity-building outcomes evaluation using pre/postintervention measures. The United States. A total of 512 learners working in roles (government or adjacent to) that support public health. PHE, a cohort-based facilitated asynchronous online course comprising 5 units, 18 modules, 54 learning outcomes, and 266 teaching and applied assessment elements designed to build public health strategic skills. Two outputs and 3 outcomes were used to assess and improve progress in achieving our goal of building generalizable and transferrable public health ability and confidence among diverse public health workers: Use of PHE , PHE completion rate , Learner competence , Change in self-assessed ability , and Benefits of PHE. From September 2021 to December 2022, 4 agencies used PHE for fellowship training or employee capacity building. Some 79% (n = 512) of learners completed the training, demonstrating competence in all 54 areas assessed by expert course facilitators. Of those, 79% (n = 321) completed both optional pre- and post-PHE surveys, reporting statistically significant gains in all strategic skill domains assessed (n = 9), regardless of demographics and public health experience. Learners gained new skills and knowledge (92%), developed a better understanding of public health (86%), and broadened their public health skill base (84%). A majority can apply the knowledge and skills gained directly to their work (94%), which benefits their team (92%), and have increased their confidence as public health practitioners (49%). PHE can significantly improve learners' ability across 9 strategic skill areas in as few as 15 weeks, regardless of their demographics, training, or experience.


Team-based care and improved blood pressure control: a community guide systematic review.
Uncontrolled hypertension remains a widely prevalent cardiovascular risk factor in the U.S. team-based care, established by adding new staff or changing the roles of existing staff such as nurses and pharmacists to work with a primary care provider and the patient. Team-based care has the potential to improve the quality of hypertension management. The goal of this Community Guide systematic review was to examine the effectiveness of team-based care in improving blood pressure (BP) outcomes. An existing systematic review (search period, January 1980-July 2003) assessing team-based care for BP control was supplemented with a Community Guide update (January 2003-May 2012). For the Community Guide update, two reviewers independently abstracted data and assessed quality of eligible studies. Twenty-eight studies in the prior review (1980-2003) and an additional 52 studies from the Community Guide update (2003-2012) qualified for inclusion. Results from both bodies of evidence suggest that team-based care is effective in improving BP outcomes. From the update, the proportion of patients with controlled BP improved (median increase=12 percentage points); systolic BP decreased (median reduction=5.4 mmHg); and diastolic BP also decreased (median reduction=1.8 mmHg). Team-based care increased the proportion of people with controlled BP and reduced both systolic and diastolic BP, especially when pharmacists and nurses were part of the team. Findings are applicable to a range of U.S. settings and population groups. Implementation of this multidisciplinary approach will require health system-level organizational changes and could be an important element of the medical home.


Selective serotonin reuptake inhibitor augmentation in the treatment of negative symptoms of schizophrenia.
The treatment of negative symptoms of schizophrenia presents a major clinical challenge. This review examines the evidence pertaining to the efficacy, tolerability and safety of adding selective serotonin reuptake inhibitors (SSRIs) to antipsychotic agents in the treatment of negative symptoms in schizophrenia. Important methodological issues such as differentiating primary and secondary negative symptoms are discussed. The balance of available evidence indicates that at least some SSRIs, fluvoxamine and fluoxetine, can ameliorate primary negative symptoms in chronic schizophrenia patients who are treated with typical antipsychotics. The combination is safe and well tolerated although, as antipsychotic drug concentrations may be elevated, attention to dose and drug monitoring should be considered as appropriate. The effect of SSRI augmentation of atypical antipsychotics requires further study. Combination with clozapine may require particular caution because of potential toxicity if serum clozapine levels rise steeply. SSRI augmentation may be a useful addition to the treatment of schizophrenia.


Bioactive mono-dispersed nanospheres with long-term antibacterial effects for endodontic sealing.
Endodontic sealers with antibacterial capability play an important role in preventing reinfection of an endodontically treated root canal and improving the long-term success of root canal treatment. However, current endodontic sealers rapidly lose their antibacterial properties after fixation. In this work, we designed and synthesized quaternized mono-dispersed bioactive nanospheres as a potential substrate for the development of a long-term antibacterial endodontic sealer with excellent cytocompatibility and biocompatibility. First, mono-dispersed silica-based bioactive glass nanospheres (SBG-NS) were prepared via a modified sol-gel process. Next, a series of quaternary ammonium methacrylate salts (QAMs) with broad antibacterial spectra were synthesized and grafted onto the surfaces of the SBG-NS via a two-step coupling approach. The antibacterial effect of the quaternary ammonium polymethacrylate (QAPM)-containing SBG-NS (SBG-QAPM) against persistent microorganisms associated with infected root canals was evaluated using a direct contact test. Evaluations of the SBG-QAPM cytocompatibility and biocompatibility were performed using LIVE/DEAD staining, 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl-2, 5-tetrazoliumbromide (MTT) assay, and a calvarial implantation model. The results showed that the SBG-QAPMs had the strongest long-term antibacterial effect against the Enterococcus faecalis, Streptococcus mutans, and Streptococcus sanguis during the study period, the best cytocompatibility, and the lowest systemic inflammation compared to three commercial products: ProRoot MTA, Endomethasone C, and AH Plus. In addition, the SBG-QAPMs showed excellent stability in aqueous solution. This work indicates that the SBG-QAPMs are promising substrates for the development of long-term antibacterial endodontic sealers.


Perspectives on the etiology of chronic rhinosinusitis: an immune barrier hypothesis.
Chronic rhinosinusitis (CRS) has been defined as persistent symptomatic inflammation of the nasal and sinus mucosa resulting from the interaction of multiple host and environmental factors. Recent studies have implicated Alternaria fungi or toxigenic Staphylococcus aureus as critical agents in CRS pathogenesis. The emphasis on environmental agents in CRS etiology has focused interest toward elimination of those agents as the prime mechanism of therapy. This viewpoint is in marked contrast to the current perspective on some other chronic inflammatory epithelial disorders that afflict the skin, lungs, and gut, wherein host factors are believed to predispose to disease expression in the presence of ubiquitous environmental agents. The current review evaluates CRS etiology from this perspective and considers that CRS develops, in part, as an outcome of a dysfunctional host response. Specifically, evidence from our laboratory and others will be reviewed indicating that CRS is associated with a failure of the mechanical and immunologic barriers across the nasal mucosa. The hypothesis would further propose that genetic and epigenetic variation predisposes susceptible individuals to barrier failure in the presence of environmental stress leading to CRS. From this unifying perspective, bacteria and fungi are seen as disease modifiers rather than primary etiologic agents. The goal is to place concepts of CRS pathophysiology in a framework consistent with a current understanding of chronic inflammation in general and epithelial disease in particular.


6th Annual Bioanalysis in Clinical Research conference.
The 6th Annual Bioanalysis in Clinical Research conference held recently in London, UK, targeted numerous themes of significant current interest within the discipline of bioanalysis. The conference invited a diverse speaker panel and attracted an audience consisting of researchers from the pharmaceutical industry, CROs and academia. The range of topics presented covered LC-MS and ligand-binding assays, small- and large-molecule quantification, regulatory issues and concerns and new technologies. Within the scope of LC-MS bioanalysis, presentation topics included new developments in dried blood spot technologies, the use of direct analysis MS techniques, eliminating matrix effects through direct-electron ionization MS, and the complications of developing and validating LC-MS methods for the quantitative determination of endogenous biomarkers. With respect to ligand binding, the importance of assay validation being a continuous process, extending into study analysis, was a recurrent theme in several presentations along with the hot topic of immunogenicity. Of relevance to both analytical disciplines were the presentations on regulatory topics covering the EMA guidelines on method validation and bioanalysis within bioequivalence clinical studies.


Global biogeochemical implications of mercury discharges from rivers and sediment burial.
Rivers are an important source of mercury (Hg) to marine ecosystems. Based on an analysis of compiled observations, we estimate global present-day Hg discharges from rivers to ocean margins are 27 ± 13 Mmol a(-1) (5500 ± 2700 Mg a(-1)), of which 28% reaches the open ocean and the rest is deposited to ocean margin sediments. Globally, the source of Hg to the open ocean from rivers amounts to 30% of atmospheric inputs. This is larger than previously estimated due to accounting for elevated concentrations in Asian rivers and variability in offshore transport across different types of estuaries. Riverine inputs of Hg to the North Atlantic have decreased several-fold since the 1970s while inputs to the North Pacific have increased. These trends have large effects on Hg concentrations at ocean margins but are too small in the open ocean to explain observed declines of seawater concentrations in the North Atlantic or increases in the North Pacific. Burial of Hg in ocean margin sediments represents a major sink in the global Hg biogeochemical cycle that has not been previously considered. We find that including this sink in a fully coupled global biogeochemical box model helps to balance the large anthropogenic release of Hg from commercial products recently added to global inventories. It also implies that legacy anthropogenic Hg can be removed from active environmental cycling on a faster time scale (centuries instead of millennia). Natural environmental Hg levels are lower than previously estimated, implying a relatively larger impact from human activity.


Novel Antioxidant Peptides Derived from Feather Keratin Alleviate H2O2-Induced Oxidative Damage in HepG2 Cells via Keap1/Nrf2 Pathway.
Reactive oxygen species (ROS) are crucial for signal transduction and the maintenance of cellular homeostasis. However, superfluous ROS may engender chronic pathologies. Feather keratin is a promising new source of antioxidant peptides that can eliminate excess ROS and potentially treat oxidative stress-related diseases, but the underlying mechanisms have remained elusive. This study investigated the antioxidant effects and mechanisms against H2O2-induced oxidative damage in HepG2 cells of the two latest discovered antioxidant peptides, CRPCGPTP (CP-8) and ANSCNEPCVR (AR-10), first decrypted from feather keratin. The results revealed that CP-8 and AR-10 did not exhibit cytotoxicity to HepG2 cells while reducing intracellular ROS accumulation. Simultaneously, they enhanced the activities of catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px), thus alleviating H2O2-induced cell apoptosis. Molecular docking analysis demonstrated that CP-8, AR-10 interacted well with the key amino acids in the Kelch domain of Keap1, thereby directly disrupting the Keap1-Nrf2 interaction. The peptides' biosafety and antioxidant activity via Keap1/Nrf2 signaling lay the groundwork for further animal studies and applications as functional food additives.


Environmental and lifestyle factors associated with overweight and obesity in Perth, Australia.
To examine associations between environmental and lifestyle factors and overweight or obesity. A cross-sectional survey and an environmental scan of recreational facilities. Metropolitan Perth, Western Australia. Healthy sedentary workers and homemakers aged 18 to 59 years (n = 1803) living in areas within the top and bottom quintiles of social disadvantage. Four lifestyle factors, one social environmental factor, and five physical environment factors (three objectively measured). After adjustment for demographic factors and other variables in the model, overweight was associated with living on a highway (odds ratio [OR], 4.24; 95% confidence interval [CI], 1.62-11.09) or streets with no sidewalks or sidewalks on one side only (OR, 1.35; 95% CI, 1.03-1.78) and perceiving no paths within walking distance (OR, 1.42; 95% CI, 1.08-1.86). Poor access to four or more recreational facilities (OR, 1.68; 95% CI, 1.11-2.55) and sidewalks (OR, 1.62; 95% CI, .98-2.68) and perceiving no shop within walking distance (OR, 1.84; 95% CI, 1.01-3.36) were associated with obesity. Conversely, access to a motor vehicle all the time was negatively associated with obesity (OR, .56; 95% CI, .32-.99). Watching 3 or more hours of television daily (ORs, 1.92 and 1.85, respectively) and rating oneself as less active than others (ORs, 1.66 and 4.05, respectively) were associated with both overweight and obesity. After adjustment for individual demographic factors and all other variables in the model, socioeconomic status of area of residence and leisure-time physical activity were not associated with overweight or obesity. Factors that influence overweight and obesity appear to differ, but aspects of the physical environment may be important. Objectively measured neighborhood environment factors warrant further investigation.


[Use of monoclonal antibodies in the diagnosis of ophthalmic chlamydiosis].
A total of 168 patients with various ocular diseases were tested for Chlamydia. Scrapings off the conjunctiva were examined by the fluorescent antibody technique with monoclonal antibodies. A high diagnostic efficacy of the method in patients with acute and, which is even more important, with the subacute form of ophthalmic chlamydiasis was demonstrated. Moreover, the method effectively diagnosed ophthalmic chlamydiasis in patients with inflammations of the anterior and median segments of the eye of obscure etiology.


Untangling taxonomy: a DNA barcode reference library for Canadian spiders.
Approximately 1460 species of spiders have been reported from Canada, 3% of the global fauna. This study provides a DNA barcode reference library for 1018 of these species based upon the analysis of more than 30,000 specimens. The sequence results show a clear barcode gap in most cases with a mean intraspecific divergence of 0.78% vs. a minimum nearest-neighbour (NN) distance averaging 7.85%. The sequences were assigned to 1359 Barcode index numbers (BINs) with 1344 of these BINs composed of specimens belonging to a single currently recognized species. There was a perfect correspondence between BIN membership and a known species in 795 cases, while another 197 species were assigned to two or more BINs (556 in total). A few other species (26) were involved in BIN merges or in a combination of merges and splits. There was only a weak relationship between the number of specimens analysed for a species and its BIN count. However, three species were clear outliers with their specimens being placed in 11-22 BINs. Although all BIN splits need further study to clarify the taxonomic status of the entities involved, DNA barcodes discriminated 98% of the 1018 species. The present survey conservatively revealed 16 species new to science, 52 species new to Canada and major range extensions for 426 species. However, if most BIN splits detected in this study reflect cryptic taxa, the true species count for Canadian spiders could be 30-50% higher than currently recognized.


Recent developments in the pathology of primary pulmonary salivary gland-type tumours.
Primary pulmonary salivary gland-type tumours are rare neoplasms that are thought to arise from seromucinous glands that are located in the submucosa of large airways. These neoplasms have clinical and pathologic features that are distinct from other pulmonary neoplasms. The majority of primary pulmonary salivary gland-type tumours are malignant, with the most common entities being mucoepidermoid carcinoma, adenoid cystic carcinoma, and epithelial-myoepithelial carcinoma. Less commonly seen are myoepithelial carcinoma, hyalinizing clear cell carcinoma, acinic cell carcinoma, secretory carcinoma, salivary duct carcinoma, intraductal carcinoma, and polymorphous adenocarcinoma. Benign salivary gland-type tumours of the lung include pleomorphic adenoma and sialadenoma papilliferum. Morphologic, immunophenotypic, and molecular features of these neoplasms are largely similar to salivary gland tumours elsewhere, and therefore the exclusion of metastatic disease requires clinical and radiologic correlation. However, the differential diagnostic considerations are different in the lung. The distinction of salivary gland-type tumours from their histologic mimics is important for both prognostication and treatment decisions. Overall, salivary gland type-tumours tend to have a more favourable outcome than other pulmonary carcinomas, although high-grade variants exist for many of these tumour types. Recent advances in our understanding of the spectrum of salivary gland-type tumours reported in the lung and their diversity of molecular and immunohistochemical features have helped to refine the classification of these tumours and have highlighted a few differences between salivary gland-type tumours of the lung and those primary to other sites.


Use of Inactivated Polio Vaccine Among U.S. Adults: Updated Recommendations of the Advisory Committee on Immunization Practices - United States, 2023.
Poliovirus can cause poliomyelitis and lifelong paralysis. Although wild poliovirus types 2 and 3 have been eradicated, wild poliovirus type 1 and vaccine-derived polioviruses are still circulating in multiple countries worldwide. In 2022, a case of paralytic polio caused by vaccine-derived poliovirus type 2 was identified in an unvaccinated young adult in New York. This case and subsequent detection of community transmission underscored the ongoing risk for importation of poliovirus into the United States and risk for poliomyelitis among unvaccinated persons. However, previous Advisory Committee on Immunization Practices (ACIP) recommendations for adult polio vaccination were limited to adults known to be at increased risk for exposure. During October 2022-June 2023, the ACIP Polio Vaccine Work Group reviewed data on poliovirus surveillance and epidemiology, safety and effectiveness of inactivated poliovirus vaccine (IPV), and other considerations outlined in the ACIP Evidence to Recommendations Framework. On June 21, 2023, ACIP voted to recommend that all U.S. adults aged ≥18 years who are known or suspected to be unvaccinated or incompletely vaccinated against polio complete a primary polio vaccination series with IPV. This report summarizes evidence considered for this recommendation and provides clinical guidance for the use of IPV in adults.