Visual judgment of similarity across shape transformations: evidence for a compositional model of articulated objects.
A single biological object, such as a hand, can assume multiple, very different shapes, due to the articulation of its parts. Yet we are able to recognize all of these shapes as examples of the same object. How is this invariance to pose achieved? Here, we present evidence that the visual system maintains a model of object transformation that is based on rigid, convex parts articulating at extrema of negative curvature, i.e., part boundaries. We compared similarity judgments in a task in which subjects had to decide which of the two transformed versions of a 'base' shape-one a 'biologically valid' articulation and one a geometrically similar but 'biologically invalid' articulation-was more similar to the base shape. Two types of comparisons were made: in the figure/ground-reversal, the invalid articulation consisted of exactly the same contour transformation as the valid one with reversed figural polarity. In the axis-of-rotation reversal, the valid articulation consisted of a part rotated around its concave part boundaries, while the invalid articulation consisted of the same part rotated around the endpoints on the opposite side of the part. In two separate 2AFC similarity experiments-one in which the base and transformed shapes were presented simultaneously and one in which they were presented sequentially-subjects were more likely to match the base shape to a transform when it corresponded to a legitimate articulation. These results suggest that the visual system maintains expectations about the way objects will transform, based on their static geometry.


Men, Mental Health and Elite Sport: a Narrative Review.
Mental health in elite sport is receiving more publicity due to an increase in male athletes sharing their personal experiences. Sports injury is recognised as the major risk factor for psychological distress amongst male athletes, although anecdotally this may be that athletes are more likely to discuss their emotional wellbeing when related to the injury they are experiencing. Stress can be amplified within elite sport and the pressure they experience in relation to competition and performance can be exacerbated by adverse life events. This ongoing stress does not end when their sporting career does, it can follow them into retirement. The physical and psychological demands placed upon them by the sporting environment may predispose athletes to developing depression. As an athlete's symptoms of mental illness intensify, their performance can be negatively affected leaving them vulnerable and exposed to further symptoms of common mental disorders. The pressure of performance can also expose male athletes to overtraining syndrome which can be difficult to distinguish from depression. Male athletes are more vulnerable to eating disorders compared with males in the general population and they do have anxieties, particularly around their bodies, but find it difficult to disclose their concerns. In addition to this, male athletes are more likely to use substances, including opioids to improve both sport and non-sport performance.Despite the prevalence of common mental disorders in male athletes, stigma still exists, and although some athletes discuss their issues publicly after their career has ended, the majority of athletes prefer to remain silent. There remains a view that athletes who seek help for psychological problems may be seen as weak. Although there is an improvement in help-seeking attitudes within elite sport, further research and education is needed to encourage men to talk about their mental health, share their experiences and to enjoy a greater sense of emotional wellbeing.


The association between leukocyte telomere lengths and sleep instability based on cardiopulmonary coupling analysis.
The purpose of the study is to examine the objective association between sleep stability and leukocyte telomere lengths (LTL) using cardiopulmonary coupling (CPC) analysis, which is an electrocardiogram (ECG)-based technique to quantify physiologic sleep stability. Three hundred eighty-one healthy subjects were recruited from a community-based cohort study from the Korean Genome and Epidemiology Study (KoGES), and the associations between LTL and total quantities of different frequency coupling bands were examined using generalized linear model (GLM) with adjustment of significant covariates. LTL showed a significant association with elevated narrow-band low frequency coupling (e-LFCNB, a CPC marker of periodic breathing or sleep fragmentation due to pathological respiratory chemoreflex activation) by interacting with obstructive sleep apnea (OSA) severity (p value of <0.0001). Especially, sleep stability significantly reduced with shortened LTL in OSA patients (Apnea-Hypopnea Index (AHI) ≥15) based on increased e-LFCNB which had a negative correlation with high-frequency coupling band (HFC), a marker of stable sleep. The present study suggested that shorter LTL might contribute to reduced sleep stability by interacting with OSA severity due to the stress of chronic sleep fragmentation or invariant sympathetic activity by respiratory chemoreflex activation.


[From department of military and military-sanitary disciplines to department of organization and tactics of medical service].
The article presents history of forming and activity of department of organization and tactics of medical service of Military-medical academy by Kirov S.M. for the last eight decades on the base of wide historiographic material, archival sources and not published works. There were analyzed objective suppositions of creation of the department, process of teaching of military-sanitarium disciplines in form of separated courses, on departments of military and military-sanitarium disciplines and on a separated department of organization and tactics of medical service. There was resumed scientific and pedagogic activity of the department, characterized it's modern state and scientific strength.


GPCR ontology: development and application of a G protein-coupled receptor pharmacology knowledge framework.
Novel tools need to be developed to help scientists analyze large amounts of available screening data with the goal to identify entry points for the development of novel chemical probes and drugs. As the largest class of drug targets, G protein-coupled receptors (GPCRs) remain of particular interest and are pursued by numerous academic and industrial research projects. We report the first GPCR ontology to facilitate integration and aggregation of GPCR-targeting drugs and demonstrate its application to classify and analyze a large subset of the PubChem database. The GPCR ontology, based on previously reported BioAssay Ontology, depicts available pharmacological, biochemical and physiological profiles of GPCRs and their ligands. The novelty of the GPCR ontology lies in the use of diverse experimental datasets linked by a model to formally define these concepts. Using a reasoning system, GPCR ontology offers potential for knowledge-based classification of individuals (such as small molecules) as a function of the data. The GPCR ontology is available at http://www.bioassayontology.org/bao_gpcr and the National Center for Biomedical Ontologies Web site.


Expression of a type I insulin-like growth factor receptor with low affinity for insulin-like growth factor II.
We investigated the binding properties of the type I insulin-like growth factor (IGF) receptor expressed in NIH-3T3 fibroblasts transfected with a human type I receptor cDNA. Cell surface receptors bound IGF-I with KD = 1 nM as predicted. Although recent studies have suggested that IGF-I and IGF-II bind to type I receptors with near-equal affinity, the receptors in this system bound IGF-II with much lower affinity (KD = 15-20 nM). When type I receptors from the transfected cells were solubilized and immunopurified, however, both 125I-IGF-I and 125I-IGF-II bound to the purified receptors with extremely high and relatively similar affinities (KD = 8 and 17 pM respectively). Thus the immunopurified receptors had higher affinity but lower specificity for the two ligands. The monoclonal antibody alpha IR-3 effectively inhibited IGF-I binding to cell surface receptors (75 +/- 10%), but did not inhibit IGF-II binding. In the purified receptor assay, alpha IR-3 also inhibited IGF-I binding more effectively than IGF-II binding (38 +/- 7% versus 10 +/- 4%). We conclude that the products of this cDNA can account for the binding patterns that we previously observed in receptors immunopurified from human placenta. The differential effect of alpha IR-3 on IGF-I versus IGF-II raises the possibility that these homologous growth factors bind to immunologically distinct epitopes on the type I receptor.


Superelastic Cobalt Silicate@Resorcinol Formaldehyde Resin Core-Shell Nanobelt Aerogel Monoliths with Outstanding Fire Retardant and Thermal Insulating Capability.
The practical applications of resorcinol formaldehyde resin (RFR) aerogels are prevented by their poor mechanical properties. Herein, a facile template-directed method is reported to produce macroscopic free-standing cobalt silicate (CS)@RFR core-shell nanobelt aerogels that display superelastic behavior and outstanding thermal insulating and fire-resistant capability. The synthesis relies on the polymerization of RFR on pre-formed CS nanobelts which leads to in situ formation of hydrogel monoliths that can be transformed to corresponding aerogels by a freeze-drying method. The composite nanobelt aerogel can withstand a compressive load of more than 4000 times of its own weight and fully recover after the removal of the weight. It can also sustain 1000 compressive cycles with 6.9% plastic deformation and 91.8% of the maximum stress remaining, with a constant energy loss coefficient as low as 0.16, at the set strain of 30%. The extraordinary mechanical properties are believed to be associated with the structural flexibility of the nanobelts and the RFR-reinforced joints between the crosslinked nanobelts. These inorganic-organic composite aerogels also show good thermal insulation and excellent fire-proof capability. This work provides an effective strategy for fabricating superelastic RFR-based aerogels which show promising applications in fields such as thermal insulation, energy storage, and catalyst support.


Self-immolative polymersomes for high-efficiency triggered release and programmed enzymatic reactions.
Stimuli-triggered disassembly of block copolymer vesicles or polymersomes has been conventionally achieved via solubility switching of the bilayer-forming block, requiring cooperative changes of most of the repeating units. Herein we report an alternative approach by incorporating hydrophobic blocks exhibiting stimuli-triggered head-to-tail cascade depolymerization features. Amphiphilic block copolymers bearing this motif self-assemble into self-immolative polymersomes (SIPsomes). By modular design of terminal capping moieties, visible light, UV light, and reductive milieu can be utilized to actuate SIPsomes disintegration into water-soluble small molecules and hydrophilic blocks. The design of SIPsomes allows for triggered drug co-release and controllable access toward protons, oxygen, and enzymatic substrates. We also demonstrate programmed (OR-, AND-, and XOR-type logic) enzymatic reactions by integrating SIPsome encapsulation and trigger/capping moiety-selective cascade depolymerization events.


Adipose tissue concentrations of non-persistent environmental phenols and local redox balance in adults from Southern Spain.
The aim was to evaluate the associations of environmental phenol and paraben concentrations with the oxidative microenvironment in adipose tissue. This study was conducted in a subsample (n = 144) of the GraMo cohort (Southern Spain). Concentrations of 9 phenols and 7 parabens, and levels of oxidative stress biomarkers were quantified in adipose tissue. Associations were estimated using multivariable linear regression analyses adjusted for potential confounders. Benzophenone-3 (BP-3) concentration was borderline associated with enhanced glutathione peroxidase (GPx) activity [exp(β) = 1.20, p = 0.060] and decreased levels of reduced glutathione (GSH) [exp(β) = 0.55, p = 0.070]. Concentrations of bisphenol A (BPA) and methylparaben (MeP) were associated to lower glutathione reductase (GRd) activity [exp(β) = 0.83, exp(β) = 0.72, respectively], and BPA was borderline associated to increased levels of oxidized glutathione (GSSG) [exp(β) = 1.73, p-value = 0.062]. MeP was inversely associated to both hemeoxygenase-1 (HO-1) and superoxide dismustase (SOD) activity, as well as to the levels of thiobarbituric acid reactive substances (TBARS) [0.75 < exp(β) < 0.79]. Our results suggest that some specific non-persistent pollutants may be associated with a disruption of the activity of relevant antioxidant enzymes, in addition to the depletion of the glutathione stock. They might act as a tissue-specific source of free radicals, contributing to the oxidative microenvironment in the adipose tissue.


Women's satisfaction with antenatal care: comparing women in Sweden and Australia.
Satisfaction with antenatal care could differ depending on the organisation and the context of care. To compare antenatal care in Australia and Sweden, to identify deficiencies in the content of antenatal care and what aspects contributed most in dissatisfaction with antenatal care. A longitudinal survey of 123 Australian and 386 Swedish women recruited during one year in regional hospitals in Sweden and Australia. Data collected by three questionnaires. Women in Australia had more antenatal visits, less continuity of midwife caregiver but were more satisfied with antenatal education and the emotional aspects of antenatal care. Although the overall satisfaction was high, deficiencies were found in more than half of the studied variables in the content of care. Women in Sweden were more dissatisfied with information about labour and birth (OR 3.1; 1.8-5.3) and information about the time following birth (OR 3.8; 2.2-6.3), but more satisfied with the involvement of the father (OR 0.3; 0.2-0.6). Factors that contributed most to dissatisfaction with antenatal care overall were deficiency in information about pregnancy related issues (OR 3.4; 1.3-8.7) and not being taken seriously by the midwife (OR 4.1; 1.6-10.1). Satisfaction with antenatal care was high in both groups of women. Australian women were more satisfied than the Swedish women with the emotional aspects of care. Deficiencies were found in more than half of the variables measured relating to the specific aspects of care. Lack of information and not being treated seriously were important factors for not being satisfied.


Reverse interferon signature is characteristic of antigen-presenting cells in human and rat spondyloarthritis.
In HLA-B27-transgenic rats, the development of a disorder that mimics spondyloarthritis (SpA) is highly correlated with dendritic cell (DC) dysfunction. The present study was undertaken to analyze the underlying mechanisms of this via transcriptome analysis. Transcriptome analysis of ex vivo-purified splenic CD103+CD4+ DCs from B27-transgenic rats and control rats was performed. Transcriptional changes in selected genes were confirmed by quantitative reverse transcriptase-polymerase chain reaction. A meta-analysis of our rat data and published data on gene expression in macrophages from ankylosing spondylitis (AS) patients was further performed. Interferon (IFN) signaling was the most significantly affected pathway in DCs from B27-transgenic rats; the majority of genes connected to IFN were underexpressed in B27-transgenic rats as compared to controls. This pattern was already present at disease onset, persisted over time, and was conserved in 2 disease-prone B27-transgenic rat lines. In DCs from B27-transgenic rats, we further found an up-regulation of suppressor of cytokine signaling 3 (which may account for reverse IFN signaling) and a down-regulation of interleukin-27 (a cytokine that opposes Th17 differentiation and promotes Treg cells). The meta-analysis of data on conventional DCs from rats and data on monocyte-derived macrophages from humans revealed 7 IFN-regulated genes that were negatively regulated in both human and rat SpA (i.e., IRF1, STAT1, CXCL9, CXCL10, IFIT3, DDX60, and EPSTI1). Our results suggest that expression of HLA-B27 leads to a defect in IFNγ signaling in antigen-presenting cells in both B27-transgenic rats and SpA patients, which may result in Th17 expansion and Treg cell alteration (as shown in B27-transgenic rats) and contribute to disease pathogenesis.


A suppressive oligodeoxynucleotide expressing TTAGGG motifs modulates cellular energetics through the mTOR signaling pathway.
Immune-mediated inflammation must be down-regulated to facilitate tissue remodeling during homeostatic restoration of an inflammatory response. Uncontrolled or over-exuberant immune activation can cause autoimmune diseases, as well as tissue destruction. A151, the archetypal example of a chemically synthesized suppressive oligodeoxynucleotide (ODN) based on repetitive telomere-derived TTAGGG sequences, was shown to successfully down-regulate a variety of immune responses. However, the degree, duration and breadth of A151-induced transcriptome alterations remain elusive. Here, we performed a comprehensive microarray analysis in combination with Ingenuity Pathway Analysis (IPA) using murine splenocytes to investigate the underlying mechanism of A151-dependent immune suppression. Our results revealed that A151 significantly down-regulates critical mammalian target of rapamycin (mTOR) activators (Pi3kcd, Pdpk1 and Rheb), elements downstream of mTOR signaling (Rps6ka1, Myc, Stat3 and Slc2a1), an important component of the mTORC2 protein complex (Rictor) and Mtor itself. The effects of A151 on mTOR signaling were dose- and time-dependent. Moreover, flow cytometry and immunoblotting analyses demonstrated that A151 is able to reverse mTOR phosphorylation comparably to the well-known mTOR inhibitor rapamycin. Furthermore, Seahorse metabolic assays showed an A151 ODN-induced decrease in both oxygen consumption and glycolysis implying that a metabolically inert state in macrophages could be triggered by A151 treatment. Overall, our findings suggested novel insights into the mechanism by which the immune system is metabolically modulated by A151 ODN.


Association of hospital volume with readmission rates: a retrospective cross-sectional study.
To examine the association of hospital volume (a marker of quality of care) with hospital readmission rates. Retrospective cross-sectional study. 4651 US acute care hospitals. 6,916,644 adult discharges, excluding patients receiving psychiatric or medical cancer treatment. We used Medicare fee-for-service data from 1 July 2011 to 30 June 2012 to calculate observed-to-expected, unplanned, 30 day, standardized readmission rates for hospitals and for specialty cohorts medicine, surgery/gynecology, cardiorespiratory, cardiovascular, and neurology. We assessed the association of hospital volume by quintiles with 30 day, standardized readmission rates, with and without adjustment for hospital characteristics (safety net status, teaching status, geographic region, urban/rural status, nurse to bed ratio, ownership, and cardiac procedure capability. We also examined associations with the composite outcome of 30 day, standardized readmission or mortality rates. Mean 30 day, standardized readmission rate among the fifth of hospitals with the lowest volume was 14.7 (standard deviation 5.3) compared with 15.9 (1.7) among the fifth of hospitals with the highest volume (P<0.001). We observed the same pattern of lower readmission rates in the lowest versus highest volume hospitals in the specialty cohorts for medicine (16.6 v 17.4, P<0.001), cardiorespiratory (18.5 v 20.5, P<0.001), and neurology (13.2 v 14.0, p=0.01) cohorts; the cardiovascular cohort, however, had an inverse association (14.6 v 13.7, P<0.001). These associations remained after adjustment for hospital characteristics except in the cardiovascular cohort, which became non-significant, and the surgery/gynecology cohort, in which the lowest volume fifth of hospitals had significantly higher standardized readmission rates than the highest volume fifth (difference 0.63 percentage points (95% confidence interval 0.10 to 1.17), P=0.02). Mean 30 day, standardized mortality or readmission rate was not significantly different between highest and lowest volume fifths (20.4 v 20.2, P=0.19) and was highest in the middle fifth of hospitals (range 20.6-20.8). Standardized readmission rates are lowest in the lowest volume hospitals-opposite from the typical association of greater hospital volume with better outcomes. This association was independent of hospital characteristics and was only partially attenuated by examining mortality and readmission together. Our findings suggest that readmissions are associated with different aspects of care than mortality or complications.


Formulation and optimization of controlled release mucoadhesive tablets of atenolol using response surface methodology.
The aim of the current study was to design oral controlled release mucoadhesive compressed hydrophilic matrices of atenolol and to optimize the drug release profile and bioadhesion using response surface methodology. Tablets were prepared by direct compression and evaluated for bioadhesive strength and in vitro dissolution parameters. A central composite design for 2 factors at 3 levels each was employed to systematically optimize drug release profile and bioadhesive strength. Carbopol 934P and sodium carboxymethylcellulose were taken as the independent variables. Response surface plots and contour plots were drawn, and optimum formulations were selected by feasibility and grid searches. Compressed matrices exhibited non-Fickian drug release kinetics approaching zero-order, as the value of release rate exponent (n) varied between 0.6672 and 0.8646, resulting in regulated and complete release until 24 hours. Both the polymers had significant effect on the bioadhesive strength of the tablets, measured as force of detachment against porcine gastric mucosa (P < .001). Polynomial mathematical models, generated for various response variables using multiple linear regression analysis, were found to be statistically significant (P < .01). Validation of optimization study, performed using 8 confirmatory runs, indicated very high degree of prognostic ability of response surface methodology, with mean percentage error (+/- SD) as -0.0072 +/- 1.087. Besides unraveling the effect of the 2 factors on the various response variables, the study helped in finding the optimum formulation with excellent bioadhesive strength and controlled release.


The design of multi-stage tuberculin surveys: some suggestions for sampling.
Tuberculin surveys of children to estimate national or regional infection prevalences are commonly designed as multi-stage surveys. These surveys require strategies for the efficient sampling of sub-units at each stage. To develop guidelines for sampling in tuberculin surveys. Sampling theory was used to develop a simple and efficient sampling strategy for planning and analysing tuberculin surveys. The issue of sample sizes is considered. Formulae for the calculation of infection prevalences and their confidence intervals are developed. Sample sizes are discussed. We recommend that districts be sampled using sampling proportional to size, in which larger units have a larger probability of being included in the sample. Schools are sampled next using simple random sampling, where each school within a district has the same probability of being included in the sample. In each school all eligible children are Mantoux tested. The number of children tested per district should be approximately constant. Increasing the number of selected districts is usually more efficient for increasing the precision of the estimate than increasing the number of children per district beyond several hundred to a few thousand.


The recombination landscape around forensic STRs: Accurate measurement of genetic distances between syntenic STR pairs using HapMap high density SNP data.
Family studies can be used to measure the genetic distance between same-chromosome (syntenic) STRs in order to detect physical linkage or linkage disequilibrium. However, family studies are expensive and time consuming, in many cases uninformative, and lack a reliable means to infer the phase of the diplotypes obtained. HapMap provides a more comprehensive and fine-scale estimation of recombination rates using high density multi-point SNP data (average inter-SNP distance: 900 nucleotides). Data at this fine scale detects sub-kilobase genetic distances across the whole recombining human genome. We have used the most recent HapMap SNP data release 22 to measure and compare genetic distances, and by inference fine-scale recombination rates, between 29 syntenic STR pairs identified from 39 validated STRs currently available for forensic use. The 39 STRs comprise 23 core loci: SE33, Penta D & E, 13 CODIS and 7 non-CODIS European Standard Set STRs, plus supplementary STRs in the recently released Promega CS-7™ and Qiagen Investigator HDplex™ kits. Also included were D9S1120, a marker we developed for forensic use unique to chromosome 9, and the novel D6S1043 component STR of SinoFiler™ (Applied Biosystems). The data collated provides reliable estimates of recombination rates between each STR pair, that can then be placed into haplotype frequency calculators for short pedigrees with multiple meiotic inputs and which just requires the addition of allele frequencies. This allows all current STR sets or their combinations to be used in supplemented paternity analyses without the need for further adjustment for physical linkage. The detailed analysis of recombination rates made for autosomal forensic STRs was extended to the more than 50 X chromosome STRs established or in development for complex kinship analyses.


Risk of progression to diabetes of low titer ICA-positive first-degree relatives of type I diabetics in southern Germany.
In a prospective study to evaluate the prevalence and predictive potential of circulating cytoplasmatic islet cell antibodies (ICA) and competitive insulin autoantibodies (CIAA), we screened 406 non-diabetic first-degree relatives of patients with Type I diabetes mellitus (n = 154 for CIAA). The prevalence of ICA was 2.5% (10/406) and of CIAA 0.6% (1/154) in ICA- and 10% (1/10) in ICA+ relatives at initial screening. The titer of ICA positivity in all relatives varied between 1:1 and 1:4. Values of elevated CIAA were 256 nU/ml of the CIAA+/ICA+, and 97 nU/ml of the CIAA+/ICA- relatives (normal range less than or equal to 39 nU/ml). Sera for repeat ICA and CIAA determination was obtained, and 70% of relatives were found to be again ICA+ after 1.5 years, 40% after 3 years, and 10% after 5.7 years. Both CIAA+ relatives were found to be again CIAA+ on follow-up. Intravenous glucose tolerance tests (IVGTT) were performed in all antibody-positive relatives. No decrease in first-phase insulin secretion (1 + 3 min) below the 1st percentile was observed in any of the ICA+ relatives during follow-up. No ICA+, but one CIAA+/ICA- relative had developed Type I diabetes after 5.6 years of follow-up. In summary, these results indicate that low titer ICA (less than 40 JDF units) are often transient and relatives with low titer ICA rarely progress to Type I diabetes. Elevated CIAA appear to be constant over time and associated with increased progression to overt diabetes.


Evidence suggesting that reindeer mothers allonurse according to the direct reciprocity and generalized reciprocity decision rules.
Allonursing is the nursing of the offspring of other mothers. Cooperation is an emergent property of evolved decision rules. Cooperation can be explained by at least three evolved decision rules: 1) direct reciprocity, i.e. help someone who previously helped you, 2) kin discrimination, i.e. preferentially direct help to kin than to non-kin, and 3) generalized reciprocity, i.e. help anyone if helped by someone. We assessed if semi-domesticated reindeer, Rangifer tarandus, mothers allonursed according to the decision rules of direct reciprocity, generalized reciprocity and kin discrimination over 2 years. To assess if reindeer mothers allonursed according to the direct reciprocity decision rule, we predicted that mothers should give more help to those who previously helped them more often. To assess if reindeer mothers allonursed according to the kin discrimination decision rule, we predicted that help given should increase as pairwise genetic relatedness increased. To assess if reindeer mothers allonursed according to the generalized reciprocity decision rule, we predicted that the overall number of help given by reindeer mothers should increase as the overall number of help received by reindeer mothers increased. The number of help given i) increased as the number of help received from the same partner increased in the 2012 group but not in both 2013 groups, ii) was not influenced by relatedness, and iii) was not influenced by an interaction between the number of help received from the same partner and relatedness. iv) The overall number of help given increased as the overall number of help received increased. The results did not support the prediction that reindeer mothers allonursed according to the kin discrimination decision rule. The results suggest that reindeer mothers may allonurse according to the direct reciprocity and generalized reciprocity decision rules.


Molecular biomarkers in the diagnostic of patients with colorectal cancer.
Colorectal cancer (CRC) is currently a well-known and studied issue in experimental research. Worldwide it is the third most common cancer in men and the second most common cancer in women. 70-80% of cases occur sporadically. Most CRCs develop from adenomas. The transition from normal epithelium to adenoma and finally into carcinoma is associated with acquired molecular events. In 5-10 % of cases, CRC develops from germline mutations in cancer-predisposing genes. 15% of patients have a family history of CRC that suggests a hereditary contribution, common exposures or shared risk factors among family members. Genetic alterations in cancer-related genes represent prognostic and predictive CRC biomarkers. Genetic testing of individuals with newly diagnosed CRC as well as of asymptomatic relatives can lead to improved outcomes for the patient and at-risk family members. Discovery of circulating cell-free tumor DNA (ctDNA) promises an improvement of the CRC diagnostics. ctDNA shares common genetic alterations with the primary tumor so it allows non-invasive monitoring of the disease over time. This review is focused on the principal molecular biomarkers associated with CRC and on the key characteristics of initiation and progression of CRC including chromosomal instability, microsatellite instability and signaling pathways where this deregulation leads to tumorigenesis.


The clinical management of co-morbidity.
The clinical management of co-morbidity of psychiatric illness and substance abuse disorders (SAD) is complex. Each condition requires management in its own right. Either conjoint treatment is required or clinicians in psychiatric services must develop expertise in the management of SAD and clinicians in SAD services must develop expertise in the management of psychiatric illness. To date few serious attempts have been made for the development of integrated services in Australia. Specific clinical issues are highlighted; the principles of intervention are presented and the use of a systematic protocol is suggested.


DO SONS OR DAUGHTERS GIVE MORE MONEY TO PARENTS IN URBAN CHINA?
The patriarchal structure of the traditional Chinese family suggests that sons, more than daughters, provide financial support to elderly parents. The norm of receiving support in old age primarily from sons, however, may have been undermined by dramatic demographic, economic, and cultural changes occurring over the last several decades in China, especially in urban areas. We examine gender differences in adult children's financial support to parents using a recent dataset ("Study of Family Life in Urban China") collected in 1999 (N = 1,801). The results show that married daughters, especially those living with parents, provide more financial support to parents than married sons do. This significant gender difference can be primarily explained by daughters' resources, such as education and income.


Effectiveness of gamma knife radiosurgery in the management of trigeminal neuralgia associated with multiple sclerosis: a systematic review and meta-analysis.
Trigeminal neuralgia (TN) is a chronic condition characterized by intense facial pain akin to electric shocks, often associated with the trigeminal nerve. It can be either idiopathic or secondary, with multiple sclerosis (Ms) being a significant contributing factor. Non-responsive patients may opt for minimally invasive procedures, such as gamma knife radiosurgery (GKRS), which offers precise, non-invasive treatment and is frequently chosen as a primary approach. This meta-analysis evaluates the long-term efficacy of GKRS in TN management in Ms patients. We conducted a focused search across various databases. Inclusion criteria encompassed studies with ≥ 30 patients using GKRS for TN in Ms, reporting pertinent clinical outcomes. Primary outcomes assessed GKRS efficacy through Barrow Neurological Institute Pain scores. Secondary outcomes encompassed bothersome numbness, facial numbness, and recurrence. Data analysis employed OpenMeta, random effect models, and odds ratios with 95% confidence intervals. Heterogeneity was assessed using I2 statistics. Fourteen studies with 752 cases of GKRS for TN were included. Regarding the outcomes, 83% of patients experienced a positive initial pain response, while the overall treatment success rate was 51%. Additionally, 19.6% of patients reported facial numbness, 4.1% experienced bothersome numbness, and 40% faced recurrence. The odds ratio for positive initial pain response was 0.83 (95% CI, 0.76-0.89), while for treatment success, it was 0.51 (95% CI, 0.379-0.639). Facial numbness had an odds ratio of 0.196 (95% CI, 0.130-0.262), bothersome numbness had an odds ratio of 0.041 (95% CI, 0.013-0.069), and recurrence had an odds ratio of 0.403 (95% CI, 0.254-0.551). In conclusion, treating trigeminal neuralgia in multiple sclerosis patients remains challenging. GKRS shows promise, but customized treatment approaches tailored to individual patient characteristics are urgently needed to address the unique challenges of this condition.


Angiopoietin-2 induces human glioma invasion through the activation of matrix metalloprotease-2.
A hallmark of highly malignant human gliomas is their infiltration of the brain. We analyzed a large number of primary human glioma biopsies and found high levels of expression of an angiogenic regulator, angiopoietin-2 (Ang2), in the invasive areas, but not in the central regions, of those tumors. In the invasive regions where Ang2 was overexpressed, increased levels of matrix metalloprotease-2 (MMP-2) were also apparent. Consonant with these features, intracranial xenografts of glioma cells engineered to express Ang2 were highly invasive into adjacent brain parenchyma compared with isogenic control tumors. In regions of the Ang2-expressing tumors that were actively invading the brain, high levels of expression of MMP-2 and increased angiogenesis were also evident. A link between these two features was apparent, because stable expression of Ang2 by U87MG cells or treatment of several glioma cell lines with recombinant Ang2 in vitro caused activation of MMP-2 and acquisition of increased invasiveness. Conversely, MMP inhibitors suppressed Ang2-stimulated activation of MMP-2 and Ang2-induced cell invasion. These results suggest that Ang2 plays a critical role in inducing tumor cell infiltration, and that this invasive phenotype is caused by activation of MMP-2.


Unlocking the Potential of Tin-Based Perovskites: Properties, Progress, and Applications in New-Era Electronics.
Electronics have greatly promoted the development of modern society and the exploration of new semiconducting materials with low cost and high mobility continues to attract interest in the advance of next-generation electronic devices. Among emerging semiconductors, the metal-halide perovskite, especially the nontoxic tin (Sn)-based candidates, has recently made breakthroughs in the field of diverse electronic devices due to its excellent charge transport properties and cost-effective large-area deposition capability at low temperatures. To enable a more comprehensive understanding of this emerging research field and promote the development of new-generation perovskite electronics, this review aims to provide an in-depth understanding with the discussion of unique physical properties of Sn-based perovskites and the summarization of recent research progress of Sn-based perovskite field-effect transistors (FETs) and diverse electronic devices. The unique character of negligible ion migration is also discussed, which is fundamentally different from the lead-based counterparts and provides a great prerequisite for device application. The following section highlights the potential broad applications of Sn-perovskite FETs as a competitive and feasible technology. Finally, an outlook and remaining challenges are given to advance the progression of Sn-based perovskite FETs, especially on the origin and solution of stability problems toward high-performance Sn-based perovskite electronics.


VCF-Explorer: filtering and analysing whole genome VCF files.
The decreasing cost in high-throughput technologies led to a number of sequencing projects consisting of thousands of whole genomes. The paradigm shift from exome to whole genome brings a significant increase in the size of output files. Most of the existing tools which are developed to analyse exome files are not adequate for larger VCF files produced by whole genome studies. In this work we present VCF-Explorer, a variant analysis software capable of handling large files. Memory efficiency and avoiding computationally costly pre-processing step enable to carry out the analysis to be performed with ordinary computers. VCF-Explorer provides an easy to use environment where users can define various types of queries based on variant and sample genotype level annotations. VCF-Explorer can be run in different environments and computational platforms ranging from a standard laptop to a high performance server. VCF-Explorer is freely available at: http://vcfexplorer.sourceforge.net/. email@example.com. Supplementary data are available at Bioinformatics online.


Tumor Membrane Vesicle Vaccine Augments the Efficacy of Anti-PD1 Antibody in Immune Checkpoint Inhibitor-Resistant Squamous Cell Carcinoma Models of Head and Neck Cancer.
Immune checkpoint inhibitor (ICI) immunotherapy improved the survival of head and neck squamous cell carcinoma (HNSCC) patients. However, more than 80% of the patients are still resistant to this therapy. To test whether the efficacy of ICI therapy can be improved by vaccine-induced immunity, we investigated the efficacy of a tumor membrane-based vaccine immunotherapy in murine models of HNSCC. The tumors, grown subcutaneously, are used to prepare tumor membrane vesicles (TMVs). TMVs are then incorporated with glycolipid-anchored immunostimulatory molecules GPI-B7-1 and GPI-IL-12 by protein transfer to generate the TMV vaccine. This TMV vaccine inhibited tumor growth and improved the survival of mice challenged with SCCVII tumor cells. The tumor-free mice survived for several months, remained tumor-free, and were protected following a secondary tumor cell challenge, suggesting that the TMV vaccine induced an anti-tumor immune memory response. However, no synergy with anti-PD1 mAb was observed in this model. In contrast, the TMV vaccine was effective in inhibiting MOC1 and MOC2 murine oral cancer models and synergized with anti-PD1 mAb in extending the survival of tumor-bearing mice. These observations suggest that tumor tissue based TMV vaccines can be harnessed to develop an effective personalized immunotherapy for HNSCC that can enhance the efficacy of immune checkpoint inhibitors.


A chimeric Plasmodium falciparum merozoite surface protein vaccine induces high titers of parasite growth inhibitory antibodies.
The C-terminal 19-kDa domain of Plasmodium falciparum merozoite surface protein 1 (PfMSP119) is an established target of protective antibodies. However, clinical trials of PfMSP142, a leading blood-stage vaccine candidate which contains the protective epitopes of PfMSP119, revealed suboptimal immunogenicity and efficacy. Based on proof-of-concept studies in the Plasmodium yoelii murine model, we produced a chimeric vaccine antigen containing recombinant PfMSP119 (rPfMSP119) fused to the N terminus of P. falciparum merozoite surface protein 8 that lacked its low-complexity Asn/Asp-rich domain, rPfMSP8 (ΔAsn/Asp). Immunization of mice with the chimeric rPfMSP1/8 vaccine elicited strong T cell responses to conserved epitopes associated with the rPfMSP8 (ΔAsn/Asp) fusion partner. While specific for PfMSP8, this T cell response was adequate to provide help for the production of high titers of antibodies to both PfMSP119 and rPfMSP8 (ΔAsn/Asp) components. This occurred with formulations adjuvanted with either Quil A or with Montanide ISA 720 plus CpG oligodeoxynucleotide (ODN) and was observed in both inbred and outbred strains of mice. PfMSP1/8-induced antibodies were highly reactive with two major alleles of PfMSP119 (FVO and 3D7). Of particular interest, immunization with PfMSP1/8 elicited higher titers of PfMSP119-specific antibodies than a combined formulation of rPfMSP142 and rPfMSP8 (ΔAsn/Asp). As a measure of functionality, PfMSP1/8-specific rabbit IgG was shown to potently inhibit the in vitro growth of blood-stage parasites of the FVO and 3D7 strains of P. falciparum. These data support the further testing and evaluation of this chimeric PfMSP1/8 antigen as a component of a multivalent vaccine for P. falciparum malaria.


Early Utilization of Mechanical Circulatory Support in Acute Myocardial Infarction Complicated by Cardiogenic Shock: The National Cardiogenic Shock Initiative.
Acute myocardial infarction complicated by cardiogenic shock (AMI-CS) is associated with significant morbidity and mortality. Mechanical circulatory support (MCS) devices increase systemic blood pressure and end organ perfusion while reducing cardiac filling pressures. The National Cardiogenic Shock Initiative (NCT03677180) is a single-arm, multicenter study. The purpose of this study was to assess the feasibility and effectiveness of utilizing early MCS with Impella in patients presenting with AMI-CS. The primary end point was in-hospital mortality. A total of 406 patients were enrolled at 80 sites between 2016 and 2020. Average age was 64±12 years, 24% were female, 17% had a witnessed out-of-hospital cardiac arrest, 27% had in-hospital cardiac arrest, and 9% were under active cardiopulmonary resuscitation during MCS implantation. Patients presented with a mean systolic blood pressure of 77.2±19.2 mm Hg, 85% of patients were on vasopressors or inotropes, mean lactate was 4.8±3.9 mmol/L and cardiac power output was 0.67±0.29 watts. At 24 hours, mean systolic blood pressure improved to 103.9±17.8 mm Hg, lactate to 2.7±2.8 mmol/L, and cardiac power output to 1.0±1.3 watts. Procedural survival, survival to discharge, survival to 30 days, and survival to 1 year were 99%, 71%, 68%, and 53%, respectively. Early use of MCS in AMI-CS is feasible across varying health care settings and resulted in improvements to early hemodynamics and perfusion. Survival rates to hospital discharge were high. Given the encouraging results from our analysis, randomized clinical trials are warranted to assess the role of utilizing early MCS, using a standardized, multidisciplinary approach.


Glasgow Blatchford Score of limited benefit for low-risk urban patients: a mixed methods study.
Most patients with upper gastrointestinal bleeding (UGIB) are hospitalized. Risk-stratifying UGIB with scoring tools may decrease avoidable admissions, thereby reducing the cost of care. We sought to describe how frequently low-risk UGIB patients present to urban emergency departments (ED) and the proportion who are admitted to examine how incorporating risk scores into decision support might diminish healthcare utilization in this population. This is a retrospective cohort study of ED patients presenting from 2009 - 2013 to three urban hospitals that do not use electronic UGIB decision support. We used ED disposition diagnosis codes (ICD-9) to identify patients followed by manual chart review for verification and additional data collection. Patients with a Glasgow Blatchford Score (GBS) of 0 were classified as low risk. We also surveyed ED physicians at these hospitals to assess their beliefs about UGIB decision support. Over the study period, 66 patients (13.2 per year) presented to the ED with low-risk UGIB. Of these, 10 patients (15.2 %) were admitted and none required endoscopic hemostasis. Most survey respondents (55.6 %, n = 20) were aware of UGIB risk scores but a minority (19.4 %, n = 7) used one. Low-risk UGIB patients infrequently present to the ED and only a minority are admitted. Despite advocacy to incorporate decision support into routine clinical care, ED physicians independently identified low risk patients. There is insufficient evidence to suggest the magnitude of this problem is large enough to warrant implementation of decision support for low risk UGIB.


Diabetes management in cancer patients. An Italian Association of Medical Oncology, Italian Association of Medical Diabetologists, Italian Society of Diabetology, Italian Society of Endocrinology and Italian Society of Pharmacology multidisciplinary consensus position paper.
Cancer management has significantly evolved in recent years, focusing on a multidisciplinary team approach to provide the best possible patient care and address the various comorbidities, toxicities, and complications that may arise during the patient's treatment journey. The co-occurrence of diabetes and cancer presents a significant challenge for health care professionals worldwide. Management of these conditions requires a holistic approach to improve patients' overall health, treatment outcomes, and quality of life, preventing diabetes complications and cancer treatment side-effects. In this article, a multidisciplinary panel of experts from different Italian scientific societies provide a critical overview of the co-management of cancer and diabetes, with an increasing focus on identifying a novel specialty field, 'diabeto-oncology', and suggest new co-management models of cancer patients with diabetes to improve their care. To better support cancer patients with diabetes and ensure high levels of coordinated care between oncologists and diabetologists, 'diabeto-oncology' could represent a new specialized field that combines specific expertise, skills, and training.


Prevalence of Long-Term Opioid Use in Long-Stay Nursing Home Residents.
Overall and long-term opioid use among older adults have increased since 1999. Less is known about opioid use in older adults in nursing homes (NHs). Cross-sectional. U.S. NHs (N = 13,522). Long-stay NH resident Medicare beneficiaries with a Minimum Data Set 3.0 (MDS) assessment between April 1, 2012, and June 30, 2012, and 120 days of follow-up (N = 315,949). We used Medicare Part D claims to measure length of opioid use in the 120 days from the index assessment (short-term: ≤30 days, medium-term: >30-89 days, long-term: ≥90 days), adjuvants (e.g., anticonvulsants), and other pain medications (e.g., corticosteroids). MDS assessments in the follow-up period were used to measure nonpharmacological pain management use. Modified Poisson models were used to estimate adjusted prevalence ratios (aPR) and 95% confidence intervals (CI) for age, gender, race and ethnicity, cognitive and physical impairment, and long-term opioid use. Of all long-stay residents, 32.4% were prescribed any opioid, and 15.5% were prescribed opioids long-term. Opioid users (versus nonusers) were more commonly prescribed pain adjuvants (32.9% vs 14.9%), other pain medications (25.5% vs 11.0%), and nonpharmacological pain management (24.5% vs 9.3%). Long-term opioid use was higher in women (aPR = 1.21, 95% CI = 1.18-1.23) and lower in racial and ethnic minorities (non-Hispanic blacks vs whites: APR = 0.93, 95% CI = 0.90-0.94) and those with severe cognitive impairment (vs no or mild impairment, aPR = 0.82, 95% CI = 0.79-0.83). One in seven NH residents was prescribed opioids long-term. Recent guidelines on opioid prescribing for pain recommend reducing long-term opioid use, but this is challenging in NHs because residents may not benefit from nonpharmacological and nonopioid interventions. Studies to address concerns about opioid safety and effectiveness (e.g., on pain and functional status) in NHs are needed.


The impact of outpatient drug benefits on the use and costs of health care services for the elderly.
In light of the current debate surrounding the extension of Medicare benefits to cover outpatient drugs, it is important to increase our understanding of the impact of drug payment programs on overall health care outcomes and expenditures. In this retrospective study of health care use among Medicare beneficiaries in New Jersey and eastern Pennsylvania, we studied the impact of New Jersey's Pharmaceutical Assistance for the Aged (PAA) program on health care costs. Using multiple regression analysis, we found that New Jersey Medicare recipients used, on average, $238.50 less in inpatient hospital care under the PAA program than did their counterparts in eastern Pennsylvania, which did not have a drug payment assistance program in place. Although administrative costs may have reduced overall savings, it seems reasonable to conclude that the PAA program resulted in no overall health care cost increases.


Spinal instrumentation for primary pyogenic infection report of 31 patients.
The role of spinal instrumentation in the presence of infection is still controversial. Radical debridements of infected vertebrae and disc material and bone grafting usually leaves the spine unstable without some surgical stabilisation. We reviewed 31 cases of primary pyogenic spinal infection treated by radical debridement, bone grafting and posterior (30) or anterior (1) spinal instrumentation. The indication for surgery was the failure of conservative treatment (8), progressive neurological deficit (19) or the lack of diagnosis (3). The clinical, laboratory and radiological parameters were assessed pre and postoperatively. The mean period of follow-up was 3.8 years (1-12 years). The neurological deficit was progressive in 19 patients, following surgery all these patients were improved. The neurological deficit was established in one patient; following surgery, his neurological deficit did not improve. The infection was eradicated in all our patients. The following complications were encountered: (1) three patients developed deep wound infection, which responded to repeated debridement; (2) one death resulted from nosocomial septicaemia, (3) reoperation was carried out on one patient for implant failure and on another for a dislodged anterior bone graft. We conclude that spinal instrumentation may be indicated when after radical debridement of infected vertebrae and disc material and bone grafting the stability of the spine is still compromised. According to the location of the infection and the availability of suitable implants, anterior or posterior instrumentation may be necessary. With appropriate antimicrobial agents, the outcome has been satisfactory in our patients.


Expression of PCNA and bcl-2 in basaloid squamous cell carcinoma of the larynx: a controlled study.
We investigated the difference in the biologic nature of typical squamous cell carcinoma (SCC) and basaloid SCC (BSCC) of the larynx by studying proliferation and antiapoptotic markers. We performed an immunohistochemical analysis of the expression of proliferating cell nuclear antigen (PCNA) and bcl-2 protein in 15 patients with laryngeal BSCC and 15 stage- and site-matched controls with typical laryngeal SCC. We found no significant difference between the two groups in the PCNA index or the frequency of bcl-2 overexpression, nor did we find any significant difference in survival. Our findings indicate that the biologic nature of typical laryngeal SCC and laryngeal BSCC is similar. In addition, our follow-up data suggest that the clinical course of laryngeal BSCC is no worse than that of typical laryngeal SCC.


Lipid exposure elicits differential responses in gene expression and DNA methylation in primary human skeletal muscle cells from severely obese women.
The skeletal muscle of obese individuals exhibits an impaired ability to increase the expression of genes linked with fatty acid oxidation (FAO) upon lipid exposure. The present study determined if this response could be attributed to differential DNA methylation signatures. RNA and DNA were isolated from primary human skeletal muscle cells (HSkMC) from lean and severely obese women following lipid incubation. mRNA expression and DNA methylation were quantified for genes that globally regulate FAO [PPARγ coactivator (PGC-1α), peroxisome proliferator-activated receptors (PPARs), nuclear respiratory factors (NRFs)]. With lipid oversupply, increases in NRF-1, NRF-2, PPARα, and PPARδ expression were dampened in skeletal muscle from severely obese compared with lean women. The expression of genes downstream of the PPARs and NRFs also exhibited a pattern of not increasing as robustly upon lipid exposure with obesity. Increases in CpG methylation near the transcription start site with lipid oversupply were positively related to PPARδ expression; increases in methylation with lipid were depressed in HSkMC from severely obese women. With severe obesity, there is an impaired ability to upregulate global transcriptional regulators of FAO in response to lipid exposure. Transient changes in DNA methylation patterns and differences in the methylation signature with severe obesity may play a role in the transcriptional regulation of PPARδ in response to lipid. The persistence of differential responses to lipid in HSkMC derived from lean and obese subjects supports the possibility of stable epigenetic programming of skeletal muscle cells by the respective environments.


Two different heavy chains are found in smooth muscle myosin.
Two putative myosin heavy chains designated SM1 and SM2 were detected on a 3.5% polyacrylamide-sodium dodecyl sulfate gel electrophoresis system loaded with homogenates of several mammalian smooth muscles. The two polypeptides were present in nearly equal amounts in all smooth muscle tissues tested and in myosin purified from swine carotid media and stomach. Both proteins were equally stained by smooth muscle-specific myosin antibodies. The smaller of the polypeptides had a mobility nearly identical to that of the single heavy chain observed in purified fast-twitch skeletal myosin. Electrophoresis of pyrophosphate extracts from swine carotid media, swine stomach, rabbit thoracic aorta, and guinea pig taenia coli on nondenaturing pyrophosphate gels revealed a single protein band. When subsequently electrophoresed on a sodium dodecyl sulfate gel, the native bands from swine tissue extracts revealed the two putative heavy chains in nearly equal amounts, as well as a large amount of a higher molecular weight peptide whose properties reflect those of filamen. Sodium dodecyl sulfate gel analysis of the myosin band from pyrophosphate gels of purified swine stomach myosin showed exclusively the two heavy chains in a nearly 1:1 ratio. Smooth muscle myosin migrates homogeneously on pyrophosphate gels, and the virtual equality of the two heavy chains may reflect the presence of large amounts of a myosin isoenzyme, which is a heavy-chain heterodimer.


Pubovaginal sling: 4-YEAR outcome analysis and quality of life assessment.
Stress urinary incontinence is a common disease with a devastating impact on patient quality of life. Needle suspension procedures, which produce disappointing long-term results for type II stress incontinence, are being replaced by pubovaginal slings which previously were reserved solely for the treatment of type III stress incontinence. We report the long-term outcomes of pubovaginal slings for the treatment of types II and III stress urinary incontinence, and assess its quality of life impact. From January 1993 until December 1996, 247 females 10 to 84 years old (mean age 54.5) with type II (54%) or III (46%) stress urinary incontinence diagnosed by fluoroscopic urodynamics received a pubovaginal sling. Concomitant urge incontinence was present in 109 patients (44%). Quality of life was assessed with the Urogenital Distress Inventory short form. At a mean followup of 51 months (range 22 to 68) the continence rates were 88% overall, 91% for type II and 84% for type III. Preoperative urge incontinence resolved in 81 of 109 patients (74%), while de novo urge incontinence developed in 10 (7%). Intermittent urethral catheterization duration averaged 8.4 days, with 5 women undergoing urethrolysis for a hypersuspended urethra. Secondary procedures were required in 9 patients with type II and 5 with type III incontinence, and included transurethral collagen injections in 6 and repeat pubovaginal slings in 8. There was a 4% complication rate due to pelvic hematoma in 2 cases, incisional hernia in 2, deep venous thrombosis in 1 and pulmonary embolus in 1. Of the 247 patients 235 (95%) completed the quality of life questionnaire with 92% reporting a high degree of satisfaction with low (less than 20 of 100 points) symptom distress scores. Pubovaginal slings are effective and durable, and significantly improve quality of life in patients with types II and III stress urinary incontinence.


Detrending knee joint vibration signals with a cascade moving average filter.
Knee joint vibration signals are very useful for computer-aided analysis of the pathological conditions in the knee. In a vibration arthrometry test, the legs of patients with knee joint disorders may tremble due to the reaction of pain, which causes the baseline wander that may affect the diagnostic decision making in medical study. This paper presents a new type of cascade moving average filter with hierarchical layers to remove the baseline wander in the raw knee joint vibration signals. The first layer of the cascade filter contains two moving averaging operators with the same order. The five tail inputs of the first moving averaging operator are overlapping with the beginning inputs of the successive operator. The piecewise linear trends estimated by the moving average operators in the first layer were smoothed in the final cascade filter output. The simulation results showed that the cascade filter can effectively remove the baseline wander in the raw knee joint vibration signals.


[Peculiarities of uric acid balance disorders in patients with type 2 diabetes and metabolic syndrome].
Hyperuricemia (HU) is considered to be a sign of metabolic syndrome as a consequence of purine metabolism disorder. To investigate alterations in uric acid (UA) methabolism, 90 subjects (M/F 53/37, aged 58 +/- 4 yr) with type 2 diabetes mellitus (DM2) were divided into 5 groups depending on the amount of excreted UA and its content in blood plasma. HU was found in 29% of patients, while hyperpoduction of UA was characteristic in 87% patients. Normo- or hypouricemia in majority of patients were mostly connected to kidney hyperfiltration and "compensatory" hyperuricosuria. HU with decreased UA excretion ("kidney" HU) was characteristic of severe DM2 with reduced kidney filtration rate. "Metabolic" HU with increased formation and excretion rated of UA was observed only in obese men. Increased insulinemia levels and insulin resistance index (IR) were found in obese patients in comparison with subjects with normal weight, independently of the type of UA excretion disorder. IR strongly correlated with serum UA levels in all groups of patients. The results suggest the significance of insulin resistance and abdominal obesity in UA metabolism in DM2.


SARS-COV-2 (Covid-19) and male fertility: Where are we?
Severe acute respiratory syndrome coronavirus 2 (SARS-COV-2), a single-stranded RNA virus, was found to be the causal agent of the disease called coronavirus disease. During December 2019, China informed the World Health Organization (WHO) of an outbreak of cases of pneumonia of unknown etiology, which caused severe-acute respiratory distress. The disease was termed coronavirus disease 2019 (Covid-19). Due to alarming levels of spread and severity, on the 11th of March 2020, the WHO declared the outbreak as a global pandemic. As of September 14, 2020, more than 29 million cases have been reported, with over 900,000 deaths globally. Since the outbreak, although not conclusive, discoveries have been made regarding the understanding of the epidemiology, etiology, clinical features, clinical treatment, and prevention of the disease. SARS-COV-2 has been detected in saliva, respiratory fluids, blood, urine, and faeces. Findings are however controversial regarding its presence in the semen or the testis. Hence, this review aimed to further analyse the literature concerning (i) the effects of previously identified human coronaviruses on male fertility (ii) the impact of Covid-19 on male fertility and (iii) the implication for general health in terms of infection and transmission.


Targeted Therapies for Microvascular Disease.
Coronary microvascular dysfunction (CMD) is a common cause of ischemia but no obstructive coronary artery disease that results in an inability of the coronary microvasculature to meet myocardial oxygen demand. CMD is challenging to diagnose and manage due to a lack of mechanistic research and targeted therapy. Recent evidence suggests we can improved patient outcomes by stratifying antianginal therapies according to the diagnosis revealed by invasive assessment of the coronary microcirculation. This review article appraises the evidence for management of CMD, which includes treatment of cardiovascular risk, antianginal therapy and therapy for atherosclerosis.


Attenuation of Cigarette Smoke-Induced Emphysema in Mice by Apolipoprotein A-1 Overexpression.
Chronic inflammation, oxidative stress, and proteolysis participate primarily in the pathogenesis of chronic obstructive pulmonary disease (COPD)/emphysema. COPD is a highly prevalent smoking-related disease for which no effective therapy exists to improve the disease course. Although apolipoprotein A-1 (ApoA1) has antiinflammatory and antioxidant properties as well as cholesterol efflux potential, its role in cigarette smoke (CS)-induced emphysema has not been determined. Therefore, we investigated whether human ApoA1 transgenic (TG) mice, with conditionally induced alveolar epithelium to overexpress ApoA1, are protected against the CS-induced lung inflammatory response and development of emphysema. In this study, ApoA1 levels were significantly decreased in the lungs of patients with COPD and in the lungs of mice exposed to CS. ApoA1 TG mice did not develop emphysema when chronically exposed to CS. Compared with the control TG mice, ApoA1 overexpression attenuated lung inflammation, oxidative stress, metalloprotease activation, and apoptosis in CS-exposed mouse lungs. To explore a plausible mechanism of antiapoptotic activity of ApoA1, alveolar epithelial cells (A549) were treated with CS extract (CSE). ApoA1 prevented CSE-induced translocation of Fas and downstream death-inducing signaling complex into lipid rafts, thereby inhibiting Fas-mediated apoptosis. Taken together, the data showed that ApoA1 overexpression attenuated CS-induced lung inflammation and emphysema in mice. Augmentation of ApoA1 in the lung may have therapeutic potential in preventing smoking-related COPD/emphysema.


Acromioclavicular reconstruction using hook plate and anterior tibial tendon allograft with triple tunnel: The early results of revision surgery using a novel surgical technique.
In this study, a new modified surgical technique is presented for anatomic acromioclavicular (AC) joint reconstruction made by the application of anterior tibialis tendon autograft, three-way tunnel (two clavicular and one coracoid) and hook plate. The study is aimed to evaluate the post-operative short-term results of patients who underwent this treatment. A total of 11 patients underwent AC joint reconstruction because of persistent AC subluxation. In this reconstruction, a triple tunnel was made between the coracoid and the clavicle to anatomically restore the coracoclavicular (CC) ligament and an allograft was passed through the tunnels resembling conoid and trapezoid ligaments. The tendon had to be non-weight bearing at the appropriate tension to provide rapid and appropriate integration of the tendon in the tunnel. This was maintained by applying a hook plate. The hook plate method was used to protect the reconstructed ligament during the healing process as it has a similar hardness to that of the natural AC joint and provides rigid fixation. For a more comprehensive description of the technique, a cadaver demonstration was also performed. The mean follow-up period was 25.3 months (range: 18-34 month). None of the patients had a loss of reduction at the final follow-up. When the constant scores were examined, of the total 11 patients, 2 (18.2%) 38,39 had excellent results, 6 (54.5%) had good results and 3 (27.3%) had fair results. It can be seen that this newly described reconstruction technique has successful short-term results as an anatomic method and can be used effectively in revision cases. However, there is a need for further biomechanical and clinical studies to make comparisons with other techniques.


Acid sphingomyelinase modulates the autophagic process by controlling lysosomal biogenesis in Alzheimer's disease.
In Alzheimer's disease (AD), abnormal sphingolipid metabolism has been reported, although the pathogenic consequences of these changes have not been fully characterized. We show that acid sphingomyelinase (ASM) is increased in fibroblasts, brain, and/or plasma from patients with AD and in AD mice, leading to defective autophagic degradation due to lysosomal depletion. Partial genetic inhibition of ASM (ASM(+/-)) in a mouse model of familial AD (FAD; amyloid precursor protein [APP]/presenilin 1 [PS1]) ameliorated the autophagocytic defect by restoring lysosomal biogenesis, resulting in improved AD clinical and pathological findings, including reduction of amyloid-β (Aβ) deposition and improvement of memory impairment. Similar effects were noted after pharmacologic restoration of ASM to the normal range in APP/PS1 mice. Autophagic dysfunction in neurons derived from FAD patient induced pluripotent stem cells (iPSCs) was restored by partial ASM inhibition. Overall, these results reveal a novel mechanism of ASM pathogenesis in AD that leads to defective autophagy due to impaired lysosomal biogenesis and suggests that partial ASM inhibition is a potential new therapeutic intervention for the disease.


Effects of long-term fluoride exposure on cognitive ability and the underlying mechanisms: Role of autophagy and its association with apoptosis.
Autophagy and apoptosis are two important cellular processes that are crucial for neurodevelopment. Evidence shows that apoptosis is implicated in fluoride neurotoxicity. However, the biological roles of autophagy, especially its interplay with apoptosis in the neurotoxicity induced by long-term fluoride exposure remain unclear. Here we present in vivo and in vitro evidence that fluoride-induced defective autophagy elicits excessive apoptosis, thus inducing neurotoxicity. Using Sprague-Dawley rats exposed to sodium fluoride from 60 days before pregnancy until 6 months post-delivery as in vivo model, we showed that fluoride impaired the learning and memory abilities of offspring rats, with decreased neuronal number, suppressed autophagy and enhanced apoptosis in hippocampus. These results were validated in human neuroblastoma SH-SY5Y cells in vitro. Mechanistically, mTOR signaling, responsible for autophagy induction, was activated in vivo and in vitro, and targeting inhibition of mTOR with rapamycin protected SH-SY5Y cells from defective autophagy and excessive apoptosis, thereby enhancing neuronal survival. Furthermore, circulating levels of autophagy markers were low in children with higher fluoride body burden and lower intelligence quotient scores. Collectively, our results suggest that defective autophagy plays a pivotal role in fluoride neurotoxicity, and mTOR might be a promising target for the prevention and treatment of fluoride neurotoxicity.


Optical, Structural, and Crystal Defects Characterizations of Dip Synthesized (Fe-Ni) Co-Doped ZnO Thin Films.
Sol-gel technique is used to synthesize as-grown zinc oxide (ZnO) and iron-nickel (Fe-Ni) co-doped ZnO thin films deposited on glass substrates using dip coating technique. The structural properties and crystal imperfections of as-prepared thin films are investigated. We performed the structural analysis of films using X-ray diffraction (XRD). The XRD analysis reveal that the as-prepared films exhibit wurtzite structure. Furthermore, XRD-line profile analysis is performed to study the correlation between structural properties and imperfections of the nanocomposite thin films. The crystallite size and microstrains parameters are predicted using the Williamson-Hall method. We found that the crystallites size increases as the co-doped (Fe-Ni) concentration is increased. However, microstrains of the nanocomposite films decreases as (Fe-Ni) concentration is increased. The optical properties of the (Fe-Ni) co-doped nanocomposite films are investigated by performing UV-Vis (250 nm-700 nm) spectrophotometer measurements. We found that as the (Fe-Ni) concentration level is steadily increased, transmittance of the undoped ZnO thin films is decreased. Remarkably, refractive index of undoped ZnO thin films is found to exhibit values extending from 1.55 to1.88 that would increase as (Fe-Ni) concentration is increased.


Video-mediastinoscopy in management of patients with lung cancer: a preliminary study.
Cervical mediastinoscopy is widely employed for biopsy of mediastinal lymph nodes and staging of lung cancer. The application of video-assisted technology to mediastinoscopy in a series of patients with lung cancer has not been reported. Preliminary experience with the use of video-mediastinoscopy in diagnosis and staging of lung cancer is presented. Fifteen patients with lung cancer were studied. Results of previous computed tomography scans had shown the presence of enlarged mediastinal lymph nodes in the retrovascular plane in all of the cases. Video-mediastinoscopy was performed under general anesthesia using a specifically designed rigid scope connected to a mono-charged-coupled device video camera (model INH 002756; Karl Storz-Endoskope, Tuttlingen, Germany). Neither fatalities nor major complications related to the procedure were observed. In all cases, video-mediastinoscopy proved useful for diagnosis or staging of lung cancer, therefore contributing to clinical decision making. The optimal visualization of mediastinal structure and the possibility for the surgeon to operate with both hands are appreciable characteristics of this technique.


Fatty acids and insulin sensitivity.
Given the pathophysiological importance of insulin resistance, the potential impact of dietary fatty acids is highly relevant. The effects of different types of dietary fatty acids on insulin sensitivity in humans are discussed, with focus on recent controlled studies. Observational studies assessing fatty acid composition in serum or tissues suggest that insulin resistance is associated with relatively high intakes of saturated fat (e.g. palmitic acid) and low intakes of polyunsaturated fat (e.g. linoleic acid), findings that are supported by recent clinical data. Most controlled studies have hitherto examined the effect of monounsaturated fat on insulin sensitivity, several indicating that it has beneficial effects when substituted for saturated fat. More clinical data comparing n-6 polyunsaturated, monounsaturated and saturated fat are needed to identify the optimal dietary fat composition, especially in patients with insulin resistance/obesity and diabetes. The total fat content of the background diet should also be considered in future studies. Finally, we and others hypothesize that dietary fatty acids may partly mediate their effects on insulin action by regulating the activity of lipogenic enzymes and desaturases. Substituting saturated fat with unsaturated fat seems to have beneficial effects on insulin sensitivity, although the clinical significance of modifying fat quality alone is still unclear.


Electrophysiological patterns of diabetic polyneuropathy.
This study evaluates the pattern of electrodiagnostic (EDX) abnormalities in diabetic sensorimotor polyneuropathies. EDX data from 112 consecutive patients with type 2 diabetes mellitus with distal, predominantly sensory, polyneuropathies were reviewed. Motor conduction velocities (CV), distal motor latencies (DML), compound muscle action potential (CMAP) amplitudes, distal to proximal amplitude ratios (PID), and F-wave latencies (FWL) were analyzed. Data were normalized based on normative reference values, and the proportion of nerves with abnormal values in the lower and upper limbs were evaluated. These data were also analyzed in relation to whether there was possible demyelinating versus axonal injury. Statistical analyses included comparison of the proportions of abnormal nerves in upper versus lower limbs as well as using Generalized Estimating Equations (GEE) to account for correlated observations for each patient between lower and upper limbs and adjusting for patient age effect. CVs were significantly more abnormal in the legs than the arms (p < 0.0006) and decreased CMAP amplitudes meeting criteria for axonal injury were also more frequent in the legs (p < 0.0001). Using the GEE model, axonal injury was more common in the legs while demyelinating injury was more common in the arms based on FWLs, especially in younger persons (e.g., 40 years old vs. 50 years old). These differences are not readily explained by the duration of the diabetes. Since in diabetics "axonal" type injury may be more common in the legs while "demyelinating" injury more frequent in the arms, this study emphasizes the limitation of this type of classification, and supports the idea that the pattern of EDX abnormalities in different types of neuropathies may be more helpful.


Players' performance during worst-case scenarios in professional soccer matches: a systematic review.
Since the analysis of worst-case scenarios (WCS) has been increasing knowledge about match demands and possible impacts for the training process, it seems important to summarize the evidence to provide useful information for the soccer community. Thus, the purpose of this systematic review was to summarize the evidence about WCS in professional soccer. A systematic review of PubMed, SPORTDiscus, and FECYT (Web of Sciences, CCC, DIIDW, KJD, MEDLINE, RSCI, and SCIELO) was performed according to the guidelines for performing systematic reviews in sport science. From the 85 studies initially identified, 12 were fully reviewed, and their outcome measures were extracted and analyzed. There was an inverse relationship between the duration of WCS windows and running output during match play. Occurrences of WCS during soccer matches were also position-dependent across studies, at least, when analyzing performance with the total distance covered variable, although different outputs were identified between women and men players. Future research should consider analyzing the impact of contextual variables (match status, team formation, and match location) on peak match values and the weight of these moderators.


Child sexual abuse reported by an English national sample: characteristics and demography.
The 2007 adult psychiatric morbidity survey in England provides detailed information of high quality about sexual abuse. Given the major psychiatric implications of child sexual abuse (CSA), we aimed to establish its sociodemographic distribution in the general population. The experience of sexual abuse was elicited in a random sample of the English household population (N = 7,353), using computer assisted self-completion interviewing. Respondents were handed a laptop, and entered their responses to detailed questions. The interviewer was blind to their responses. CSA was defined as occurring before the age of 16. 2.9% of women and 0.8% of men reported CSA involving non-consensual intercourse, figures that rose to 11.1 and 5.3% if experiences involving sexual touching were included. CSA was common before puberty, but peaked in adolescence. CSA greatly increased the chance in adulthood both of further sexual abuse (OR 10.6; CI 8.9-12.6), and of prostitution (OR 3.3; CI 1.9-5.5). There was no association with ethnicity or social class, but people over 65 were less likely to report CSA. The odds of CSA were doubled in those not brought up with both biological parents until the age of 16. CSA is common, particularly in women, and is not the preserve of any particular social group. Its frequency and its association with psychiatric consequences render it a major public health issue.


Tropolone natural products.
Covering: 2008 to 2018 This review provides a comprehensive overview of newly discovered natural products containing a tropolonoid motif covering 2008 up to 2018 and depicts the ecological context in which they have been isolated. This review has a strong focus on describing the different analytical tools and molecular biological approaches used to identify the underlying biosynthetic pathways.


Changes in forest land use and management in Sabah, Malaysian Borneo, 1990-2010, with a focus on the Danum Valley region.
In an earlier special issue of this journal, Marsh & Greer summarized forest land use in Sabah at that time and gave an introduction to the Danum Valley Conservation Area. Since that assessment, during the period 1990-2010, the forests of Sabah and particularly those of the ca 10 000 km(2) concession managed on behalf of the State by Yayasan Sabah (the Sabah Foundation) have been subject to continual, industrial harvesting, including the premature re-logging of extensive tracts of previously only once-logged forest and large-scale conversion of natural forests to agricultural plantations. Over the same period, however, significant areas of previously unprotected pristine forest have been formally gazetted as conservation areas, while much of the forest to the north, the south and the east of the Danum Valley Conservation Area (the Ulu Segama and Malua Forest Reserves) has been given added protection and new forest restoration initiatives have been launched. This paper analyses these forest-management and land-use changes in Sabah during the period 1990-2010, with a focus on the Yayasan Sabah Forest Management Area. Important new conservation and forest restoration and rehabilitation initiatives within its borders are given particular emphasis.


miR‑3120/Hsc70 participates in forced swim stress‑induced mechanical hyperalgesia in rats in an inflammatory state.
The heat shock cognate 71 kDa protein (Hsc70) is a stress‑inducible ATPase that can protect cells against harmful stimuli. Transient receptor potential vanilloid 1 (TRPV1) is a well‑documented nociceptor. Notably, Hsc70 can inhibit TRPV1 expression and function, suggesting that Hsc70 may have pain regulation potential. However, the role of Hsc70 in stress‑induced hyperalgesia remains unclear. In the present study, the participation of Hsc70 and its regulator microRNA (miR)‑3120 were investigated in forced swim (FS) stress‑induced mechanical hyperalgesia in rats in an inflammatory state. Complete Freund's adjuvant (CFA) hind paw injection was performed to induce inflammatory pain in rats (CFA rats). Furthermore, in FS + CFA rats, FS stress was performed for 3 days before CFA injection. The levels of Hsc70, miR‑3120 and their downstream molecule TRPV1 were measured in the dorsal root ganglion (DRG) with western blotting, immunofluorescence, reverse transcription‑quantitative polymerase chain reaction and fluorescence in situ hybridization. The results revealed that FS stress significantly exacerbated CFA‑induced mechanical pain. Furthermore, CFA upregulated Hsc70 and TRPV1 expression, which was partially inhibited or further enhanced by FS stress, respectively. In FS + CFA rats, intrathecal injection of a lentiviral vector overexpressing Hsc70 (LV‑Hsc70) could decrease TRPV1 expression and improve the mechanical pain. Additionally, the expression levels of miR‑3120, a regulator of Hsc70, were markedly upregulated on day 3 following FS stress. Finally, miR‑3120 was identified to be colocalized with Hsc70 and expressed in all sizes of DRG neurons. In CFA rats, DRG injection of miR‑3120 agomir to induce overexpression of miR‑3120 resulted in similar TRPV1 expression and behavioral changes as those caused by FS stress, which were abolished in the presence of LV‑Hsc70. These findings suggested that miR‑3120/Hsc70 may participate in FS stress‑induced mechanical hyperalgesia in rats in an inflammatory state, possibly via disinhibiting TRPV1 expression in the DRG neurons.


Correlation between He-Ne scatter and 2.7-microm pulsed laser damage at coating defects.
A reported correlation between defect-initiated pulsed laser damage and local predamage scatter in multilayer infrared mirror coatings has been analyzed in detail. Examination of a much larger data base confirms the previous result on dielectric-enhanced reflectors with polished substrates over a wide range of energy densities above the damage onset. Scatter signals from individual undamaged defects were detected using a He-Ne scatter probe with a focal spot that nearly coincides with the 150-microm-diam (D1/e(2)) focal spot of the damage-probe beam. Subsequent damage frequency measurements (1-on-1) were made near normal or at 45 degrees incidence with 100-ns pulses at 2.7-microm wavelength. The correlation is characterized by an increase in damage frequency with increasing predamage scatter signal and by equivalence of the defect densities indicated by the two probes. Characteristics of the correlation are compared with a simple model based on focal spot intensity profiles. Conditions that limit correlation are discussed, including variable scatter from defects and background scatter from diamond-turned substrates. Results have implication for nondestructive defect detection and coating quality control.


In vitro myocardial performance after lethal and nonlethal doses of endotoxin.
The present study was initiated to determine whether the myocardial effects of an in vivo injection of endotoxin into rats were correlated with the dose and thus the lethality of the endotoxin administered. All animals in this study were used 4 h after a bolus injection of 1,000, 100, 10, or 1 microgram/100 g body wt of Escherichia coli endotoxin. At this time, mean arterial blood pressure had returned to control levels but cardiac output was still depressed at the three higher doses as previously reported [Am. J. Physiol. 248 (Regulatory Integrative Comp. Physiol. 17): R471-R478, 1985]. Intrinsic function of the myocardium was assessed using the isolated perfused working heart preparation. Cardiac output and pressure development were measured at varying preloads and at two levels of aortic outflow resistance. In vitro approaches were chosen for this study to eliminate peripheral vascular changes and humoral or neural alterations that might influence myocardial performance in vivo. Results indicate that coronary vascular resistance was increased in all hearts from endotoxin-treated animals compared with controls. In addition, myocardial performance was impaired at several doses of endotoxin, and the degree of dysfunction was dependent on the dose of endotoxin administered. Dysfunction, i.e., a depression in cardiac output times peak systolic pressure, was evident at the two higher doses in which there was 50 and 10% lethality by 24 h and also in the lower dose of 10 micrograms/100 g, which was nonlethal. Cardiac output appeared to be very sensitive to the consequences of endotoxin administration. Defects in myocardial performance could be revealed by increasing preload or afterload stress on the hearts.(ABSTRACT TRUNCATED AT 250 WORDS)


[Radiographic studies of ossification of the hoof cartilage of horses and its clinical evaluation].
Radiographic examination is a valuable means for the identification of ossified lateral cartilage. The extent and stages of development of the ossification can be determined. The active stage of development of ossified lateral cartilage, which by itself can provoke lameness, can be defined. By means of the X-ray it is tried to differentiate the three kinds of ossification: the enchondral, the peri- and parachondral ossification of the lateral cartilage. Centres of ossification and fractures of the ossified lateral cartilage are described.


Poor oral health affects survival in head and neck cancer.
Poor oral health has emerged as a risk factor for squamous cell carcinoma of the head and neck (HNSCC) but its impact on survival has not been examined. We sought to estimate the impact of oral health indicators on survival in a population-based HNSCC cohort. Cases (n=1381) and age-, sex- and race-matched controls (n=1396) were participants in the Carolina Head and Neck Cancer Epidemiologic Study (CHANCE). Vital status was determined via linkage with the National Death Index. Survival was considered at 5years post-diagnosis or study-enrollment for controls. Oral health was assessed using self-reported indicators including frequency of routine dental exams and tooth brushing. We used Kaplan-Meyer analyses and Cox regression to estimate adjusted hazard ratios (HR) and 95% confidence intervals (CI). Routine dental visits during the preceding 10years were associated with decreased mortality risk (>10 visits: HR=0.6, 95% CI=0.4-0.8) after adjusting for confounders. This effect was most pronounced for oral cavity cancer-(e.g., >10 visits: HR=0.4, 95% CI=0.2-0.9). Dental visits were also positively associated with survival among controls. No other routine health screening (e.g., eye exams) was associated with survival. We found significant associations between markers of oral health and survival among both HNSCC cases and controls. This association was most pronounced for sites closer to the dentition. Oral health may have a direct effect on tumor biology due to the associated immune or inflammatory response. It may also represent a proxy for wellness or unmeasured social determinants of health.


Fibroblasts that overexpress 15-lipoxygenase generate bioactive and minimally modified LDL.
Several lines of evidence suggest that the cellular enzyme 15 lipoxygenase (15-LO) may be important in promoting the oxidation of lipoproteins in vivo. In previous studies we have shown that fibroblasts transfected with 15-LO "seed" LDL with lipoperoxides such that subsequent oxidation readily generates an LDL that is taken up by macrophages through scavenger receptors. We now demonstrate that LDL incubated with 15-LO cells is "minimally modified" and has bioactive properties. Characterization of LDL incubated with 15-LO cells reveals that lipid peroxidation is modest, with low levels of TBARS generated (12.6 +/- 4.7 nmole MDA per mg protein) and small amounts of 18:2 lost as a result of oxidation (7%, compared with extensive loss [82%] with copper oxidation). The 15-LO-conditioned LDL showed mildly increased electrophoretic mobility on agarose gels, and on polyacrylamide gels it showed only mild protein degradation compared with copper-oxidized LDL. Additionally 15-LO-conditioned LDL competed very well for the LDL receptor of fibroblasts but did not compete for macrophage uptake of 125I-acetylated LDL. Importantly, compared with LDL incubated on beta-galactosidase (lac Z)-transfected control cells, LDL incubated on 15-LO cells stimulated monocyte chemotaxis (15-LO-LDL, 6.9 +/- 1.2 monocytes per field versus lac Z-LDL, 0 +/- 0.9 monocytes per field) and when added to endothelial cells enhanced adhesion (15-LO-LDL, 31.1 +/- 5.0 monocytes per field versus lac Z-LDL, 0 +/- 2.0 monocytes per field). Preincubation of 15-LO cells with 15-LO inhibitors significantly inhibited the generation of bioactive LDL. Lipid extracts of LDL conditioned on 15-LO cells showed chemotactic activity not related to lysophosphatidylcholine levels. Preincubation of target endothelial cells with several different platelet-activating factor receptor antagonists prevented stimulation of monocyte adhesion by 15-LO-conditioned LDL. When probucol- or vitamin E-enriched LDL was incubated with 15-LO cells it was less oxidized and less bioactive, which suggests that these cells seed LDL with LOOH, which then requires further propagation of lipid peroxidation to yield bioactivity. These studies demonstrate that fibroblasts expressing 15-LO reliably produce a bioactive "minimally modified" LDL, which may explain in part how cellular 15-LO activity may generate atherogenic LDL in vivo.


A Noninvasive Method for Quantifying Cerebral Blood Flow by Hybrid PET/MRI.
Although PET with 15O-water is the gold standard for imaging cerebral blood flow (CBF), quantification requires measuring the arterial input function (AIF), which is an invasive and noisy procedure. To circumvent this problem, we propose a noninvasive PET/MRI approach that eliminates the need to measure AIF by using global CBF determined by phase-contrast (PC) MRI as a reference region. This approach not only is noninvasive but also involves no additional imaging time, because PC MRI and 15O-water PET are acquired simultaneously. The purpose of this study was to test the accuracy of this hybrid method in an animal model in which AIF was measured directly and CBF was varied by changing the arterial CO2 tension. Methods: PET and MRI data were simultaneously acquired in juvenile pigs at hypocapnia (n = 5), normocapnia (n = 5), and hypercapnia (n = 4). CBF was measured by the MRI reference method and by PET alone using an MRI-compatible blood sampling system to measure AIF. Results: Global CBF estimates from PC MRI and 15O-water PET agreed well, with a correlation coefficient of 0.9 and a slope of 0.88. Strong positive correlations (R2 > 0.96) were also found between regional CBF generated by the PET-only and the MRI-reference methods. Conclusion: These findings demonstrate the accuracy of this hybrid PET/MRI approach, which might prove useful in patients for whom obtaining accurate CBF measurements is challenging.


Safety and efficacy of intracranial vascularized submental lymph node transfer for treating hydrocephalus.
Hydrocephalus is routinely treated with ventriculoperitoneal shunt drainage of cerebrospinal fluid (CSF), a procedure plagued by high morbidity and frequent revisions. Vascularized submental lymph node (VSLN) transplants act as lymphatic pumps to drain interstitial fluid (ISF) from lymphedematous extremities. As the field of neuro-lymphatics comes to fruition, we hypothesize the efficacy of VSLN in the drainage of intracranial CSF-ISF. We report novel placement of VSLN in the temporal subdural space in two patients diagnosed with symptomatic communicating hydrocephalus. At a minimum follow-up of 1 month postoperatively, both experienced radiological and clinical improvements.


Alcohol treatment research follow-up interviews and drinking behaviors.
This study, drawing upon data collected as part of a randomized clinical trial of alcohol treatment matching effects, investigates the relationship between research follow-up assessment interviews and subsequent drinking behaviors. Subjects (N = 188; 143 men) participated in a day hospital substance-use disorder treatment program at either a private psychiatric hospital (n = 151) or a community hospital (n = 37) and were classified into one of three research groups: regularly scheduled follow-up interviews, missed scheduled follow-up interviews, and delayed Year-2 follow-up interviews. Complete data relevant to the present study were collected on 157 subjects. Study results provided support for a subject reactivity effect related to the research follow-up interview; that is, those subjects classified within the regularly scheduled follow-up interviews condition had the better drinking outcomes. Furthermore, by the end of the second follow-up year, subjects classified within the delayed Year-2 follow-up interviews condition had the poorest drinking outcomes. There may be considerable potential for subject reactivity effects, specific to the research assessment interview, to confound study results. Therefore, the interpretation of data from alcohol treatment outcome studies that fail to control for such potential confounding effects must be viewed with caution. Researchers are advised to control for these potentially confounding effects via methodological and/or statistical mechanisms.


Reconstruction and functional characterization of the human mitochondrial metabolic network based on proteomic and biochemical data.
Diverse datasets including genomic, proteomic, isotopomer, and DNA sequence variation are becoming available for human mitochondria. Thus there is a need to integrate these data within an in silico modeling framework where mitochondrial biology and related disorders can be studied and analyzed. This paper reports a reconstruction and characterization of the human mitochondrial metabolic network based on proteomic and biochemical data. The 189 reactions included in this reconstruction are both elementally and charge-balanced and are assigned to their respective cellular compartments (mitochondrial, cytosol, or extracellular). The capabilities of the reconstructed network to fulfill three metabolic functions (ATP production, heme synthesis, and mixed phospholipid synthesis) were determined. Network-based analysis of the mitochondrial energy conversion process showed that the overall ATP yield per glucose is 31.5. Network flexibility, characterized by allowable variation in reaction fluxes, was evaluated using flux variability analysis and analysis of all of the possible optimal flux distributions. Results showed that the network has high flexibility for the biosynthesis of heme and phospholipids but modest flexibility for maximal ATP production. A subset of all of the optimal network flux distributions, computed with respect to the three metabolic functions individually, was found to be highly correlated, suggesting that this set may contain physiological meaningful fluxes. Examinations of optimal flux distributions also identified correlated reaction sets that form functional modules in the network.


Cholesterol enrichment increases basal and agonist-stimulated calcium influx in rat vascular smooth muscle cells.
The effect of cholesterol enrichment on vascular smooth muscle cell (VSMC) calcium homeostasis was studied by evaluating calcium uptake, efflux, and intracellular content in cultured VSMC derived from the rat pulmonary artery. Incubation of VSMC with liposomes consisting of free cholesterol (FC) and phospholipid (2:1 molar ratio, 1 mg FC/ml medium) for 24 h resulted in a 69 +/- 19% increase (P less than 0.01; n = 10) in FC which was associated with a 73 +/- 11% increase (P less than 0.005; n = 10) in intracellular calcium content as assessed by isotopic equilibrium with 45Ca2+ and a 65 +/- 11% increase (P less than 0.024; n = 3) as assessed by atomic absorption spectroscopy. Cholesterol enrichment caused a marked increase in the unidirectional calcium uptake rate from 0.026 +/- 0.03 to 0.158 +/- 0.022 nmol calcium/s per mg protein (P less than 0.01; n = 3), but had no effect on calcium efflux. Nifedipine (1 microM) reduced (P less than 0.05; n = 6) the effect of cholesterol enrichment on unidirectional calcium uptake by 78 +/- 16%; and verapamil (10 microM), diltiazem (1 microM), and nifedipine (1 microM) each significantly inhibited the effect of cholesterol enrichment on intracellular calcium accumulation. Exposure of cholesterol-enriched VSMC to cholesterol-poor liposomes for 24 h returned both FC and calcium contents to control levels. Serum- and serotonin-stimulated calcium uptakes were potentiated 3.7- and 1.7-fold, respectively, in cholesterol-enriched VSMC, whereas endothelin, vasopressin, and thrombin-stimulated calcium uptakes were not affected. We conclude that VSMC FC content plays a role in regulating cellular calcium homeostasis, both under basal conditions and in response to selected agonists.


SecA-dependent quality control of intracellular protein localization.
Complex secretion machineries mediate protein translocation across cellular membranes. These machines typically recognize their substrates via signal sequences, which are required for proper targeting to the translocon. We report that during posttranslational secretion the widely conserved targeting factor SecA performs a quality-control function that is based on a general chaperone activity. This quality-control mechanism involves assisted folding of signal sequenceless proteins, thereby excluding them from the secretion process. These results suggest that SecA channels proteins into one of two key pathways, posttranslational secretion or folding in the cytoplasm. Implications of this finding for intracellular protein localization are discussed.