Phylogenetic diversity of insecticolous fusaria inferred from multilocus DNA sequence data and their molecular identification via FUSARIUM-ID and Fusarium MLST.
We constructed several multilocus DNA sequence datasets to assess the phylogenetic diversity of insecticolous fusaria, especially focusing on those housed at the Agricultural Research Service Collection of Entomopathogenic Fungi (ARSEF), and to aid molecular identifications of unknowns via the FUSARIUM-ID and Fusarium MLST online databases and analysis packages. Analyses of a 190-taxon, two-locus dataset, which included 159 isolates from insects, indicated that: (i) insect-associated fusaria were nested within 10 species complexes spanning the phylogenetic breadth of Fusarium, (ii) novel, putatively unnamed insecticolous species were nested within 8/10 species complexes and (iii) Latin binomials could be applied with confidence to only 18/58 phylogenetically distinct fusaria associated with pest insects. Phylogenetic analyses of an 82-taxon, three-locus dataset nearly fully resolved evolutionary relationships among the 10 clades containing insecticolous fusaria. Multilocus typing of isolates within four species complexes identified surprisingly high genetic diversity in that 63/65 of the fusaria typed represented newly discovered haplotypes. The DNA sequence data, together with corrected ABI sequence chromatograms and alignments, have been uploaded to the following websites dedicated to identifying fusaria: FUSARIUM-ID (http://isolate.fusariumdb.org) at Pennsylvania State University's Department of Plant Pathology and Fusarium MLST (http://www.cbs.knaw.nl/fusarium) at the Centraalbureau voor Schimmelcultures (CBS-KNAW) Fungal Biodiversity Center.


Sugar/osmoticum levels modulate differential abscisic acid-independent expression of two stress-responsive sucrose synthase genes in Arabidopsis.
Sucrose synthase (Sus) is a key enzyme of sucrose metabolism. Two Sus-encoding genes (Sus1 and Sus2) from Arabidopsis thaliana were found to be profoundly and differentially regulated in leaves exposed to environmental stresses (cold stress, drought or O(2) deficiency). Transcript levels of Sus1 increased on exposure to cold and drought, whereas Sus2 mRNA was induced specifically by O(2) deficiency. Both cold and drought exposures induced the accumulation of soluble sugars and caused a decrease in leaf osmotic potential, whereas O(2) deficiency was characterized by a nearly complete depletion in sugars. Feeding abscisic acid (ABA) to detached leaves or subjecting Arabidopsis ABA-deficient mutants to cold stress conditions had no effect on the expression profiles of Sus1 or Sus2, whereas feeding metabolizable sugars (sucrose or glucose) or non-metabolizable osmotica [poly(ethylene glycol), sorbitol or mannitol] mimicked the effects of osmotic stress on Sus1 expression in detached leaves. By using various sucrose/mannitol solutions, we demonstrated that Sus1 was up-regulated by a decrease in leaf osmotic potential rather than an increase in sucrose concentration itself. We suggest that Sus1 expression is regulated via an ABA-independent signal transduction pathway that is related to the perception of a decrease in leaf osmotic potential during stresses. In contrast, the expression of Sus2 was independent of sugar/osmoticum effects, suggesting the involvement of a signal transduction mechanism distinct from that regulating Sus1 expression. The differential stress-responsive regulation of Sus genes in leaves might represent part of a general cellular response to the allocation of carbohydrates during acclimation processes.


Nanofiltration and Fenton's process over iron shavings for surfactants removal.
The presence of surfactants in wastewater composition tends to jeopardize the efficiency of the traditional aerobic treatment processes. In this regard, the application of Fenton's reaction and nanofiltration as single processes and integrated (nanofiltration followed by Fenton's process) was investigated on the abatement of a solution containing two surfactants usually found in effluents coming from detergent industry (dodecylbenzene--DDB and sodium lauryl ether sulphate--SLES). The potential of a solid waste (iron shavings) as catalyst in the Fenton's process was evaluated and the reaction system was optimized regarding the key operating parameters (iron and hydrogen peroxide concentration and pH). The highest chemical oxygen demand (COD) degradation (66%) was attained for pH 3, [H2O2] = 32 mM and 50 g/L of iron shavings. Besides, it was concluded that oxidation was due to hydroxyl radicals adsorbed on the metal surface even if bulk interaction between hydrogen peroxide and dissolved iron cannot be neglected. The main variables ruling nanofiltration were evaluated (pH, temperature and cross-flow rate). Eighty-four percent of COD rejection was determined at pH 7.5, cross-flow 14.4 cm3 s(-1), 20 degrees C and 15 bar of pressure drop. Finally, nanofiltration followed by Fenton's process under the best conditions was integrated; however, no significant improvement was attained with 85% of COD being globally removed.


Hepatic hydrothorax.
Hepatic hydrothorax is defined as a transudative pleural effusion, usually greater than 500 mL, in patients with portal hypertension without any other underlying primary cardiopulmonary cause. It develops most likely because of diaphragmatic defects that allow for passage of fluid from the peritoneal space to the pleural space. Because of the mechanical constraints of the thoracic cavity, this complication of portal hypertension can be challenging to treat because patients will become symptomatic when as little as 500 mL of fluid is present in the pleural space. Treatments include salt restriction, diuretics, thoracentesis, transjugular intrahepatic portosystemic shunt, video-assisted thoracoscopy, and pleurodesis. It is important to note that a chest tube is not a potential treatment option; a hepatic hydrothorax should not be treated with a chest tube unless there is frank pus in the pleural fluid or a pneumothorax is present. The ultimate treatment is a liver transplant; the development of a hepatic hydrothorax thus warrants a referral to a liver transplant center.


What you see is where you go: visibility influences movement decisions of a forest bird navigating a three-dimensional-structured matrix.
Animal spatial behaviour is often presumed to reflect responses to visual cues. However, inference of behaviour in relation to the environment is challenged by the lack of objective methods to identify the information that effectively is available to an animal from a given location. In general, animals are assumed to have unconstrained information on the environment within a detection circle of a certain radius (the perceptual range; PR). However, visual cues are only available up to the first physical obstruction within an animal's PR, making information availability a function of an animal's location within the physical environment (the effective visual perceptual range; EVPR). By using LiDAR data and viewshed analysis, we modelled forest birds' EVPRs at each step along a movement path. We found that the EVPR was on average 0.063% that of an unconstrained PR and, by applying a step-selection analysis, that individuals are 1.55 times more likely to move to a tree within their EVPR than to an equivalent tree outside it. This demonstrates that behavioural choices can be substantially impacted by the characteristics of an individual's EVPR and highlights that inferences made from movement data may be improved by accounting for the EVPR.


ASC-J9 ameliorates spinal and bulbar muscular atrophy phenotype via degradation of androgen receptor.
Motor neuron degeneration resulting from the aggregation of the androgen receptor with an expanded polyglutamine tract (AR-polyQ) has been linked to the development of spinal and bulbar muscular atrophy (SBMA or Kennedy disease). Here we report that adding 5-hydroxy-1,7-bis(3,4-dimethoxyphenyl)-1,4,6-heptatrien-3-one (ASC-J9) disrupts the interaction between AR and its coregulators, and also increases cell survival by decreasing AR-polyQ nuclear aggregation and increasing AR-polyQ degradation in cultured cells. Intraperitoneal injection of ASC-J9 into AR-polyQ transgenic SBMA mice markedly improved disease symptoms, as seen by a reduction in muscular atrophy. Notably, unlike previous approaches in which surgical or chemical castration was used to reduce SBMA symptoms, ASC-J9 treatment ameliorated SBMA symptoms by decreasing AR-97Q aggregation and increasing VEGF164 expression with little change of serum testosterone. Moreover, mice treated with ASC-J9 retained normal sexual function and fertility. Collectively, our results point to a better therapeutic and preventative approach to treating SBMA, by disrupting the interaction between AR and AR coregulators.


Clinical feasibility of mandibular implant overdenture retainers submitted to immediate load.
Millions of people around the world do not have access to the benefits of osseointegration. Treatments involving oral rehabilitation with overdentures have been widely used by specialists in the oral medicine field. This is an alternative therapy for retention and stability achievement in total prosthesis with conventional treatment, and two implants are enough to establish a satisfactory overdenture. The objectives of the study were to evaluate 16 patients of both sexes, with an average age of 47.4±4 years, using electromyographic analysis of masseter and temporal muscles and analyse the increase of incisive and molar maximal bite force with their existing complete dentures and following mandibular implant overdenture therapy to assess the benefits of this treatment. For these tests, the Myosystem-BR1 electromyograph and the IDDK Kratos dynamometer were used. Statistical analysis was performed using the repeated measures test (SPSS 17.0). A decrease in electromyographic activity during the rest, lateral and protrusion movements and increase of the maximal incisive and molar bite force after 15months with a mandibular implant overdenture was observed. All the patients in this study reported a considerable improvement in the masticatory function and prostheses stability following treatment. It is possible to propose that the use of mandibular implants overdenture should become the selected treatment for totally edentulous patients to facilitate oral function and quality of life.


Epigenetic reprogramming modulates malignant properties of human liver cancer.
Reversal of DNA hypermethylation and associated gene silencing is an emerging cancer therapy approach. Here we addressed the impact of epigenetic alterations and cellular context on functional and transcriptional reprogramming of hepatocellular carcinoma (HCC) cells. Our strategy employed a 3-day treatment of established and primary human HCC-derived cell lines grown as a monolayer at various cell densities with the DNMT1 inhibitor zebularine (ZEB) followed by a 3D culture to identify cells endowed with self-renewal potential. Differences in self-renewal, gene expression, tumorigenicity, and metastatic potential of spheres at generations G1-G5 were examined. Transient ZEB exposure produced differential cell density-dependent responses. In cells grown at low density, ZEB caused a remarkable increase in self-renewal and tumorigenicity associated with long-lasting gene expression changes characterized by a stable overexpression of cancer stem cell-related and key epithelial-mesenchymal transition genes. These effects persisted after restoration of DNMT1 expression. In contrast, at high cell density, ZEB caused a gradual decrease in self-renewal and tumorigenicty, and up-regulation of apoptosis- and differentiation-related genes. A permanent reduction of DNMT1 protein using short hairpin RNA (shRNA)-mediated DNMT1 silencing rendered HCC cells insensitive both to cell density and ZEB effects. Similarly, WRL68 and HepG2 hepatoblastoma cells expressing low DNMT1 basal levels also possessed a high self-renewal, irrespective of cell density or ZEB exposure. Spheres formed by low-density cells treated with ZEB or shDNMT1 displayed a high molecular similarity which was sustained through consecutive generations, confirming the essential role of DNMT1 depletion in the enhancement of cancer stem cell properties. These results identify DNA methylation as a key epigenetic regulatory mechanism determining the pool of cancer stem cells in liver cancer and possibly other solid tumors.


Effect of 5-fluorouracil in cholesteatoma development in an animal model.
This investigation was designed to evaluate the effects of the antimetabolite 5-fluorouracil (5-FU) on cholesteatoma formation in a chinchilla model. The animals received middle ear applications of propylene glycol according to a procedure previously shown to produce cholesteatomas in 60% to 70% of animals. A 5% solution of 5-FU was then applied to the lateral surface of the tympanic membrane (TM) and, after 1 month, temporal bones were taken for histologic study. No macroscopically visible cholesteatomas were present in any of the 16 temporal bones included in the study. However, microscopic invasion of epidermis to the medial side of the TM was observed in four specimens; perforations were present in three of these. Although there was considerable variability in the response to 5-FU application, the majority of specimens showed little or no proliferation of connective tissue in the lamina propria of the TM. In the four specimens in which epidermis reached the medial side of the TM, it did so either by migration through microscopic breaks in the fibrous layer or via TM perforations. Thus, 5-FU did not completely inhibit migration of epidermis into the middle ear. However, the results of this study indicate that it does tend to reduce the proliferation of TM epidermis and connective tissue, thereby reducing the likelihood of cholesteatoma formation in the experimental model.


Prevalence of Genital Human Papillomavirus Infection and Human Papillomavirus Vaccination Rates Among US Adult Men: National Health and Nutrition Examination Survey (NHANES) 2013-2014.
Human papillomavirus (HPV) is a common sexually transmitted infection that is a major cause of noncervical anogenital and oropharyngeal cancers. Prophylactic HPV vaccine is available for primary prevention. However, the population prevalence data for male genital HPV infection is not well known, while the HPV vaccination coverage is low in the United States. To estimate the prevalence of genital HPV infection and the HPV vaccination rate in the United States among adult men and to examine potential risk factors for HPV infection. The National Health and Nutrition Examination Survey (NHANES) samples a representative cross-section of the US population. Men aged 18 to 59 years were examined in mobile examination centers during the NHANES 2013-2014. DNA was extracted from self-collected penile swab specimens, and HPV genotyping was performed by polymerase chain reaction amplification. Demographic and vaccination information was gathered via self-report during home-based standardized interviews. Binary multivariable logistic regression was used to estimate the odds of HPV infection. The prevalence of genital HPV infection and the HPV vaccination coverage rate among adult men. During the NHANES 2013-2014, a total of 1868 men aged 18 to 59 years were examined. The overall genital HPV infection prevalence was 45.2% (95% CI, 41.3%-49.3%). The infection prevalence with at least 1 high-risk HPV subtype defined by DNA testing was 25.1% (95% CI, 23.0%-27.3%). In vaccine-eligible men, the prevalence of infection with at least 1 HPV strain targeted by the HPV 4-valent vaccine and HPV 9-valent vaccine was 7.1% (95% CI, 5.1%-9.5%) and 15.4% (95% CI, 11.7%-19.6%), respectively. Among vaccine-eligible men, the HPV vaccination coverage was 10.7% (95% CI, 7.8%-14.6%). Among men aged 18 to 59 years in the United States, the overall prevalence of genital HPV infection was 45.2% (95% CI, 41.3%-49.3%). The overall genital HPV infection prevalence appears to be widespread among all age groups of men, and the HPV vaccination coverage is low.


Neuro-evolutionary patterning of sociality.
Evolutionary shifts in species-typical group size ('sociality') probably reflect natural selection on motivational processes such as social arousal, approach-avoidance, reward, stress/anxiety and dominance. Using four songbird species that differ selectively in sociality (one territorial, one modestly gregarious, and two highly gregarious species), we here examined immediate early gene (IEG) responses of relevant brain regions following exposure to a same-sex conspecific. The paradigm limited behavioural performance, thus species differences should reflect divergence in motivational and/or perceptual processes. Within the extended medial amygdala (which is involved in appetitive approach, social arousal and avoidance), we observed species differences in IEG response that are negatively graded in relation to sociality. In addition, brain areas that are involved in social stress and dominance-related behaviour (ventrolateral septum, anterior hypothalamus and lateral subdivision of the ventromedial hypothalamus) exhibited IEG responses that dichotomously distinguish the territorial species from the three gregarious species. The IEG responses of areas involved in reward (nucleus accumbens and ventral pallidum) and general stress processes (e.g. paraventricular hypothalamus, lateral bed nucleus of the stria terminalis and most areas of the lateral septum) do not correlate with sociality, indicating that social evolution has been accompanied by selection on a relatively discrete suite of motivational systems.


The endorsement of general and artificial intelligence reporting guidelines in radiological journals: a meta-research study.
Complete reporting is essential for clinical research. However, the endorsement of reporting guidelines in radiological journals is still unclear. Further, as a field extensively utilizing artificial intelligence (AI), the adoption of both general and AI reporting guidelines would be necessary for enhancing quality and transparency of radiological research. This study aims to investigate the endorsement of general reporting guidelines and those for AI applications in medical imaging in radiological journals, and explore associated journal characteristic variables. This meta-research study screened journals from the Radiology, Nuclear Medicine & Medical Imaging category, Science Citation Index Expanded of the 2022 Journal Citation Reports, and excluded journals not publishing original research, in non-English languages, and instructions for authors unavailable. The endorsement of fifteen general reporting guidelines and ten AI reporting guidelines was rated using a five-level tool: "active strong", "active weak", "passive moderate", "passive weak", and "none". The association between endorsement and journal characteristic variables was evaluated by logistic regression analysis. We included 117 journals. The top-five endorsed reporting guidelines were CONSORT (Consolidated Standards of Reporting Trials, 58.1%, 68/117), PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses, 54.7%, 64/117), STROBE (STrengthening the Reporting of Observational Studies in Epidemiology, 51.3%, 60/117), STARD (Standards for Reporting of Diagnostic Accuracy, 50.4%, 59/117), and ARRIVE (Animal Research Reporting of In Vivo Experiments, 35.9%, 42/117). The most implemented AI reporting guideline was CLAIM (Checklist for Artificial Intelligence in Medical Imaging, 1.7%, 2/117), while other nine AI reporting guidelines were not mentioned. The Journal Impact Factor quartile and publisher were associated with endorsement of reporting guidelines in radiological journals. The general reporting guideline endorsement was suboptimal in radiological journals. The implementation of reporting guidelines for AI applications in medical imaging was extremely low. Their adoption should be strengthened to facilitate quality and transparency of radiological study reporting.


In vitro muscle cell proliferation and protein turnover as affected by serum from pigs fed antimicrobials.
The effect of antimicrobial supplementation of pigs on the capacity of their sera to influence proliferation and protein turnover in cultured muscle cells was evaluated. Mitogenic activity of sera increased when pigs were fed ASP250 (P less than .005) or carbadox (P less than .001), whereas the mitogenic activity of serum from pigs receiving the basal diet remained unchanged (P = .5). Additionally, sera from ASP250-fed pigs significantly decreased (P less than .001) total cellular protein degradation compared with sera obtained from the same pigs prior to supplementation. Neither ASP250 nor carbadox stimulated proliferation of myogenic cells when added to the culture media. Inclusion of ASP250 in swine diets altered the composition of their sera in a way that stimulated muscle cell proliferation and reduced the rate of protein degradation in cultured myogenic cells. Likewise, the inclusion of carbadox in swine diets increased the ability of their sera to stimulate cultured muscle cell proliferation.


The AOM/DSS murine model for the study of colon carcinogenesis: From pathways to diagnosis and therapy studies.
Colorectal cancer (CRC) is a major health problem in industrialized countries. Although inflammation-linked carcinogenesis is a well accepted concept and is often observed within the gastrointestinal tract, the underlying mechanisms remain to be elucidated. Inflammation can indeed provide initiating and promoting stimuli and mediators, generating a tumour-prone microenvironment. Many murine models of sporadic and inflammation-related colon carcinogenesis have been developed in the last decade, including chemically induced CRC models, genetically engineered mouse models, and xenoplants. Among the chemically induced CRC models, the combination of a single hit of azoxymethane (AOM) with 1 week exposure to the inflammatory agent dextran sodium sulphate (DSS) in rodents has proven to dramatically shorten the latency time for induction of CRC and to rapidly recapitulate the aberrant crypt foci-adenoma-carcinoma sequence that occurs in human CRC. Because of its high reproducibility and potency, as well as the simple and affordable mode of application, the AOM/DSS has become an outstanding model for studying colon carcinogenesis and a powerful platform for chemopreventive intervention studies. In this article we highlight the histopathological and molecular features and describe the principal genetic and epigenetic alterations and inflammatory pathways involved in carcinogenesis in AOM/DSS-treated mice; we also present a general overview of recent experimental applications and preclinical testing of novel therapeutics in the AOM/DSS model.


Colocating Wound Care for Patients with Sickle Cell Ulcers in a Hematology Clinic.
Leg ulcers affect 15% of people with sickle cell disease. However, wound centers typically treat few people with this condition, which makes it difficult to concentrate clinical expertise or support the scientific study of this orphan disease. This article describes an initiative to increase engagement in care through a partnership between wound healing and hematology leadership that led to colocating wound services within a sickle cell clinic. Via a retrospective chart review, the authors collected records of all adult patients with sickle cell disease who received wound care in the last decade, including 7 years of wound center data and 3 years of data from the colocated services. Patient and visit characteristics were analyzed using descriptive analytics. The general wound center had previously treated 35 patients with sickle cell ulcers over 7 years. In contrast, colocated services engaged 56 patients within 3 years, including 20 who transferred care and 36 new patients. The majority of patients at the colocated site were women, unlike at the wound center (58% vs 47%, P = .07). Results indicated that 36% of patients healed initial wounds, and 45% had new wound occurrences. Colocation successfully increases the number of patients with sickle cell ulcers who will engage in wound care at a single site, laying the foundation for clinical studies to improve the evidence base for this difficult-to-treat condition.


Blood Utilization and Clinical Outcomes in Extracorporeal Membrane Oxygenation Patients.
Patients requiring extracorporeal membrane oxygenation (ECMO) support are critically ill and have substantial transfusion requirements, which convey both risks and benefits. A retrospective analysis was conducted to assess the association between blood component administration and adverse outcomes in adult, pediatric, and neonatal ECMO patients. We evaluated 217 ECMO patients at a single center hospitalized between January 2009 and June 2016. Three cohorts (88 adult, 57 pediatric, and 72 neonatal patients) were included for assessment of patient characteristics, blood utilization, and clinical outcomes. Univariable and multivariable analyses were used to assess the association between transfusions and clinical outcomes (primary outcome: mortality and secondary outcomes: morbid events). The analysis included the main exposure of interest (total number of blood component units transfused) and potential confounding variables (age group cohort, case mix index, sex, ECMO mode and duration, and primary ECMO indication). After adjustment for confounders, with each additional blood component unit transfused, there was an estimated increase in odds for mortality by 1% (odds ratio [OR] = 1.01; 95% confidence interval [CI], 1.00-1.02; P = .013) and an increase in odds for thrombotic events by 1% (OR = 1.01; 95% CI, 1.00-1.02; P = .007). Mortality was higher in the adult (57 of 88; 64.8%) and pediatric (37 of 57; 64.9%) than in the neonatal cohort (19 of 72; 26.4%) (P < .0001). Median total blood components transfused per day followed a similar pattern for the adult (2.3 units; interquartile range [IQR] = 0.8-7.0), pediatric (2.9 units; IQR = 1.1-10), and neonatal (1.0 units; IQR = 0.7-1.6) cohorts (P < .0001). Over the entire hospitalization, the total median blood components transfused was highest in the neonatal (41 units; IQR = 24-94) and pediatric (41 units; IQR = 17-113) compared to the adult (30 units; IQR = 9-58) cohort (P = .007). There was no significant interaction between total units transfused over the hospital stay and age cohort for mortality (P = .35). Given the association between transfusion and adverse outcomes, effective blood management strategies may be beneficial in ECMO patients.


Scaling metabolism from individuals to reef-fish communities at broad spatial scales.
Fishes contribute substantially to energy and nutrient fluxes in reef ecosystems, but quantifying these roles is challenging. Here, we do so by synthesising a large compilation of fish metabolic-rate data with a comprehensive database on reef-fish community abundance and biomass. Individual-level analyses support predictions of Metabolic Theory after accounting for significant family-level variation, and indicate that some tropical reef fishes may already be experiencing thermal regimes at or near their temperature optima. Community-level analyses indicate that total estimated respiratory fluxes of reef-fish communities increase on average ~2-fold from 22 to 28 °C. Comparisons of estimated fluxes among trophic groups highlight striking differences in resource use by communities in different regions, perhaps partly reflecting distinct evolutionary histories, and support the hypothesis that piscivores receive substantial energy subsidies from outside reefs. Our study demonstrates one approach to synthesising individual- and community-level data to establish broad-scale trends in contributions of biota to ecosystem dynamics.


Palmar dermatoglyphics in carcinoma breast of Indian women.
The present study was planned to assess the relationship of palmar dermatoglyphic patterns of hands in women with breast cancer and or at risk for developing breast cancer. This study was conducted on 100 histopathologically confirmed breast cancer patients in women and their digital dermatoglyphic patterns were studied to assess their association with the type and onset of breast cancer. Simultaneously 100 age-matched controls were also selected with no self or familial history of a diagnosed breast cancer and the observations were recorded. The differences of qualitative (dermatoglyphic patterns) data were tested for their significance using the chi-square test, and Student's t-test was used for quantitative (ridge counts and pattern intensity index) data analysis. The results of the study indicated statistically significant changes in finger ridge count and fingertip pattern in cases of carcinoma breast as compared to the control group. Palmar dermatoglyphics is simple, inexpensive, anatomical and non-invasive and may be used as a reliable indicator for screening of high-risk population in developing country like India, for early detection and early therapy, thus reducing the morbidity and mortality in cases of carcinoma breast.


Initial burden of disease estimates for South Africa, 2000.
This paper describes the first national burden of disease study for South Africa. The main focus is the burden due to premature mortality, i.e. years of life lost (YLLs). In addition, estimates of the burden contributed by morbidity, i.e. the years lived with disability (YLDs), are obtained to calculate disability-adjusted life years (DALYs); and the impact of AIDS on premature mortality in the year 2010 is assessed. Owing to the rapid mortality transition and the lack of timely data, a modelling approach has been adopted. The total mortality for the year 2000 is estimated using a demographic and AIDS model. The non-AIDS cause-of-death profile is estimated using three sources of data: Statistics South Africa, the National Department of Home Affairs, and the National Injury Mortality Surveillance System. A ratio method is used to estimate the YLDs from the YLL estimates. The top single cause of mortality burden was HIV/AIDS followed by homicide, tuberculosis, road traffic accidents and diarrhoea. HIV/AIDS accounted for 38% of total YLLs, which is proportionately higher for females (47%) than for males (33%). Pre-transitional diseases, usually associated with poverty and underdevelopment, accounted for 25%, non-communicable diseases 21% and injuries 16% of YLLs. The DALY estimates highlight the fact that mortality alone underestimates the burden of disease, especially with regard to unintentional injuries, respiratory disease, and nervous system, mental and sense organ disorders. The impact of HIV/AIDS is expected to more than double the burden of premature mortality by the year 2010. This study has drawn together data from a range of sources to develop coherent estimates of premature mortality by cause. South Africa is experiencing a quadruple burden of disease comprising the pre-transitional diseases, the emerging chronic diseases, injuries, and HIV/AIDS. Unless interventions that reduce morbidity and delay morbidity become widely available, the burden due to HIV/AIDS can be expected to grow very rapidly in the next few years. An improved base of information is needed to assess the morbidity impact more accurately.


Present and past dynamics of Inughuit resource spaces.
Information from a collaborative GPS tracking project, Piniariarneq, involving 17 occupational hunters from Qaanaaq and Savissivik, Northwest Greenland, is used to explore the resource spaces of hunters in Avanersuaq today. By comparison with historical records from the time of the Thule Trading Station and the decades following its closure, we reveal a marked variability in resource spaces over time. It is argued that the dynamics of resources and resource spaces in Thule are not underlain by animal distribution and migration patterns, or changes in weather and sea ice conditions alone; but also by economic opportunities, human mobility, settlement patterns, particular historical events and trajectories, and not least by economic and political interests developed outside the region.


Liver hyperplasia after tamoxifen induction of Myc in a transgenic medaka model.
Myc is a global transcriptional regulator and one of the most frequently overexpressed oncoproteins in human tumors. It is well established that activation of Myc leads to enhanced cell proliferation but can also lead to increased apoptosis. The use of animal models expressing deregulated levels of Myc has helped to both elucidate its function in normal cells and give insight into how Myc initiates and maintains tumorigenesis. Analyses of the medaka (Oryzias latipes) genome uncovered the unexpected presence of two Myc gene copies in this teleost species. Comparison of these Myc versions to other vertebrate species revealed that one gene, myc17, differs by the loss of some conserved regulatory protein motifs present in all other known Myc genes. To investigate how such differences might affect the basic biological functions of Myc, we generated a tamoxifen-inducible in vivo model utilizing a natural, fish-specific Myc gene. Using this model we show that, when activated, Myc17 leads to increased proliferation and to apoptosis in a dose-dependent manner, similar to human Myc. We have also shown that long-term Myc17 activation triggers liver hyperplasia in adult fish, allowing this newly established transgenic medaka model to be used to study the transition from hyperplasia to liver cancer and to identify Myc-induced tumorigenesis modifiers.


Combined deletion of Bap1, Nf2, and Cdkn2ab causes rapid onset of malignant mesothelioma in mice.
We have generated mouse models of malignant mesothelioma (MM) based upon disruption of the Bap1, Nf2, and Cdkn2ab tumor suppressor loci in various combinations as also frequently observed in human MM. Inactivation of all three loci in the mesothelial lining of the thoracic cavity leads to a highly aggressive MM that recapitulates the histological features and gene expression profile observed in human patients. The tumors also show a similar inflammatory phenotype. Bap1 deletion alone does not cause MM but dramatically accelerates MM development when combined with Nf2 and Cdkn2ab (hereafter BNC) disruption. The accelerated tumor development is accompanied by increased Polycomb repression and EZH2-mediated redistribution of H3K27me3 toward promoter sites with concomitant activation of PI3K and MAPK pathways. Treatment of BNC tumor-bearing mice with cisplatin and pemetrexed, the current frontline treatment, prolongs survival. This makes the autochthonous mouse model described here very well suited to explore the pathogenesis of MM and validate new treatment regimens for MM, including immunotherapy.


[Biochemical, enzymatic and genetic study of hypoxanthine guanine phosphoribosyl transferase (HPRT) deficiency].
The objective of this study was to analyze the diagnosis of HPRT deficiency, perform a thorough purine metabolism study and to establish the carrier and prenatal diagnosis in 16 HPRT deficient families. Plasma and urinary concentrations of uric acid, creatinine and oxypurines, APRT and HPRT activities in hemolysates and HPRT in intact erythrocytes and adenine 8-C14 urinary excretion were analyzed. Carrier diagnosis was made by hair root enzyme analysis and genetic studies. These studies allowed the diagnosis of HPRT deficiency in 20 patients. Carrier diagnosis could be performed in 23 women at risk and in a 9 week old female fetus. The study results suggest that HPRT deficiency accounts for increased purine nucleotide degradation. This increase results in elevated urinary and plasma concentrations of hypoxanthine, xanthine and uric acid. The clinical severity of the disease is not related to the degree of urinary or plasma concentrations of oxypurines. Hair root analysis generally allows the diagnosis of carrier status, but the carrier state cannot be fully excluded in women at risk. When the familial mutation causing the defect in HPRT is known, analysis of the differences in the restriction pattern of the HPRT gene (natural or due to directed mutagenesis) allow a rapid and reliable diagnosis of carrier status and HPRT deficiency.


The Role of Quercetin for the Treatment of Endometriosis and Endometrial Cancer: A Comprehensive Review.
Endometrial glands and stroma can be seen outside the uterine cavity in endometriosis, a gynecological disorder linked to estrogen dependency. Hormonal therapies, surgical excision, and non-steroidal anti-inflammatory drug therapy are among the traditional endometriosis treatments, however, various side effects limit their efficacy. Therefore, it is vital to research complementary and alternative therapeutic modalities to decrease the side effects of conventional therapies. While the search for the best endometriosis treatment continues, the focus is being paid to the assistance provided by polyphenols, notably quercetin. A broad spectrum of health-improving benefits of quercetin includes interactions with endometriosis-related molecular targets such as cell proliferation, apoptosis, invasiveness, inflammation, and oxidative stress. According to already-known research, medicines that mimic the physiological effects of quercetin are good candidates for creating novel endometriosis therapies. This review aims to comprehensively review quercetin's potential as a non-pharmacological treatment for endometriosis by interacting with several cellular and molecular targets.


In defense of the quasimolecular ion.
The term quasimolecular ion has been used to describe ions comprising a molecule and weakly bound positive or negative ion or an ion formed by the loss of a proton from a molecule. This term was used in mass spectrometry from the late 1960s after the development of chemical ionization but has been deprecated in recent terms recommendations due to what is perceived as its overly broad use. This letter argues that the term is well defined and has a long history of use in mass spectrometry and other fields and should be considered as a recommended term.


Differential distribution of major brain gangliosides in the adult mouse central nervous system.
Gangliosides - sialic acid-bearing glycolipids - are major cell surface determinants on neurons and axons. The same four closely related structures, GM1, GD1a, GD1b and GT1b, comprise the majority of total brain gangliosides in mammals and birds. Gangliosides regulate the activities of proteins in the membranes in which they reside, and also act as cell-cell recognition receptors. Understanding the functions of major brain gangliosides requires knowledge of their tissue distribution, which has been accomplished in the past using biochemical and immunohistochemical methods. Armed with new knowledge about the stability and accessibility of gangliosides in tissues and new IgG-class specific monoclonal antibodies, we investigated the detailed tissue distribution of gangliosides in the adult mouse brain. Gangliosides GD1b and GT1b are widely expressed in gray and white matter. In contrast, GM1 is predominately found in white matter and GD1a is specifically expressed in certain brain nuclei/tracts. These findings are considered in relationship to the hypothesis that gangliosides GD1a and GT1b act as receptors for an important axon-myelin recognition protein, myelin-associated glycoprotein (MAG). Mediating axon-myelin interactions is but one potential function of the major brain gangliosides, and more detailed knowledge of their distribution may help direct future functional studies.


Effects of dedifferentiated fat cells on neurogenic differentiation and cell proliferation in neuroblastoma cells.
Mesenchymal stem cells (MSCs) can induce differentiation of neuroblastoma (NB) cells. Properties of dedifferentiated fat cells (DFATs) are similar to those of MSCs. Here, we investigated whether DFATs can induce NB cell differentiation and suppress cell proliferation. DFATs were obtained from mature adipocytes isolated from adipose tissue from a ceiling culture. NB cells were cultured in a medium with or without DFATs and, subsequently, cultured in a DFAT-conditioned medium (CM) with or without phosphatidylinositol 3-kinase (PI3K) inhibitor. The neurite lengths were measured, and mRNA expression levels of the neurofilament (NF) and tubulin beta III (TUBβ3) were assessed using quantitative real-time RT-PCR. Cell viability was assessed using the WST-1 assay. NB cells cultured with DFATs caused elongation of the neurites and upregulated the expression of NF and Tubβ3. NB cells cultured in DFAT-CM demonstrated increased cell viability. NB cells cultured with DFAT-CM and PI3K inhibitors suppressed cell viability. NB cells cultured with DFAT-CM and PI3K inhibitor demonstrated increased neurite length and expression, and upregulation of Tubβ3. The combined use of DFAT-CM and PI3K inhibitors suppresses the proliferation of NB cells and induces their differentiation. Thus, DFAT may offer new insights into therapeutic approaches in neuroblastoma.


Electrophysiological evidence of the time course of attentional bias in non-patients reporting symptoms of depression with and without co-occurring anxiety.
Anxiety is characterized by attentional biases to threat, but findings are inconsistent for depression. To address this inconsistency, the present study systematically assessed the role of co-occurring anxiety in attentional bias in depression. In addition, the role of emotional valence, arousal, and gender was explored. Ninety-two non-patients completed the Penn State Worry Questionnaire (Meyer et al., 1990; Molina and Borkovec, 1994) and portions of the Mood and Anxiety Symptom Questionnaire (Watson et al., 1995a,1995b). Individuals reporting high levels of depression and low levels of anxiety (depression only), high levels of depression and anxiety (combined), or low levels of both (control) completed an emotion-word Stroop task during event-related brain potential recording. Pleasant and unpleasant words were matched on emotional arousal level. An attentional bias was not evident in the depression-only group. Women in the combined group had larger N200 amplitude for pleasant than unpleasant stimuli, and the combined group as a whole had larger right-lateralized P300 amplitude for pleasant than unpleasant stimuli, consistent with an early and later attentional bias that is specific to unpleasant valence in the combined group. Men in the control group had larger N200 amplitude for pleasant than unpleasant stimuli, consistent with an early attentional bias that is specific to pleasant valence. The present study indicates that the nature and time course of attention prompted by emotional valence and not arousal differentiates depression with and without anxiety, with some evidence of gender moderating early effects. Overall, results suggest that co-occurring anxiety is more important than previously acknowledged in demonstrating evidence of attentional biases in depression.


Consciousness and cerebral baseline activity fluctuations.
The origin of within-subject variability in perceptual experiments is poorly understood. We here review evidence that baseline brain activity in the areas involved in sensory perception predict subsequent variations in sensory awareness. We place these findings in light of recent findings on the architecture of spontaneous BOLD fluctuations in the awake human brain, and discuss the possible origins of the observed baseline brain activity fluctuations.


[Brazilian Nursing Association: 70 years of struggle for life].
This work is about the Brazilian Nursing Association (ABEn), its origin, its expansion and projection based on its philosophy and highlighting its achievements from its origin in 1926 until today when its 70th anniversary is being celebrated. This work aims at reporting this institution history and narrating the support provided so that nursing may contribute decisively to the construction of a body of profession knowledge itself, the legal definition of professional practice, teaching regulamentation through its commissions. Methodology has been composed of bibliographic research and interviews with active professionals. It has been concluded that ABEn is stronger and stronger and aware of the way on how to achieve many other goals which will bear great conquests which will contribute for granting nursing power and space as a profession set to the human, therefore, to a better life, with more love, peace and social justice.


Association between acquired rifamycin resistance and the pharmacokinetics of rifabutin and isoniazid among patients with HIV and tuberculosis.
The occurrence of acquired rifamycin resistance despite use of directly observed therapy for tuberculosis is associated with advanced human immunodeficiency virus (HIV) disease and highly intermittent administration of antituberculosis drugs. Beyond these associations, the pathogenesis of acquired rifamycin resistance is unknown. We performed a pharmacokinetic substudy of patients in a trial of treatment with twice-weekly rifabutin and isoniazid. A total of 102 (60%) of 169 patients in the treatment trial participated in the pharmacokinetic substudy, including 7 of 8 patients in whom tuberculosis treatment failure or relapse occurred in association with acquired rifamycin-resistant mycobacteria (hereafter, "ARR failure or relapse"). The median rifabutin area under the concentration-time curve (AUC(0-24)) was lower for patients with than for patients without ARR failure or relapse (3.3 vs. 5.2 microg*h/mL; P = .06, by the Mann-Whitney exact test). In a multivariate analysis adjusted for CD4+ T cell count, the mean rifabutin AUC(0-24) was significantly lower for patients with ARR failure or relapse than for other patients (3.0 microg*h/mL [95% confidence interval {CI}, 1.9-4.5] vs. 5.2 microg*h/mL [95% CI, 4.6-5.8]; P = .02, by analysis of covariance). The median isoniazid AUC(0-12) was not significantly associated with ARR failure or relapse (20.6 vs. 28.0 microg*h/mL; P = .24, by the Mann-Whitney exact test). However, in a multivariate logistic regression model that adjusted for the rifabutin AUC(0-24), a lower isoniazid AUC(0-12) was associated with ARR failure or relapse (OR, 10.5; 95% CI, 1.1-100; P = .04). Lower plasma concentrations of rifabutin and, perhaps, isoniazid were associated with ARR failure or relapse in patients with tuberculosis and HIV infection treated with twice-weekly therapy.


Increased Retention of Gadolinium in the Inflamed Brain After Repeated Administration of Gadopentetate Dimeglumine: A Proof-of-Concept Study in Mice Combining ICP-MS and Micro- and Nano-SR-XRF.
The aim of this study was to determine in vivo if brain inflammation leads to increased gadolinium (Gd) retention in brain tissue after repeated applications of Gd-based contrast agents (GBCAs). Experimental autoimmune encephalomyelitis (EAE) was induced in female SJL/J mice (n = 6). Experimental autoimmune encephalomyelitis and healthy control mice (n = 4) received 2.5 mmol/kg Gd-DTPA over 10 days (8 injections, cumulated dose of 20 mmol/kg), starting at day 14 post immunization when EAE mice reached the maximal clinical disability. In a group of mice, T1-weighted 2-dimensional RARE images were acquired before the first GBCA injection and 1 day after the last injection. Mice were killed either 1 day or 10 days after the last Gd application. From each single animal, a brain hemisphere was used for Gd detection using inductively coupled plasma mass spectrometry, whereas the other hemisphere was processed for histology and synchrotron x-ray fluorescence spectroscopy (SR-XRF) analysis. Gadolinium deposition in inflamed brains was mapped by SR-XRF 1 day after the last Gd-DTPA injections, although only mild signal hyperintensity was found on unenhanced T1-weighted images. In addition, using inductively coupled plasma mass spectrometry, we detected and quantified Gd in both healthy and EAE brains up to 10 days after the last injections. However, EAE mouse brains showed higher levels of Gd (mean ± SD, 5.3 ± 1.8 μg/g; range, 4.45-8.03 μg/g) with respect to healthy controls (mean ± SD, 2.4 ± 0.6 μg/g; range, 1.8-3.2 μg/g). By means of micro-SR-XRF, we identified submicrometric Gd hotspots in all investigated samples containing up to 5893 μg Gd/g tissue. Nano-SR-XRF further indicated that Gd small hotspots had an average size of ~160 nm diameter and were located in areas of high inflammatory activity. After repeated administrations of Gd-DTPA, ongoing inflammation may facilitate the retention of Gd in the brain tissue. Thus, neuroinflammation should be considered as a risk factor in the recommendation on use of linear GBCA-enhanced MRI.


Definition of irreparable rotator cuff tear: a scoping review of prospective surgical therapeutic trials to evaluate current practice.
The definition of irreparable rotator cuff tear (IRCT) is controversial. This scoping review provides definitions used to describe IRCT in the literature. This scoping review (1) identified criteria used in the definition of IRCT and (2) investigated the current state of those criteria in prospective surgical therapeutic trials. This scoping review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews. PubMed, Scopus, and Web of Science were searched in March 2023. Studies were screened against predetermined inclusion and exclusion criteria. Criteria regarding clinical symptoms, preoperative images, and intraoperative findings were captured respectively. A total of 41 prospective studies were eligible for inclusion, and 35 studies (85.4%) defined IRCT. IRCT was defined on the basis of the following main criteria: preoperative image findings (28/35), intraoperative findings (24/35), and symptoms (16/35). With regard to preoperative images, IRCT was mainly defined on the basis of retraction of the tendon in the coronal plane (22/28), the severity of fatty degeneration (19/28), and ruptured tendon number or width of the defect in the sagittal plane (17/28). This scoping review highlights the lack of a standardized definition for IRCT in clinical practice, with common predictive criteria including a duration of over 6 months, retraction beyond 5 cm, Goutallier grade 3 fatty infiltration, and the rupture of two or more tendons. However, surgeons should apply more than one criterion when examining preoperative images and confirm reparability during surgery. A more objective manner of evaluating intraoperative reparability is necessary.


CIP2A protein expression in high-grade, high-stage bladder cancer.
Bladder cancer is one of the most common cancers in the United States. Numerous markers have been evaluated for suitability of bladder cancer detection and surveillance. However, few of them are acceptable as a routine tool. Therefore, there exists a continuing need for an assay that detects the presence of bladder cancer in humans. It would be advantageous to develop an assay with a protein that is associated with the development of bladder cancer. We have identified the cancerous inhibitor of PP2A (CIP2A) protein as a novel bladder cancer biomarker. In this study, Western blot analysis was used to assess the expression level of CIP2A protein in bladder cancer cell lines and bladder cancer patient tissues (n = 43). Our studies indicated CIP2A protein was abundantly expressed in bladder cancer cell lines but not in nontumor epithelial cell lines. Furthermore, CIP2A was specifically expressed in transitional cell carcinoma (TCC) of the bladder tumor tissues but not in adjacent nontumor bladder tissue. Our data showed that CIP2A protein detection in high-grade TCC tissues had a sensitivity of 65%, which is 3.4-fold higher than that seen in low-grade TCC tissues (19%). The level of CIP2A protein expression increased with the stage of disease (12%, 27%, 67%, and 100% for pTa, pT1, pT2, and pT3 tumor, respectively). In conclusion, our studies suggest that CIP2A protein is specifically expressed in human bladder tumors. CIP2A is preferentially expressed in high-grade and high-stage TCC tumors, which are high-risk and invasive tumors. Our studies reported here support the role of CIP2A in bladder cancer progression and its usefulness for the surveillance of recurrence or progression of human bladder cancer.


Insulin stimulates tyrosine phosphorylation of its receptor beta-subunit in intact rat hepatocytes.
We studied the phosphorylation of the beta subunit of the insulin receptor in intact freshly isolated rat hepatocytes, labelled with [32P]Pi. Insulin receptors partially purified by wheat-germ agglutinin chromatography were immunoprecipitated with either antibodies to insulin receptor or antibodies to phosphotyrosine. Receptors derived from cells incubated in the absence of insulin contained only phosphoserine. Addition of insulin to hepatocytes led to a dose-dependent increase in receptor beta-subunit phosphorylation, with half-maximal stimulation being observed at 2 nM-insulin. Incubation of cells with 100 nM-insulin showed that, within 1 min of exposure to the hormone, maximal receptor phosphorylation occurred, which was followed by a slight decrease and then a plateau. This insulin-induced stimulation of its receptor phosphorylation was largely accounted for by phosphorylation on tyrosine residues. Sequential immunoprecipitation of receptor with anti-phosphotyrosine antibodies and with anti-receptor antibodies, and phosphoamino acid analysis of the immunoprecipitated receptors, revealed that receptors that failed to undergo tyrosine phosphorylation were phosphorylated on serine residues. The demonstration of a functional hormone-sensitive insulin-receptor kinase in normal cells strongly supports a role for this receptor enzymic activity in mediating biological effects of insulin.


The effect of partial protein synthesis inhibition on cell proliferation in higher plants.
Meristematic cells from Allium cepa L. roots can attain a steady state of growth in the presence of anisomycin at concentrations that effectively reduce the rate of protein synthesis. Under these conditions the lengths of cell cycle periods increase but not in the same proportion as the generation time (t). Mitosis is hardly affected and S period is slightly lengthened. G2 increases less in proportion to t, while G1 is extended much higher in proportion to t. Natural synchronous populations have been used to study cell cycle parameters during transition from the physiological steady state to the new one created by the presence of the drug. G2 was the same during transition as during steady-state growth. G1 was much shorter during transition. Average cell mass at division was reduced, and a negative correlation was observed between the length of G2 and the size of the cell at termination of DNA synthesis. We propose that in higher plants, G2 length is regulated by cell mass at completion of DNA synthesis (G2 being shorter in big cells than in small cells), though there is no cell size requirement for mitosis.


The need for a large-scale trial of fibrate therapy in diabetes: the rationale and design of the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study. [ISRCTN64783481].
Fibrates correct the typical lipid abnormalities of type 2 diabetes mellitus, yet no study, to date, has specifically set out to evaluate the role of fibrate therapy in preventing cardiovascular events in this setting. Subjects with type 2 diabetes, aged 50-75 years, were screened for eligibility to participate in a long-term trial of comicronized fenofibrate 200 mg daily compared with matching placebo to assess benefits of treatment on the occurrence of coronary and other vascular events. People with total cholesterol levels 3.0-6.5 mmol/L plus either a total-to-HDLc ratio > 4.0 or triglyceride level > 1.0 mmol/L with no clear indication for lipid-modifying therapy were eligible. A total of 9795 people were randomized into the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial. All received dietary advice, followed by a 6-week single-blind placebo run-in, then a 6-week active run-in period before randomization. Participants are being followed up every 6 months for outcome events and safety assessments. The study is designed to yield at least 500 coronary events (primary endpoint: first nonfatal myocardial infarction or coronary death) over 5 years, to have 80% power to identify as statistically significant at 2P = 0.05 a 22% reduction in such events, using intention-to-treat methods. Type 2 diabetes is the most common endocrine disorder worldwide, and its prevalence is increasing. The current evidence about use of fibrates in type 2 diabetes, from around 2000 people treated, will increase with FIELD to evidence from around 12000. FIELD will establish the role of fenofibrate treatment in reducing cardiovascular risk in people with type 2 diabetes. The main results are expected to be available in late 2005.


Treatment considerations for vertebroplasty in men.
Vertebroplasty is now a widely accepted image-guided intervention in patients with compression fracture. The purpose of this report is to look specifically at the male population undergoing vertebroplasty and identfy the management considerations distinct to men. The hospital medical records and radiographic studies of 24 men treated with vertebroplasty between February 1999 and November 2000 were retrospectively reviewed. Five patients presented with idiopathic or secondary osteoporosis. In two of these five men, malignancies were discovered by core biopsies taken at the time of vertebroplasty. Thirteen patients (54%) had secondary osteoporosis. Of this group, 10 patients (42%) were steroid dependent and three (13%) were hypogonadal. Five patients (21%) had traumatic events leading to fracture. One presented with known metastases. Primary osteoporosis in men is unusual. In male patients without a definable cause of osteoporosis, known metastatic disease, or a significant history of trauma, the routine performance of a vertebral biopsy through the vertebroplasty needle before the injection of bone cement is indicated to identify unexpected neoplasm.


Selective adhesion of mast cells to tracheal epithelial cells in vitro.
In allergic and nonallergic lung diseases, if intraluminal mast cells adhere to airway epithelium, inflammatory mediators released from activated mast cells may reach high local concentrations and thus greatly affect airway function. To determine whether mast cells adhere to airway epithelial cells, radiolabeled or unlabeled dog mastocytoma cells were incubated with cultured dog tracheal epithelial cells, with extracellular matrix substrates, and with cryostat-cut sections of dog trachea. Mast cells adhered well to cultured epithelial cells (35 +/- 13% adhesion, mean +/- 1 SD, n = 23) but adhered poorly to types I and IV collagen or to fibronectin (less than 7.5% mean adhesion in all cases). Similarly, in tracheal tissue sections, mast cells adhered preferentially to epithelial cells in surface epithelium or in submucosal glands but not to basal membrane or connective tissue. Adhesion to cultured epithelial cells was a characteristics of a subpopulation of mast cells, could persist for more than 48 h, did not require energy or the presence of divalent cations, and was not mediated by a known family of leukocyte-associated adhesion glycoproteins. Adhesion was completely abolished by pretreatment of mast cells with pronase E or proteinase K but not with trypsin (up to 10 micrograms/ml at 37 degrees C for 20 min each). In contrast, pretreatment of cultured epithelial cells with any of these proteinases had no effect on adhesion. It is concluded that dog mastocytoma mast cells adhere to dog tracheal epithelial cells and do so selectively. It is suggested that mast cell adhesion to airway epithelium may play a role in the effectiveness of mast cell-epithelial cell interactions, and thus, in certain lung diseases, airway function may be affected by intraluminal mast cells more than is currently appreciated.


Cardiac function in adolescents with obesity: cardiometabolic risk factors and impact on physical fitness.
To gain greater insights in the etiology and clinical consequences of altered cardiac function in obese adolescents. Therefore, we aimed to examine cardiac structure and function in obese adolescents, and to examine associations between altered cardiac function/structure and cardiometabolic disease risk factors or cardiopulmonary exercise capacity. In 29 obese (BMI 31.6 ± 4.2 kg/m², age 13.4 ± 1.1 years) and 29 lean (BMI 19.5 ± 2.4 kg/m², age 14.0 ± 1.5 years) adolescents, fasted blood samples were collected to study hematology, biochemistry, liver function, glycemic control, lipid profile, and hormones, followed by a transthoracic echocardiography to assess cardiac structure/function, and a cardiopulmonary exercise test (CPET) to assess cardiopulmonary exercise parameters. Regression analyses were applied to examine relations between altered echocardiographic parameters and blood parameters or CPET parameters in the entire group. In obese adolescents, left ventricular septum thickness, left atrial diameter, mitral A-wave velocity, E/e' ratio were significantly elevated (p < 0.05), as opposed to lean controls, while mitral e'-wave velocity was significantly lowered (p < 0.01). Elevated homeostatic model assessment of insulin resistance and blood insulin, c-reactive protein, and uric acid concentrations (all significantly elevated in obese adolescents) were independent risk factors for an altered cardiac diastolic function (p < 0.01). An altered cardiac diastolic function was not related to exercise tolerance but to a delayed heart rate recovery (HRR; p < 0.01). In obese adolescents, an altered cardiac diastolic function was independently related to hyperinsulinemia and whole-body insulin resistance, and only revealed by a delayed HRR during CPET. This indicates that both hyperinsulinemia, whole-body insulin resistance, and delayed HRR could be regarded as clinically relevant outcome parameters.


Increased expression of the inositol 1,4,5-trisphosphate receptor in human leukaemic (HL-60) cells differentiated with retinoic acid or dimethyl sulphoxide.
The Ins(1,4,5)P3 receptor was examined in human promyelocytic leukaemic cells (HL-60) and in HL-60 cells differentiated towards granulocytes with either retinoic acid (RA) or dimethyl sulphoxide (Me2SO). HL-60 cell membranes enriched in marker enzyme activities of the endoplasmic reticulum and the plasma membrane possess a high-affinity binding site for [3H]Ins(1,4,5)P3 (KD = 22 nM). Electrotransfer studies indicate that Ins(1,4,[32P]5)P3 binds specifically to a 260 kDa protein of HL-60 cell membranes. This Ins(1,4,5)P3-binding protein selectively binds Ca(2+)-mobilizing inositol phosphates and other inositol phosphates which also bind to the purified InsP3 receptor, suggesting that the Ins(1,4,5)P3-binding protein of HL-60 cell membranes is the InsP3 receptor. When HL-60 cells are incubated with 1 microM-RA or with 1.25% Me2SO the cells differentiate within 5-7 days into cells resembling neutrophils in both structure and function. Treated cells cease to proliferate, acquire the ability to reduce Nitro Blue Tetrazolium dye, and undergo morphological changes typical of differentiated granulocytes. Concomitant with HL-60 cell differentiation, the maximal [3H]Ins(1,4,5)P3 binding in membranes increases 3-4-fold, with no change in KD. The results suggest that there is an absolute increase in the level of the InsP3 receptor during HL-60 cell differentiation and that the expression of this signal-transducing protein may be specifically regulated by differentiation factors.


Selective, tight-binding inhibitors of integrin alpha4beta1 that inhibit allergic airway responses.
Integrin alpha4beta1 mediates leukocyte recruitment, activation, mediator release, and apoptosis inhibition, and it plays a central role in inflammatory pathophysiology. High-affinity, selective inhibitors of alpha4beta1, based on the Leu-Asp-Val (LDV) sequence from the alternatively spliced connecting segment-1 (CS-1) peptide of cellular fibronectin, are described that employ a novel N-terminal peptide "cap" strategy. One inhibitor, BIO-1211, was approximately 10(6)-fold more potent than the starting peptide and exhibited tight-binding properties (koff = 1.4 x 10(-4) s-1, KD = 70 pM), a remarkable finding for a noncovalent, small-molecule inhibitor of a protein receptor. BIO-1211 was also 200-fold selective for the activated form of alpha4beta1, and it stimulated expression of ligand-induced epitopes on the integrin beta1 subunit, a property consistent with occupancy of the receptor's ligand-binding site. Pretreatment of allergic sheep with a 3-mg nebulized dose of BIO-1211 inhibited early and late airway responses following antigen challenge and prevented development of nonspecific airway hyperresponsiveness to carbachol. These results show that highly selective and potent small-molecule antagonists can be identified to integrins with primary specificity for peptide domains other than Arg-Gly-Asp (RGD); they confirm the generality of integrins as small molecule targets; and they validate alpha4beta1 as a therapeutic target for asthma.


International Practice Patterns for the Management of Acute Postsurgical and Postintravitreal Injection Endophthalmitis: European Vitreo-Retinal Society Endophthalmitis Study Report 1.
To study the practice patterns for the management of acute postoperative and postinjection endophthalmitis. Retrospective, interventional, nonrandomized, multicenter study. Data on 237 eyes diagnosed with acute endophthalmitis occurring after intraocular surgery or procedures provided by 57 retina specialists from 28 countries. Rates of pars plana vitrectomy (PPV), repeat intravitreal injection, and adjunctive therapeutic regimens (local and systemic antibiotics and steroids). Of 237 analyzed eyes, acute endophthalmitis secondary to cataract surgery or secondary lens implantation represented 64.6% of cases (153 eyes), whereas the remaining were secondary to intravitreal injections (35 eyes [14.8%]), PPV (29 eyes [12.2%]), and other intraocular surgeries (20 eyes [8.4%]). All eyes received intravitreal antibiotics on the same day of diagnosis. Overall, early PPV was used within the first week of presentation in 176 eyes (74.3%). There was no statistical difference in the proportion of eyes requiring a second intravitreal injection of antibiotics whether the eye was managed primarily with intravitreal antibiotics alone versus early PPV plus intravitreal antibiotics (29.5% [18 eyes] vs. 25.0% [44 eyes], respectively). Adjunctive therapies in the form of intravitreal steroids, systemic steroids, and systemic antibiotics were used in 25.3%, 21.9%, and 66.6% of eyes, respectively. The absence of disc or macular view and absence of endophthalmitis after cataract surgery were associated with an increased likelihood for early PPV (odds ratios 4.1 and 5.1, respectively). Pars plana vitrectomy was frequently performed regardless of the presenting vision in eyes with endophthalmitis after cataract surgery and intravitreal injections. Increased vitreous opacification was associated with a higher probability for performing PPV.


Diagnosing and treating asymptomatic tuberculosis infection.
To summarize relevant parts of the guidelines recommended by the Canadian and American Thoracic Societies for diagnosis and management of asymptomatic tuberculosis (TB) infection. The latest guidelines published by the Canadian and American Thoracic Societies were reviewed. Unfortunately, neither of these guidelines state explicitly how recommendations were derived. The references accompanying each set of guidelines, however, suggest that they were developed by extensive literature review of the subject and consensus among expert panels. Only higher-risk patients should receive a TB screening test (Mantoux test) to minimize the possibility of false-positive test results. The cutoff points for positive tests vary to reflect the pretest likelihood of TB infection. An induration 5 mm or greater is considered positive in patients at highest risk of TB infection, that is, HIV-infected patients, close contacts of active TB cases, and patients with chest x-ray abnormalities suggestive of previous untreated TB. All other patients are considered positive if they have induration greater than 10 mm according to the Canadian guideline. A 15-mm cutoff point, however, is used for patients without risk factors in the American guideline. All patients with positive Mantoux test results should be considered infected with TB. Infected patients should be offered 6 to 12 months of isoniazid prophylaxis if they have HIV infection, if they have medical conditions that increase the risk of TB activation, or if they are younger than 35 years. Prophylactic treatment of infected individuals effectively prevents the spread of TB infection. Family physicians, who most often see patients in the asymptomatic stage of TB infection, are uniquely situated to prevent secondary cases of TB by offering appropriate patients prophylactic treatment. Patients should be counseled about the risk and benefit of prophylactic treatment so they give informed consent for it.


Tryptophan 65 is essential for hemolytic activity of the thermostable direct hemolysin from Vibrio parahaemolyticus.
The effect of modification of aromatic and ionizable amino acid residues on the hemolytic activity of a thermostable direct hemolysin from Vibrio parahaemolyticus was examined. Tryptophan 65, one of the two tryptophan residues per subunit, was specifically modified with N-bromosuccinimide, resulting in complete loss of hemolytic activity. However, neither nitration with tetranitromethane of one of the nine tyrosine residues nor Nlm-ethoxyformylation of two of the four histidine residues caused any change in hemolytic activity. The hemolysin was fully active upon amidation of two reactive carboxyl group. On the other hand, acetylation of amino groups and the modification of one of the three arginine residues with 1,2-cyclohexanedione resulted in a partial loss of the hemolytic activity. The results suggest that Trp65 is essential for the hemolytic activity of V. parahaemolyticus hemolysin.


Parenting Interventions for Mothers With Problematic Substance Use: A Systematic Review of Research and Community Practice.
Women with problematic substance use are frequently referred to interventions to promote positive parenting. Parenting interventions that attend to the unique risks faced by this population may enhance engagement and outcomes. While reviews of extant parenting interventions in the research literature have been undertaken, no studies have examined parenting interventions being implemented in community practice and the extent to which these are informed by current research. We systematically compared parenting interventions offered in 12 maternal substance use treatment programs in one Canadian province with those described in the research literature (K = 21). Few parenting interventions were replicated, either within or across the two samples. However, parenting interventions within both samples were largely similar in their objectives. Across both research and community samples, approximately half of the interventions were developed or adapted for a problematic substance use population. Parenting knowledge, psychosocial risk, and maternal emotional regulation were most commonly addressed. Risks pertaining to the impact of drug craving and substance-related changes in neurobiology associted with parenting were less commonly addressed. Findings highlight current strengths and limitations of parenting interventions within research and community settings, with recommendations offered for future research and knowledge translation.


Mobile and wearable technologies in healthcare for the ageing population.
The 16th World Congress on Medical and Health Informatics (MedInfo 2017) was held August 21-25, 2017, in Hangzhou, China. It provided a valuable platform for sharing the latest medical and health informatics research and related applications to the scientists, medical practitioners, entrepreneurs, and educators as well as students. During this event, on August 23, 2017, an important related topic was presented in a panel discussion entitled "Wearable technologies: Advancing the healthcare in ageing population" by panelists Shabbir Syed-Abdul, Panagiotis Bamidis, Chun-Por Wong, and Xinxin Zhu. Recent advances in health technologies, focusing on the aging population, their benefits and challenges were discussed, and these topics are summarized in this paper. The need for technology to improve of the life of older population, influential and beneficial technologies, for delivering these technologies to patients are described in this paper.


Pharmacokinetics of intravenous erythromycin lactobionate.
In a previous study with erythromycin lactobionate it was shown that a 12-hour intravenous infusion of 2 g produced peak plasma erythromycin concentrations well above the required levels to inhibit the growth of all standard erythromycin-sensitive pathogens (including Haemophilus influenzae). Unfortunately two subjects vomited after receiving 2 litres of normal saline (in which the erythromycin lactobionate was infused). For this reason it was decided to administer half the previous dose of erythromycin lactobionate in 500 ml of 0.9N saline over 1 hour. The present study shows that the latter dose regime produces therapeutic plasma erythromycin base concentrations in the plasma in all subjects, five of whom also participated in the previous study. The infusions were well tolerated in every participant. More rapid administration enabled the baseline pharmacokinetics of this parenteral erythromycin salt to be established by two different computer programmes in healthy volunteers. It is hoped that the data outlined in this paper will prove a useful baseline for future studies with erythromycin lactobionate in healthy volunteers and patients with severe infections who receive this antibiotic.


Cytogenetics in the management of mature T-cell and NK-cell neoplasms: Guidelines from the groupe francophone de cytogénétique hématologique (GFCH).
Mature T-cell and natural killer (NK)-cell neoplasms (MTNKNs) are a highly heterogeneous group of lymphomas that represent 10-15 % of lymphoid neoplasms and have usually an aggressive behavior. Diagnosis can be challenging due to their overlapping clinical, histological and immunophenotypic features. Genetic data are not a routine component of the diagnostic algorithm for most MTNKNs. Indeed, unlike B-cell lymphomas, the genomic landscape of MTNKNs is not fully understood. Only few characteristic rearrangements can be easily identified with conventional cytogenetic methods and are an integral part of the diagnostic criteria, for instance the t(14;14)/inv(14) or t(X;14) abnormality harbored by 95 % of patients with T-cell prolymphocytic leukemia, or the ALK gene translocation observed in some forms of anaplastic large cell lymphoma. However, advances in molecular and cytogenetic techniques have brought new insights into MTNKN pathogenesis. Several recurrent genetic alterations have been identified, such as chromosomal losses involving tumor suppressor genes (SETD2, CDKN2A, TP53) and gains involving oncogenes (MYC), activating mutations in signaling pathways (JAK-STAT, RAS), and epigenetic dysregulation, that have improved our understanding of these pathologies. This work provides an overview of the cytogenetics knowledge in MTNKNs in the context of the new World Health Organization classification and the International Consensus Classification of hematolymphoid tumors. It describes key genetic alterations and their clinical implications. It also proposes recommendations on cytogenetic methods for MTNKN diagnosis.


Quantification of arabinitol in serum by selected ion monitoring as a diagnostic technique in invasive candidiasis.
D-Arabinitol was identified by mass spectrometry as a metabolite of Candida albicans and Candida tropicalis. For quantification, serum was deproteinized with acetone, the supernatant was evaporated to dryness, the silyl derivative was formed, and a portion was injected into a combined gas chromatograph-mass spectrometer system. Erythritol or 2-deoxy-galactitol was the internal standard. The protonated molecular ions, obtained in chemical ionization with isobutane, were monitored. For 39 normal subjects the mean endogenous arabinitol concentration was 0.52 microgram/ml (standard deviation, +/- 0.34). An increment of 0.2 microgram of arabinitol per ml could be quantified. Of 11 cases with diagnosed invasive candidiasis, 9 had arabinitol levels > 1.2 microgram/ml (8 microM) in the range of 1.2 to 25.0 micrograms/ml; the remaining 2 cases had levels in the normal range. Six cases of diagnosed colonized candidiasis showed normal arabinitol levels.


Comparing generalized and specific problematic smartphone/internet use: Longitudinal relationships between smartphone application-based addiction and social media addiction and psychological distress.
The literature has proposed two types of problematic smartphone/internet use: generalized problematic use and specific problematic use. However, longitudinal findings on the associations between the two types of problematic use and psychological distress are lacking among East-Asians. The present study examined temporal associations between both generalized and specific problematic use of the smartphone/internet, and psychological distress. Hong Kong University students (N = 308; 100 males; mean age = 23.75 years; SD ± 5.15) were recruited with follow-ups at three, six, and nine months after baseline assessment. All participants completed the Smartphone Application-Based Addiction Scale (for generalized problematic smartphone/internet use), the Bergen Social Media Addiction Scale (for specific problematic smartphone/internet use), and the Hospital Anxiety and Depression Scale (for psychological distress) in each assessment. Latent growth modeling (LGM) was constructed to understand temporal associations between generalized/specific problematic use and psychological distress. The LGM suggested that the intercept of generalized problematic use was significantly associated with the intercept of psychological distress (standardized coefficient [β] = 0.32; P < 0.01). The growth of generalized problematic use was significantly associated with the growth of psychological distress (β = 0.51; P < 0.01). Moreover, the intercept of specific problematic use was significantly associated with the intercept of psychological distress (β = 0.28; P < 0.01) and the growth of psychological distress (β = 0.37; P < 0.01). The initial level of problematic use of smartphone/internet increased the psychological distress among university students. Helping young adults address problematic use of the smartphone/internet may prevent psychological distress.


Exploring the Effects of Offline Paradigms and Feature Extraction Techniques on Performance of Motor Imagery Brain-Computer Interface: Longitudinal Pilot Study.
Motor Imagery (MI) Brain-Computer Interface (BCI) is a popular way of allowing disabled and healthy individuals to use brain signals to communicate with their environment, despite the technical and human factor challenges that affect MI BCI classification performance. This study explored the influence of paradigm choice and phase synchronization-based features on classification performance by comparing primary datasets to older supplemental datasets. Area Under the Curve (AUC) Receiver Operating Characteristics (ROC) curve was the metric for classification performance. Results showed that using both advanced paradigms and features significantly improved both classification and usability; TD-CSP-wPLI (16-30Hz) and S-CSP-wPLI (12-15Hz) frequency bands produced the most noticeable change in performance.


Work-related aviation fatalities in Colorado 1982-1987.
On-the-job deaths related to aviation are the seventh leading cause of fatal occupational injury in the United States. In Colorado, they comprise 37% of all air transport deaths. A review of all occupational aviation-related fatalities in Colorado during 1982-1987 identified 86 deaths. Data sources were death certificates, Workers' Compensation records, and National Transportation Safety Board reports. Of the fatalities, 5 involved commercial air service, 16 were military personnel, and 65 (76%) were associated with general aviation. Non-military occupations included 21 pilots, 5 flight instructors, 4 crop sprayers, and 3 search and rescue workers or firefighters. There were 18 people going to or from work sites. The 15 weather cases, 7 aircraft malfunctions, and 4 power transmission wire strikes were the most significant factors in two-thirds of the crashes of civilian aircraft. Even experienced pilots exercised poor judgement. The prominence of general aviation in work-related aviation fatalities indicates a need for greater attention to the safety of workers whose jobs entail flying.


DDX3 promotes tumor invasion in colorectal cancer via the CK1ε/Dvl2 axis.
DDX3, a subunit of CK1ε, phosphorylates Dvl2 to promote β-catenin activation. Overexpression of the Dvl2 protein results in potent activation of β-catenin/TCF signaling in colorectal cancer. Therefore, we hypothesized that DDX3 might promote tumor invasion via the CK1ε/Dvl2 axis due to β-catenin/TCF activation. Western blotting showed that β-catenin expression was decreased by DDX3 knockdown and increased by DDX3 overexpression in colorectal cancer cells. The TCF promoter activity and invasion capability were concomitantly increased and decreased by DDX3 manipulation in these cells. The invasion capability in colon cancer cells and xenograft lung tumor nodules induced by a DDX3-overexpressing T84 stable clone in tail-vein injection model were nearly suppressed by inhibitors of CK1ε (PF4800567) and β-catenin/TCF signaling (XAV939). Among colorectal cancer patients, DDX3 expression was positively correlated with the expression of pDvl2 and nuclear β-catenin in tumor tissues. The expression of pDvl2 occurred more frequently in high-nuclear than in low-nuclear β-catenin tumors. A prognostic significance of DDX3, pDvl2, and nuclear β-catenin on overall survival and relapse free survival was observed in this study population. We therefore suggest CK1ε or β-catenin/TCF signaling as potential targets for improving tumor regression and outcomes in colorectal cancer, particularly tumors with high-DDX3/high-nuclear β-catenin or high-DDX3/high-pDvl2/high-nuclear β-catenin expression.


Apoptosis Induced by (-)-Epicatechin in Human Breast Cancer Cells is Mediated by Reactive Oxygen Species.
(-)-Epicatechin is a phenolic compound with antioxidant activity that is present in natural food and drinks, such as cocoa and red wine. Evidence suggests that (-)-epicatechin exhibits anticancer activity; however, its mechanism of action is poorly understood. Here, we investigated the anticancer effects of (-)-epicatechin and its mechanism of action in breast cancer cells. We assessed the anticancer activity by cell proliferation assays, apoptosis by DNA fragmentation and flow cytometry. The expression of proteins associated with apoptosis was analyzed by the human apoptosis array. MitoSOXTM Red and biomarkers of oxidative damage were used to measure the effect of (-)-epicatechin on mitochondrial reactive oxygen species (ROS) and cellular damage, respectively. (-)-Epicatechin treatment caused a decreasing in the viability of MDA-MB-231 and MCF-7 cells. This cell death was associated with DNA fragmentation and an apoptotic proteomic profile. Further, (-)-epicatechin in MDA-MB-231 cells upregulated death receptor (DR4/DR5), increased the ROS production, and modulated pro-apoptotic proteins. In MCF-7 cells, (-)-epicatechin did not involve death receptor; however, an increase in ROS and the upregulation of pro-apoptotic proteins (Bad and Bax) were observed. These changes were associated with the apoptosis activation through the intrinsic pathway. In conclusion, this study shows that (-)-epicatechin has anticancer activity in breast cancer cells and provides novel insight into the molecular mechanism of (-)-epicatechin to induce apoptosis.


Additive benefits of external focus and enhanced performance expectancy for motor learning.
The authors examined the individual and combined influences of 2 factors that have been shown to benefit motor learning: an external focus of attention and enhanced performance expectancies. Another purpose of this study was to gain further insight into the mechanisms underlying these variables. In a factorial design, participants learning a novel motor skill (i.e., throwing with the non-dominant arm) were or were not given external focus instructions, and were or were not provided bogus positive social-comparative feedback to enhance their expectancies. This resulted in 4 groups: external focus, enhanced expectancy, external focus/enhanced expectancy and control. External focus instructions and enhanced expectancies had additive benefits for learning: the external focus/enhanced expectancy group demonstrated the greatest throwing accuracy on both retention and transfer tests, while the accuracy scores of the external focus and enhanced expectancy groups were lower, but higher than those of the control group. Furthermore, self-efficacy was increased by both external focus and enhanced expectancy, and predicted retention and transfer performance. Positive affect was heightened in the enhanced expectancy and external focus/enhanced expectancy groups after practice and predicted transfer performance. The findings suggest that the learning benefits of an external focus and enhanced expectancies mediate learning through partially different mechanisms.


Genetic association of daytime sleepiness and depressive symptoms in elderly men.
Clinical rating scales, self-reports, and diagnostic instruments measuring depression often inquire about daytime fatigue and tiredness. Excessive daytime sleepiness refers specifically to the tendency to feel drowsy or fall asleep during waking hours and is considered conceptually and operationally independent from the fatigue, tiredness, and sleeping difficulties that characterize depression. The objective of this study was to examine whether daytime sleepiness assessed using the Epworth Sleepiness Scale and depressive symptoms assessed using the Geriatric Depression Scale are genetically related. Cross-sectional data were collected via questionnaire in 1998-2000. Population-based sample of more than 5,000 male elderly twins aged 69-82 years old at the time of survey. N/A. There was evidence for moderate heritability for daytime sleepiness (36.9%) and depressive symptoms (30.7%). There was evidence for a significant genetic correlation (0.40) between the 2 measures, suggesting that both daytime sleepiness and depressive symptoms have some genes in common. The genetic correlation was reduced to 0.21 after adjustment for several covariates. The results showed that the often reported phenotypic correlation between daytime sleepiness and depressive symptoms is due, in part, to modest overlap in genetic factors, at least in elderly men. However, the majority of individual variation in daytime sleepiness and depressive symptoms, in particular after covariate adjustment, was attributable to individual-specific environmental factors.


Towards non-invasive peripheral stimulation as a treatment for Parkinson's disease gait.
Non-invasive coordinated reset stimulation (CRS) to the hands has been shown to improve motor ability in Parkinson's patients, but not specific for gait disturbances. The overall aim of the project is the application of vibrotactile CRS to the feet to improve gait impairments in Parkinson's disease. As a first step towards this objective, we showed that vibrotactile stimulation to the feet can elicit a cortical response and have identified differences in younger and older individuals. Our findings suggest the potential for non-invasive peripheral stimulation as a therapeutic technique.Clinical Relevance- This is an important step towards developing a non-invasive stimulation technique for the management of gait disturbances in Parkinson's disease.


Comparisons in Muscle Function and Training Rehabilitation Outcomes Between Avoidance-Endurance Model Subgroups.
Evidence suggests that chronic low back pain patients with fear-avoidance (FAR) or endurance behavior are at risk of treatment failure and pain maintenance, with bodily overuse or underuse being assumed as mediating mechanisms for pain chronification. This study sought to examine whether or not the avoidance-endurance model subgroups, FAR, distress-endurers (DER), eustress-endurers (EER), and adaptive responders (AR), differed in physical measures and outcomes after training therapy. A total of 137 chronic low back pain patients were assessed before, at the end of, and 6 months after a 6-month rehabilitation training. Patients performed maximum back extension strength and trunk range-of-motion measures, flexion-relaxation tests, and completed the following questionnaires: Avoidance-Endurance Questionnaire, Roland-Morris Disability Questionnaire, Pain Disability Index, 36-Item Short-Form Health Survey, International Physical Activity Questionnaire, and visual analog scale. Statistical analysis included cluster analysis, analysis of covariances, and mixed-effects models. At baseline, avoidance-endurance model subgroups did not differ in physical measures and activity levels. At the end of training, patients' back-related health was significantly improved in all subgroups. However, the DER and the FAR were found to be more impaired before and after the intervention compared with EER and AR, as indicated by a higher pain intensity, higher disability levels, lower quality of life, and inferior working capacity. Although FAR and DER did not differ in physical measures or activity levels from EER and AR, they demonstrated poor lower back-related health at baseline and after intervention. Thus, future research should elucidate as to which additional interventions could optimize their health.


Linking disease and community ecology through behavioural indicators: immunochallenge of white-footed mice and its ecological impacts.
1. Pathogens and immune challenges can induce changes in host phenotype in ways that indirectly impact important community interactions, including those that affect host-pathogen interactions. 2. To explore host behavioural response to immune challenge, we exposed wild white-footed mice (Peromyscus leucopus) to an immunogen from an endemic, zoonotic pathogen, the spirochete Borrelia burgdorferi. White-footed mice are a major reservoir host of Lyme disease (LD) spirochetes in northeastern USA and an abundant member of forest communities. The activity patterns, foraging behaviour, and space use of white-footed mice have implications for population growth rates of community members upon which mice incidentally prey (i.e. gypsy moths and native thrushes), as well as potentially determining host-vector encounter rates and human risk of LD. 3. Immunochallenge led to specific humoral (antibody) and cellular (i.e. elevated neutrophils and eosinophils) immune responses, supporting use of the immunogen as a surrogate for pathogenic infection. 4. Immunochallenged mice had reduced wheel-running activity early in the night when measured in the lab. However, mouse activity, as measured by track plates in natural field experiments, did not differ between mice exposed to the immunogen and unexposed mice. 5. Foraging behaviour of wild mice in the field - assessed with giving-up densities of seed at artificial feeding stations - was affected by exposure to the immunogen. Whereas immunochallenge did not influence whether foraging mice gained information on patch quality while foraging, it led to reductions in predator avoidance during foraging, suggesting that the proportion of space used by foraging mice may be greater as a result of immunochallenge. This increased space use is predicted to increase encounter rates with patchily distributed LD vectors (ticks) and with incidental prey items. 6. Thus, immunochallenge in white-footed mice, and potentially pathogenic infection, have the potential to indirectly impact community interactions, including those important for pathogen transmission.


Assessment of online patient education materials from major ophthalmologic associations.
Patients are increasingly using the Internet to supplement finding medical information, which can be complex and requires a high level of reading comprehension. Online ophthalmologic materials from major ophthalmologic associations should be written at an appropriate reading level. To assess ophthalmologic online patient education materials (PEMs) on ophthalmologic association websites and to determine whether they are above the reading level recommended by the American Medical Association and National Institutes of Health. Descriptive and correlational design. Patient education materials from major ophthalmology websites were downloaded from June 1, 2014, through June 30, 2014, and assessed for level of readability using 10 scales. The Flesch Reading Ease test, Flesch-Kincaid Grade Level, Simple Measure of Gobbledygook test, Coleman-Liau Index, Gunning Fog Index, New Fog Count, New Dale-Chall Readability Formula, FORCAST scale, Raygor Readability Estimate Graph, and Fry Readability Graph were used. Text from each article was pasted into Microsoft Word and analyzed using the software Readability Studio professional edition version 2012.1 for Windows. Flesch Reading Ease score, Flesch-Kincaid Grade Level, Simple Measure of Gobbledygook grade, Coleman-Liau Index score, Gunning Fog Index score, New Fog Count, New Dale-Chall Readability Formula score, FORCAST score, Raygor Readability Estimate Graph score, and Fry Readability Graph score. Three hundred thirty-nine online PEMs were assessed. The mean Flesch Reading Ease score was 40.7 (range, 17.0-51.0), which correlates with a difficult level of reading. The mean readability grade levels ranged as follows: 10.4 to 12.6 for the Flesch-Kincaid Grade Level; 12.9 to 17.7 for the Simple Measure of Gobbledygook test; 11.4 to 15.8 for the Coleman-Liau Index; 12.4 to 18.7 for the Gunning Fog Index; 8.2 to 16.0 for the New Fog Count; 11.2 to 16.0 for the New Dale-Chall Readability Formula; 10.9 to 12.5 for the FORCAST scale; 11.0 to 17.0 for the Raygor Readability Estimate Graph; and 12.0 to 17.0 for the Fry Readability Graph. Analysis of variance demonstrated a significant difference (P < .001) between the websites for each reading scale. Online PEMs on major ophthalmologic association websites are written well above the recommended reading level. Consideration should be given to revision of these materials to allow greater comprehension among a wider audience.


Hyperhomocysteinaemia and atherothrombosis.
Homocysteine (Hcy) is a sulfhydryl amino acid derived from the metabolic conversion of methionine that is dependent on vitamins (folic acid, B12 and B6) as cofactors or cosubstrates. In 1969, McCully first reported the presence of severe atherosclerotic lesions in patients with severe hyperhomocysteinaemia and hypothesized the existence of a pathogenic link between hyperhomocysteinaemia and atherogenesis. Several case-control and cross-sectional studies confirmed the initial hypothesis of McCully, showing that also moderate hyperhomocysteinaemia is associated with a heightened risk of occlusive arterial disease. Less consistent results have been reported by prospective cohort studies of subjects who were healthy at the time of their enrollment, whereas prospective cohort studies of patients with overt coronary artery disease or other risk conditions consistently confirmed the association between moderate hyperhomocysteinaemia and the risk of cardiovascular morbidity and mortality. More recently, an association between moderate hyperhomocysteinaemia and heightened risk of venous thromboembolism has been documented, suggesting that hyperhomocysteinaemia might be involved not only in atherogenesis, but also in thrombogenesis. The mechanisms by which hyperhomocysteinaemia might contribute to atherogenesis and thrombogenesis are incompletely understood. The mainstay of treatment of hyperhomocysteinaemia is folic acid, alone or in combination with vitamins B12 and B6. Although it is quite clear that vitamins effectively reduce the plasma levels of total Hcy, we do not yet know whether they will decrease the risk of vascular disease. The results of ongoing randomized, placebo-controlled, double-blinded trials on the effects of vitamins on thrombotic risk will help in defining whether the relationship between hyperhomocysteinaemia and thrombosis is causal, and will potentially have a dramatic impact on the prevention of thromboembolic events.


Annexin 2 is a phosphatidylinositol (4,5)-bisphosphate binding protein recruited to actin assembly sites at cellular membranes.
Annexin 2 is a Ca(2+)-regulated membrane protein and an F-actin-binding protein enriched at actin assembly sites both, on the plasma membrane and on endosomal vesicles. Here, we identify annexin 2 as a phosphatidylinositol (4,5)-bisphosphate (PtdIns(4,5)P(2))-interacting protein, thereby explaining this specific membrane association. Using the pleckstrin-homology (PH) domain of phospholipase Cdelta1 fused to yellow fluorescent protein as a marker for PtdIns(4,5)P(2), we show that annexin 2 and its ligand p11 (S100A10) are targeted to sites of PtdIns(4,5)P(2) enrichment where F-actin accumulates. At the plasma membrane, adhesion of pedestal-forming enteropathogenic Escherichia coli induces a recruitment of 1-phosphatidylinositol-4-phosphate 5-kinase (PtdIns4P 5-kinase) and an enrichment of PtdIns(4,5)P(2) and annexin 2-p11 at sites of bacterial adhesion. Induction of PtdIns(4,5)P(2)-enriched ruffles and PtdIns(4,5)P(2)-positive, actin-coated vacuoles by Arf6-mediated activation of PtdIns4P 5-kinase also leads to a concomitant accumulation of the annexin 2-p11 complex and the PH domain. Binding studies with immobilized phosphoinositides and phosphoinositide-containing liposomes reveal that the purified annexin 2-p11 complex directly and specifically binds to PtdIns(4,5)P(2) with an affinity comparable to that of the PH domain of phospholipase Cdelta1. Experiments using individual subunits identify annexin 2 as the PtdIns(4,5)P(2)-binding entity. Thus, the direct interaction of annexin 2 with PtdIns(4,5)P(2) is a means of specifically recruiting the annexin 2-p11 complex to sites of membrane-associated actin assembly.