Multiclass cancer classification using semisupervised ellipsoid ARTMAP and particle swarm optimization with gene expression data.
It is crucial for cancer diagnosis and treatment to accurately identify the site of origin of a tumor. With the emergence and rapid advancement of DNA microarray technologies, constructing gene expression profiles for different cancer types has already become a promising means for cancer classification. In addition to research on binary classification such as normal versus tumor samples, which attracts numerous efforts from a variety of disciplines, the discrimination of multiple tumor types is also important. Meanwhile, the selection of genes which are relevant to a certain cancer type not only improves the performance of the classifiers, but also provides molecular insights for treatment and drug development. Here, we use Semisupervised Ellipsoid ARTMAP (ssEAM) for multiclass cancer discrimination and particle swarm optimization for informative gene selection. ssEAM is a neural network architecture rooted in Adaptive Resonance Theory and suitable for classification tasks. ssEAM features fast, stable, and finite learning and creates hyperellipsoidal clusters, inducing complex nonlinear decision boundaries. PSO is an evolutionary algorithm-based technique for global optimization. A discrete binary version of PSO is employed to indicate whether genes are chosen or not. The effectiveness of ssEAM/PSO for multiclass cancer diagnosis is demonstrated by testing it on three publicly available multiple-class cancer data sets. ssEAM/PSO achieves competitive performance on all these data sets, with results comparable to or better than those obtained by other classifiers.


Influence of gastrectomy on cortical and cancellous bones in rats.
The aim of the present study was to examine the influence of gastrectomy (GX) on cortical and cancellous bones in rats. Twenty male Sprague-Dawley rats were randomized into the two groups of 10 animals each: a sham operation (control) group and a GX group. Seven weeks after surgery, the bone mineral content and density (BMC and BMD, resp.) and the mechanical strength of the femur were determined, and bone histomorphometric analyses were performed on the tibia. GX induced decreases in the BMC, BMD, ultimate force, work to failure, and stiffness of the femoral distal metaphysis and the BMC, BMD, and ultimate force of the femoral diaphysis. GX induced a decrease in cancellous bone mass, characterized by an increased osteoid thickness, osteoid surface, osteoid volume, and bone formation. GX also induced a decrease in cortical bone mass, characterized by increased endocortical bone resorption. The GX induced reductions in the bone mass and strength parameters were greater in cancellous bone than in cortical bone. The present study showed that the response of bone formation, resorption, and osteoid parameters to GX and the degree of GX-induced osteopenia and the deterioration of bone strength appeared to differ between cortical and cancellous bones in rats.


Prenatal nicotine exposure increases connective tissue expression in foetal monkey pulmonary vessels.
Among the many deleterious effects of maternal smoking during pregnancy on foetal development, is a higher incidence of persistent pulmonary hypertension. The recent identification of nicotinic acetylcholine receptors (nAChR) on cells of the pulmonary vessel walls suggests that maternal smoking during pregnancy may produce morphological alterations in foetal pulmonary vasculature. Timed-pregnant rhesus monkeys were treated with nicotine (1 mg x kg(-1) x day(-1)) delivered by subcutaneous osmotic mini-pumps from days 26-134 of gestation (term: 165 days). Lung sections from 134-day foetal monkeys were used for morphometric analysis, in situ hybridisation and immunohistochemical staining. Following nicotine treatment, total wall and tunica adventitia thickness of airway associated vessels (AAV) increased significantly. Nicotine exposure significantly increased collagen I and III mRNA and protein in tunica adventitia in all AAV but not in tunica media. By contrast, levels of elastin protein were significantly decreased. alpha7 nAChR were detected in AAV fibroblasts that expressed collagen mRNA. Choline acetyltransferase, the enzyme which synthesises acetylcholine, the ligand for alpha7 nAChR was also detected in endothelium and fibroblasts. These findings suggest that with smoking during pregnancy, nicotine is transported across the placenta and directly interacts with nicotinic acetylcholine receptors in pulmonary vessels to alter connective tissue expression and therefore produce vascular structural alterations.


High-Intensity Interval Training in Normobaric Hypoxia Improves Cardiorespiratory Fitness in Overweight Chinese Young Women.
Previous studies have investigated the effects of high-intensity interval training (HIIT) on cardiorespiratory fitness and body composition in overweight populations. However, the additive effect of HIIT and hypoxia on health parameters is not clear. This study compared the effects of HIIT under hypoxic conditions on cardiometabolic function with that under normoxia in overweight Chinese young women. Methods: A double-blind randomized controlled experimental design was applied. Twenty-four sedentary overweight Chinese young women (weight: 68.8 ± 7.0 kg, BMI: 25.8 ± 2.3 kg·m-2) participated in the HIIT under either normoxia (NORM, n = 13, PIO2: 150 mmHg, FIO2: 0.21) or normobaric hypoxia (HYP, n = 11, PIO2: 117 mmHg, FIO2: 0.15) for 5 weeks. HIIT was composed of 60 repetitions of 8 s maximal cycling effort interspersed with 12-s recovery per day, for 4 days per week. Cardiorespiratory fitness [peak oxygen uptake ([Formula: see text]O2peak), and peak oxygen pulse (peak O2 pulse)], serum lipid profile [triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C)], and body composition (regional and whole-body), were assessed at pre- and post-intervention during the days beyond the self-reported menstrual phase of the participants. Habitual physical activity and diary behavior were maintained during the intervention period. Results: With similar daily energy intake and physical activity, the increases in [Formula: see text]O2peak [NORM: 0.26 ± 0.37 L·min-1 (+11.8%) vs. HYP: 0.54 ± 0.34 L·min-1 (+26.1%)] and peak O2 pulse (NORM: +13.4% vs. HYP: +25.9%) for HYP were twice-larger than for NORM (p < 0.05). Although the 5-wk HIIT led to significant improvements in the ratios of TC/HDL-C (p = 0.035) and TG/HDL-C (p = 0.027), no significant group effects were found on the serum variables. Further, no significant changes in body composition or serum fasting leptin were observed in either group. Conclusion: 5-wk of HIIT improved cardiorespiratory fitness and blood lipids in overweight Chinese young females, while the additive effect of the HIIT under normobaric hypoxia solely enhanced cardiorespiratory fitness, but not body composition or serum lipid profile.


Estimation of acute fluid shifts using bioelectrical impedance analysis in horses.
Multi-frequency bioelectrical impedance analysis (MF-BIA) has been used to evaluate extracellular fluid volume (ECFV), but not fluid fluxes associated with fluid or furosemide administration in horses. If able to detect acute changes in ECFV, MF-BIA would be useful in monitoring fluid therapy in horses. The purpose of this study was to evaluate the ability of MF-BIA to detect acute fluid compartment changes in horses. We hypothesized that MF-BIA would detect clinically relevant (10-20%) changes in ECFV. Six healthy mares were used in the study. This is an original experimental study. Mares were studied in 3 experiments: (1) crystalloid expansion of normally hydrated subjects, (2) furosemide-induced dehydration followed by crystalloid administration, and (3) acute blood loss followed by readministration of lost blood. MF-BIA measurements were made before, during, and after each fluid shift and compared to known changes in volume calculated based on the intravenous fluids that were administered in addition to urinary fluid losses. Mean errors between MF-BIA estimated change and known volume change were compared using nonparametric analysis of variance. Estimated ECFV pre- and post-fluid administration similarly were compared. The level of statistical significance was set at P < .05. Results of the study revealed a statistically significant change in ECFV and total body water during crystalloid expansion and dehydration. Statistically significant changes were not observed during blood loss and administration. Mean errors between MF-BIA results and measured net changes were small. MF-BIA represents a practical and accurate means of assessing acute fluid changes during dehydration and expansion of ECFV using isotonic crystalloids with potential clinical applications in equine critical care.


Discovery and preliminary confirmation of novel early detection biomarkers for triple-negative breast cancer using preclinical plasma samples from the Women's Health Initiative observational study.
Triple-negative breast cancer is a particularly aggressive and lethal breast cancer subtype that is more likely to be interval-detected rather than screen-detected. The purpose of this study is to discover and initially validate novel early detection biomarkers for triple-negative breast cancer using preclinical samples. Plasma samples collected up to 17 months before diagnosis from 28 triple-negative cases and 28 matched controls from the Women's Health Initiative Observational Study were equally divided into a training set and a test set and interrogated by a customized antibody array. Data were available on 889 antibodies; in the training set, statistically significant differences in case versus control signals were observed for 93 (10.5 %) antibodies at p < 0.05. Of these 93 candidates, 29 were confirmed in the test set at p < 0.05. Areas under the curve for these candidates ranged from 0.58 to 0.79. With specificity set at 98 %, sensitivity ranged from 4 to 68 % with 20 candidates having a sensitivity ≥ 20 % and 6 having a sensitivity ≥ 40 %. In an analysis of KEGG gene sets, the pyrimidine metabolism gene set was upregulated in cases compared to controls (p = 0.004 in the testing set) and the JAK/Stat signaling pathway gene set was downregulated (p = 0.003 in the testing set). Numerous potential early detection biomarkers specific to triple-negative breast cancer in multiple pathways were identified. Further research is required to followup on promising candidates in larger sample sizes and to better understand their potential biologic importance as our understanding of the etiology of triple-negative breast cancer continues to grow.


Cartilage Tissue Engineering: Preventing Tissue Scaffold Contraction Using a 3D-Printed Polymeric Cage.
Scaffold contraction is a common but underestimated problem in the field of tissue engineering. It becomes particularly problematic when creating anatomically complex shapes such as the ear. The aim of this study was to develop a contraction-free biocompatible scaffold construct for ear cartilage tissue engineering. To address this aim, we used three constructs: (i) a fibrin/hyaluronic acid (FB/HA) hydrogel, (ii) a FB/HA hydrogel combined with a collagen I/III scaffold, and (iii) a cage construct containing (ii) surrounded by a 3D-printed poly-ɛ-caprolactone mold. A wide range of different cell types were tested within these constructs, including chondrocytes, perichondrocytes, adipose-derived mesenchymal stem cells, and their combinations. After in vitro culturing for 1, 14, and 28 days, all constructs were analyzed. Macroscopic observation showed severe contraction of the cell-seeded hydrogel (i). This could be prevented, in part, by combining the hydrogel with the collagen scaffold (ii) and prevented in total using the 3D-printed cage construct (iii). (Immuno)histological analysis, multiphoton laser scanning microscopy, and biomechanical analysis showed extracellular matrix deposition and increased Young's modulus and thereby the feasibility of ear cartilage engineering. These results demonstrated that the 3D-printed cage construct is an adequate model for contraction-free ear cartilage engineering using a range of cell combinations.


Nursing contributions to the elimination of health disparities among African-Americans: review and critique of a decade of research--Part III.
The excessive burden of disease experienced by African-Americans has long been described by authorities in the public, private, and professional sector as a national health concern. Several reports have been published in the peer-reviewed literature that describe the outcomes of nurse-directed studies aimed at addressing the factors associated with the disparities experienced by African-Americans and these reports were also aimed toward the design of interventions to reduce and/or eliminate them. However, little is known about the scope, quality, and impact of these efforts relative to the promotion of health and the prevention of disease among African-American population groups. This report presents the results of a review, analysis, and critique of reports of outcomes of nursing research aimed toward reducing health-related disparities among African-Americans. These reports were described in a selected group of African-American nursing organizations and journals dedicated to providing a forum for the discussion of issues focused on cultural diversity, transcultural nursing, and multicultural health care issues. Included among the journals were the Journal of the National Black Nurses Association, the Journal of the Association of Black Nursing Faculty, the Journal of Chi Eta Phi Sorority, the Journal of Cultural Diversity, the Journal of Transcultural Nursing, and the Journal of Multicultural Nursing and Health. Results of the review will be reported in three parts. The first part was reported in an earlier edition (Journal of National Black Nurses Association, Volume 15, No. 1), the second part was reported in Volume 16, No 1, of the Journal of National Black Nurses Association, and the third part is reported here. The results of this critique revealed that this body of nursing research provides the profession with a broad base of knowledge and insights. This knowledge is relative to the individual and familial impact of cardiovascular disease, cancer, diabetes, HIV/AIDS, mental health and mental illness, and sickle cell disease within the African-American community. Knowledge and insights relative to the concerns and needs of childbearing, parenting, the elderly caregivers and care giving in African-American population groups is essential if health care disparities are to be truly eliminated. This review, analysis, and critique also revealed several gaps and limitations within this body of nursing research.


Neuronal GDNF expression in the adult rat nervous system identified by in situ hybridization.
Glial cell line-derived neurotrophic factor (GDNF) is a potent neurotrophic factor which has been purified on the basis of its ability to promote the survival of dopaminergic neurons in vitro. GDNF has subsequently been cloned and its sequence shown to be distantly related to transforming growth factor-beta (TGF-beta). To identify GDNF expressing cells in the adult rat brain, in situ hybridization using a digoxygenin (DIG)-labelled riboprobe has been performed. Our results show that GDNF mRNA is mainly expressed in neurons and that its synthesis is not restricted to dopaminergic areas. It is widely expressed in the cortex, the hippocampus, the striatum, the substantia nigra, the thalamus, the cerebellum and the spinal cord. Neuronal GDNF expression varies among brain regions as determined by the intensity of the in situ signal. Double labelling of the substantia nigra using tyrosine hydroxylase immunohistochemistry, associated with GDNF in situ hybridization, show that the majority of dopaminergic neurons express GDNF. The widespread expression of GDNF throughout the adult brain suggests that its administration in Parkinson's disease should be restricted to the altered structures, in order to avoid possible deleterious side effects.


Hierarchical Self-Assembly and Chiroptical Studies of Luminescent 4d-4f Cages.
Multinuclear lanthanide-containing supramolecular cages have received increasing attention recently because of their unique electroptical and magnetic properties. Here we report the hierarchical self-assembly and chiroptical studies of a group of 4d-4f heterometallic cages synthesized from a preformed dimetalloligand [(bpy)2Pd212]2+ (2) (bpy = 2,2-bipyridine) and a variety of trivalent lanthanide ions (Ln = NdIII, EuIII, YbIII). The programmable self-assembly process leading to the trigonal bipyramidal cages formulated as {Ln2[(bpy)2Pd212]3}12+ (3) has been confirmed by one- and two-dimensional NMR, electro-spray-ionization time-of-flight mass-spectroscopy, and in one typical case by single-crystal X-ray diffraction studies. Circular dichroism and circular polarized luminescence spectra confirmed the strict control of stereoselectivity on the heterometallic cages, dictated by the chiral amide groups on the ligands. Excitation (up to 420 nm) on the dipalladium chromophores on these cages leads to the characteristic lanthanide luminescence at both the visible and the near-infrared regions, depending on the lanthanide ions used. Through the assembly-disassembly process, luminescent turn-off sensing toward penicillin among several widely used antibiotics has also been demonstrated with the Europium cage, featuring a limit of detection as low as 0.88 ppb (S/N = 3). Our results pave the way for the construction of chiral 4d-4f supramolecular cages which may find potential applications in luminescent sensing and/or labeling reagents.


Workplace intervention programmes for decreasing alcohol use in military personnel: a systematic review.
Harmful or risky-single occasion drinking (RSOD) alcohol use in the military is a significant problem. However, most studies of interventions have focused on veterans, representing a missed opportunity for intervention with active military personnel. Using the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) framework, the aim of this systematic review was to analyse and synthesise the evidence related to workplace-based interventions for reducing alcohol use in active-duty military personnel. Four electronic databases and reference lists of relevant articles were searched from database inception until 20 January 2020. This review focused on experimental and quasi-experimental studies of active-duty military personnel. Data extraction and methodological quality assessment were independently performed by two reviewers using a standardised checklist. A third reviewer was used to arbitrate the disputed studies for final selection. The search yielded seven studies from an initial 1582 records identified. A range of interventions were used in these studies (four randomised controlled trials, two non-randomised trials and one before and after cohort study), including web-based approaches, telephone-delivered interventions and individual and group-based face-to-face interventions. Seven studies found decreased drinking, measured using a range of outcomes, following the intervention. However, this was not sustained in the longer term in any of the studies. The low methodological rigour of most studies limited the capacity to demonstrate the efficacy of the interventions studied. Given the importance of reducing harmful or RSOD use of alcohol in the military, future studies would benefit from improved methodological rigour including ensuring adequate study power, randomisation, selection of validated outcome measures, including measures other than consumption (eg, attitudinal measures), and longer-term follow-up. There is also a need to develop methods that ensure participant loss to follow-up is minimised.


The associations between domain-specific sedentary behaviours and dietary habits in European adults: a cross-sectional analysis of the SPOTLIGHT survey.
Sedentary behaviour has been associated with obesity and related chronic diseases. Disentangling the nature of this association is complicated due to interactions with other lifestyle factors, such as dietary habits, yet limited research has investigated the relation between domain-specific sedentary behaviours and dietary habits in adults. The aim of this paper was to examine the association between domain-specific sedentary behaviours and dietary habits in adults and to test the moderating effect of age and gender on this association. A total of 6,037 participants from five urban regions in Europe completed an online survey, of which 6,001 were included in the analyses. Multilevel mixed-effects logistic regression analyses were used to examine main associations and interaction effects. All domain-specific sedentary behaviours, except transport-related sitting time, were significantly related to dietary habits. In general, having a higher sitting time was related to having less healthy dietary habits, especially for television viewing. Gender did not moderate any of the relations, and age was only a significant moderator in the relation between other leisure sitting time and alcohol consumption. Domain-specific sitting behaviours were related to unhealthy dietary behaviours. However, the small effect sizes suggest that individual level behavioural interventions focusing on sedentary behaviour will not be sufficient to improve dietary habits. The fact that almost none of the associations were moderated by age or gender suggests that these associations, and possibly also the effects of interventions targeting both behaviours, may hold across age and gender groups.


Menopause, menstrual and reproductive history, and bone density in northern Italy.
To analyse the relationship between menstrual and reproductive factors and the risk of low bone mineral density (BMD). This was a population based screening programme carried out between 1991 and 1993 among 1373 perimenopausal women in northern Italy by means of dual photon absorptiometry at the lumbar spine. BMD was strongly related to the age at menopause. In comparison with women reporting menopause below 45 years of age, the odds ratios (OR) of being in the lowest compared with the highest BMD tertile were 0.7 (95% confidence interval (CI) 0.3,1.5) and 0.3 (95% CI 0.1,0.8), respectively, in those with menopause at age 45-49 and above 50 years: the trend in risk was significant. Likewise, the risk of being in the lowest tertile increased with years since the menopause. Compared with women who reported they had undergone the menopause less than two years before interview, the OR of being in the lowest BMD tertile were 2.1 (95% CI 1.1,4.3), 2.3 (95% CI 1.1, 5.0), and 5.7 (95% CI 2.5,12.9) respectively in women who reported menopause 2-5, 6-9, and > or = 10 years earlier. The protective effect on bone density of late age at menopause was observed in different strata of years since menopause. Likewise, the increasing risk of a low BMD with increasing years since the menopause was evident in strata of different age at menopause. No relationships were observed between BMD and the age at menarche, characteristics of menstrual cycles, and the duration of menses. Likewise, no association emerged between reproductive history, including parity and age at first pregnancy, and BMD. In this Italian population the risk of being in the lowest BMD tertile decreased with increasing age at menopause and increased with years since menopause. No relationships emerged between BMD and other menstrual characteristics or reproductive factors.


Antivirals for influenza in healthy adults: systematic review.
Use of antivirals is recommended for the control of seasonal and pandemic influenza. Our aim was to review the evidence of efficacy, effectiveness, and safety of registered antivirals against naturally occurring influenza in healthy adults. We searched various Databases to October, 2005, and contacted manufacturers and corresponding authors. We included randomised controlled trials comparing prophylactic (n=27) or treatment (n=27) efficacy against symptomatic or asymptomatic influenza. We did a meta-analysis and expressed prophylactic efficacy as a proportion (1-relative risk [RR]). For treatment trials, because of inconsistent and non-standardised reporting, we expressed continuous outcomes either as means or as hazard ratios. We included 51 reports of 52 randomised controlled trials. Amantadine prevented 61% (95% CI 35-76) of influenza A cases and 25% (13-36) of cases of influenza-like illness, but caused nausea (OR 2.56, 1.37-4.79), insomnia and hallucinations (2.54, 1.50-4.31), and withdrawals because of adverse events (2.54, 1.60-4.06). There was no effect on asymptomatic cases (RR 0.85, 0.40-1.80). In treatment, amantadine significantly shortened duration of fever compared with placebo (by 0.99 days, -1.26 to -0.71), but had no effect on nasal shedding of influenza A viruses (0.93, 0.71-1.21). The fewer data for rimantadine showed comparable effects. In prophylaxis, compared with placebo, neuraminidase inhibitors have no effect against influenza-like illness (1.28, 0.45-3.66 for oral oseltamivir 75 mg daily, 1.51, 0.77-2.95 for inhaled zanamivir 10 mg daily). Higher doses appear to make no difference. The efficacy of oral oseltamivir 75 mg daily against symptomatic influenza is 61% (15-82), or 73% (33-89) at 150 mg daily. Inhaled zanamivir 10 mg daily is 62% efficacious (15-83). Neither neuraminidase inhibitor appeared effective against asymptomatic influenza. Oseltamivir induces nausea (OR 1.79, 1.10-2.93), especially at higher prophylactic doses (2.29, 1.34-3.92). Oseltamivir in a post-exposure prophylaxis role has a protective efficacy of 58.5% (15.6-79.6) for households and from 68% (34.9-84.2) to 89% (67-97) in contacts of index cases. In influenza cases, compared with placebo the hazard ratios for time to alleviation of symptoms were 1.33, 1.29-1.37 for zanamivir; 1.30, 1.13-1.50 for oseltamivir provided medication was started within 48 h of symptom onset. Viral nasal titres were significantly diminished by both drugs (weighted mean difference -0.62, -0.82 to -0.41). Oseltamivir at 150 mg daily was effective in preventing lower respiratory tract complications in influenza cases (OR 0.32, 0.18-0.57). We could find no credible data on the effects of oseltamivir on avian influenza. The use of amantadine and rimantadine should be discouraged. Because of their low effectiveness, neuraminidase inhibitors should not be used in seasonal influenza control and should only be used in a serious epidemic or pandemic alongside other public-health measures.


Unconventional Gas and Oil Drilling Is Associated with Increased Hospital Utilization Rates.
Over the past ten years, unconventional gas and oil drilling (UGOD) has markedly expanded in the United States. Despite substantial increases in well drilling, the health consequences of UGOD toxicant exposure remain unclear. This study examines an association between wells and healthcare use by zip code from 2007 to 2011 in Pennsylvania. Inpatient discharge databases from the Pennsylvania Healthcare Cost Containment Council were correlated with active wells by zip code in three counties in Pennsylvania. For overall inpatient prevalence rates and 25 specific medical categories, the association of inpatient prevalence rates with number of wells per zip code and, separately, with wells per km2 (separated into quantiles and defined as well density) were estimated using fixed-effects Poisson models. To account for multiple comparisons, a Bonferroni correction with associations of p<0.00096 was considered statistically significant. Cardiology inpatient prevalence rates were significantly associated with number of wells per zip code (p<0.00096) and wells per km2 (p<0.00096) while neurology inpatient prevalence rates were significantly associated with wells per km2 (p<0.00096). Furthermore, evidence also supported an association between well density and inpatient prevalence rates for the medical categories of dermatology, neurology, oncology, and urology. These data suggest that UGOD wells, which dramatically increased in the past decade, were associated with increased inpatient prevalence rates within specific medical categories in Pennsylvania. Further studies are necessary to address healthcare costs of UGOD and determine whether specific toxicants or combinations are associated with organ-specific responses.


Chromatin remodelling complexes in cerebral cortex development and neurodevelopmental disorders.
The diverse number of neurons in the cerebral cortex are generated during development by neural stem cells lining the ventricle, and they continue maturing postnatally. Dynamic chromatin regulation in these neural stem cells is a fundamental determinant of the emerging property of the functional neural network, and the chromatin remodellers are critical determinants of this process. Chromatin remodellers participate in several steps of this process from proliferation, differentiation, migration leading to complex network formation which forms the basis of higher-order functions of cognition and behaviour. Here we review the role of these ATP-dependent chromatin remodellers in cortical development in health and disease and highlight several key mouse mutants of the subunits of the complexes which have revealed how the remodelling mechanisms control the cortical stem cell chromatin landscape for expression of stage-specific transcripts. Consistent with their role in cortical development, several putative risk variants in the subunits of the remodelling complexes have been identified as the underlying causes of several neurodevelopmental disorders. A basic understanding of the detailed molecular mechanism of their action is key to understating how mutations in the same networks lead to disease pathologies and perhaps pave the way for therapeutic development for these complex multifactorial disorders.


Supervised exercise training as an adjunctive therapy for venous leg ulcers: study protocol for a randomised controlled trial.
Venous leg ulcers are common, chronic wounds that are painful and reduce quality of life. Compression therapy is known to assist in the healing of venous leg ulceration. Supervised exercise training that targets an improvement in calf muscle pump function might be a useful adjunctive therapy for enhancing ulcer healing and other aspects of physical and mental health. However, the evidence of exercise for individuals with venous ulcers is sparse. Here, we describe the protocol for a study that aims to assess the feasibility of undertaking a randomised controlled trial of a supervised exercise programme in people who are receiving compression for venous ulceration. This is a randomised, controlled, assessor-blinded, two-centre, feasibility trial with two parallel groups. Eighty adults who are receiving lower-limb compression for a venous leg ulcer will be randomly assigned to receive usual care (compression only) or usual care plus a 12-week supervised exercise programme. Participants in the exercise group will be invited to undertake three, 60-minute sessions of supervised exercise each week, and each session will involve a combination of treadmill walking, upright cycling and strength and flexibility exercises for the lower limbs. Participants will be assessed before randomisation and 3, 6 and 12 months after randomisation. Primary outcomes include rates of recruitment, retention and adherence. Secondary outcomes include time to ulcer healing, proportion of participants healed, percentage and absolute change in ulcer size, health-related quality of life (EQ-5D-5L and VEINES-QOL/Sym), lower-limb cutaneous microvascular function (laser Doppler flowmetry coupled with iontophoresis) and physical fitness (30-second sit-to-stand test, chair sit and reach test, 6-minute walk test and ankle range of motion). The costs associated with the exercise programme and health-care utilisation will be calculated. We will also complete interviews with a sub-sample of participants to explore their experiences of having a venous ulcer and the acceptability of the exercise intervention and study procedures. Data from this study will be used to refine the supervised exercise programme, investigate the acceptability of the intervention and study design and determine the most appropriate outcome measures, thereby providing estimates of the factors needed to design an adequately powered trial across several centres. Current Controlled Trials, ISRCTN10205425 (May 2014) - http://www.controlled-trials.com/ISRCTN10205425.


The Function of β2-glycoprotein I in Angiogenesis and Its in Vivo Distribution in Tumor Xenografts.
Intact β2-glycoprotein I (iβ2GPI) is a glycoprotein that regulates coagulation and fibrinolysis. Nicked β2GPI (nβ2GPI) possesses an angiogenic property at a relatively low concentration, and an antiangiogenic property at a high concentration. Here we investigated the functions of βi 2GPI and nβ2GPI in vascular endothelial growth factor (VEGF)-A-induced endothelial cell proliferation and tube formation. We used noninvasive PET imaging to analyze the in vivo distribution of intravenously injected β2GPI variants in tumor lesions in mice. iβ2GPI was incubated with plasmin to obtain nβ2GPI, and its N-terminal sequence was analyzed. nβ2GPI had at least one other cleavage site upstream of the β2GPI's domain V, whereas the former plasmin-cleavage site locates between K317 and T318. Both of intact and nicked β2GPI significantly inhibited the VEGF-A-induced cell proliferation and the tube formation of human umbilical vein endothelial cells (HUVECs). PET imaging visualized considerably distributed intensities of all tested β2GPI variants in tumor lesions of pancreatic tumor cell-xenografts. These results indicate that β2GPI may be physiologically and pathophysiologically important in the regulation of not only coagulation and fibrinolysis, but also angiogenesis.


Treatment outcomes of orthodontic treatment, corticotomy-assisted orthodontic treatment, and anterior segmental osteotomy for bimaxillary dentoalveolar protrusion.
The purpose of this study was to compare treatment outcomes of orthodontic treatment, anterior segmental osteotomy, and corticotomy-assisted orthodontic treatment for resolution of bimaxillary dentoalveolar protrusion. The samples consisted of 65 Korean adult female patients with bimaxillary dentoalveolar protrusion who had achieved a good treatment result and were divided into group 1 (orthodontic treatment), group 2 (corticotomy-assisted orthodontic treatment with skeletal anchorage in the maxilla and anterior segmental osteotomy in the mandible), or group 3 (anterior segmental osteotomy in the maxilla and mandible). The hard- and soft-tissue variables were measured from lateral cephalographic tracings at pretreatment and posttreatment stages. Statistic analyses were performed to compare differences in pretreatment and change from pretreatment to posttreatment. Group 3 showed the largest amount of basal bone retraction and the least amount of upper incisor inclination change and upper alveolar bone bending among the three groups. The amounts of change in the upper lip projection and angulation were greater in group 2 than in group 1. Group 3 showed a decrease of the upper incisal exposure, whereas group 1 showed an increase. Upper central incisor to Frankfurt horizontal plane, upper and lower alveolar ridge angle, Pog-N perpendicular, and anteroposterior discrepancy indicator were selected as significant variables for discriminating the three groups. The results of this study show that orthodontic treatment or corticotomy-assisted orthodontic treatment is indicated for those with severe incisor proclination with normal basal bone position, although corticotomy-assisted orthodontic treatment can be advantageous for adult patients concerned with treatment duration. Anterior segmental osteotomy is recommended for bimaxillary dentoalveolar protrusion patients with a gummy smile, basal bone prognathism, relatively normal incisor inclination, and relatively underdeveloped chin position.


Promoting cardiovascular health and wellness among African-Americans: Community participatory approach to design an innovative mobile-health intervention.
Despite improvements in mortality rates over the past several decades, cardiovascular (CV) disease remains the leading cause of death for African-Americans (AAs). Innovative approaches through mobile health (mHealth) interventions have the potential to support lifestyle change for CV disease prevention among AAs. We aimed to translate a behavioral theory-informed, evidence-based, face-to-face health education program into an mHealth lifestyle intervention for AAs. We describe the design and development of a culturally relevant, CV health and wellness digital application (app) and pilot testing using a community-based participatory research (CBPR) approach with AA churches. This mixed methods study used a 4-phase iterative development process for intervention design with the AA community. Phase 1 included focus groups with AA community members and church partners (n = 23) to gain insight regarding potential app end user preferences. In Phase 2, the interdisciplinary research team synthesized Phase 1 input for preliminary app design and content development. Phase 3 consisted of a sequential 3-meeting series with church partners (n = 13) for iterative app prototyping (assessment, cultural tailoring, final review). Phase 4, a single group pilot study among AA church congregants (n = 50), assessed app acceptability, usability, and satisfaction. Phase 1 focus groups indicated general and health-related apps preferences: multifunctional, high-quality graphics/visuals, evidence-based, yet simple health information and social networking capability. Phase 2 integrated these preferences into the preliminary app prototype. Phase 3 feedback was used to refine the app prototype for pilot testing. Phase 4 pilot testing indicated high app acceptability, usability, and satisfaction. This study illustrates integration of formative and CBPR approaches to design a culturally relevant, mHealth lifestyle intervention to address CV health disparities among AAs. Given the positive app perceptions, our study supports the use of an iterative development process by others interested in implementing an mHealth lifestyle intervention for racial/ethnic minority communities. Clinicaltrials.gov NCT03084822.


Congenital diaphragmatic hernia causing cardiac arrest in a 30-year-old woman.
Congenital diaphragmatic hernia (CDH) usually presents in infancy with respiratory failure requiring urgent surgical correction. Mortality in this group of patients remains poor and persistent pulmonary hypertension is a significant contributor. It is therefore rare for patients to reach adulthood undiagnosed. CDH is often identified incidentally in adults but when symptoms arise, they relate to the organ involved, and include gastrointestinal symptoms of dyspepsia and obstruction, as well as respiratory complaints such as dyspnoea. We present the case of a 30-year-old woman who was admitted with non-specific symptoms of upper abdominal discomfort but whose deteriorating condition culminated in a cardiac arrest, as an unreported presentation of CDH. The patient presented initially with severe left upper quadrant pain. Her chest x-ray on admission suggested a raised left hemidiaphragm. She went on to have computed tomography (CT) of the thorax and abdomen as well as oesophagogastroduodenoscopy, which raised the suspicion of diaphragmatic eventration. Repeat CT was performed after the patient collapsed on the ward five days following admission, revealing tracheal deviation, and a strangulated Bochdalek hernia containing stomach and spleen. After transfer to the anaesthetic room, she suffered a cardiac arrest. Advanced life support was required to return spontaneous cardiac function. She was intubated and ventilated, and a needle thoracostomy was performed to decompress the tension gastrothorax. Emergency laparotomy revealed a gangrenous stomach and spleen. Total gastrectomy with primary Roux-en-Y reconstruction, splenectomy and insertion of a feeding jejunostomy were performed. The patient recovered well postoperatively and was discharged two weeks following surgery.


Predicting cumulative load during running using field-based measures.
The main objective was to investigate whether the cumulative load of the lower limbs, defined as the product of external load and step rate, could be predicted using spatiotemporal variables gathered with a commercially available wearable device in running. Therefore, thirty-nine runners performed two running tests at 10 and 12 km/h, respectively. Spatiotemporal variables (step rate, ground contact time, and vertical oscillation) were collected using a commercially available wearable device. Kinetic variables, measured with gold standard equipment (motion capture system and instrumented treadmill) and used for the calculation of a set of variables representing cumulative load, were peak vertical ground reaction force (peak vGRF), vertical instantaneous loading rate (VILR), vertical impulse, braking impulse, as well as peak extension moments and angular impulses of the ankle, knee and hip joints. Separate linear mixed-effects models were built to investigate the prediction performance of the spatiotemporal variables for each measure of cumulative load. BMI, speed, and sex were included as covariates. Predictive precision of the models ranged from .11 to .66 (R2 m ) and .22 to .98 (R2 c ), respectively. Greatest predictive performance was obtained for the cumulative peak vGRF (R2 m = .66, R2 c = .97), VILR (R2 m = .43, R2 c = .97), braking impulse (R2 m = .52, R2 c = .98), and peak hip extension moment (R2 m = .54, R2 c = .90). In conclusion, certain variables representing cumulative load of the lower limbs in running can be predicted using spatiotemporal variables gathered with a commercially available wearable device.


Criminal victimisation and health: examining the relation in nine countries of the former Soviet Union.
Previous research suggests that criminal victimisation can impact negatively on both physical and psychological health. However, as yet, little is known about crime and its effects on population health in the former Soviet Union (fSU) - despite a sharp growth in crime rates in the countries in this region after the collapse of the communist system. Given this gap in current knowledge, this study examined two forms of crime, theft and violent victimisation, in nine fSU countries - Armenia, Azerbaijan, Belarus, Georgia, Kazakhstan, Kyrgyzstan, Moldova, Russia and Ukraine. Using nationally representative data from the Health in Times of Transition (HITT) study collected from 18,000 respondents in 2010/11, the study had two main objectives: (1) to identify which demographic and socioeconomic factors are associated with being a victim of crime; (2) to examine the relation between criminal victimisation and two health outcomes - self-rated health and psychological distress. We found that similar factors were associated with experiencing both forms of crime among respondents. Those who were younger, not married and who consumed alcohol more frequently were at increased risk of victimisation, while greater social capital was associated with lower odds for victimisation. Low education increased the risk of experiencing violence by 1.5 times. Victimisation was strongly associated with poorer health: victims of violence were 2.5 and 2.9 times more likely to report poor self-rated health and psychological distress, respectively, while the corresponding figures for theft victimisation were 1.9 and 1.8. The strong association we observed between criminal victimisation and poorer individual health suggests that, in addition to policies that reduce rates of crime, more research is now urgently needed on victimisation. Specifically, researchers should ascertain whether the association with poor health is causal, determine its potential mechanisms, and evaluate interventions that might mitigate its impact on health that are contextually appropriate in the fSU.


Sustained combustion of an animal carcass and its implications for the consumption of human bodies in fires.
When a human body is found with significant portions of its torso and limbs destroyed yet with comparatively minor damage to head, hands and feet, the mechanism of such destruction defies ready explanation, since exposure to external fires, particularly those involving flammable liquids, usually results in the destruction of hands, feet, limbs, and head prior to significant combustion of the large mass of the torso. Previous tests by these authors have demonstrated the conditions necessary to promote combustion of a body: the presence of adequate body fat, presence of a porous, rigid char to act as a wick, and an external flame source sustained for several minutes to char the body and cause the subcutaneous fat to begin rendering. In the test reported here, a freshly-slaughtered pig carcass with a net weight of 215 lb. (95 kg) was wrapped in a cotton blanket and placed on a carpet-covered plywood panel. The fire was initiated using 1 L of gasoline poured on the shoulder area of the blanket-wrapped carcass. The gasoline burned off within 4 min, having ignited a large area of the blanket and adjoining carpet. Flames from those fuel packages resulted in the establishment of a steady-state fire sustained by the rendering of the body fat, with the necessary wick provided by the charred cotton blanket and carpet. The heat release rate of this fire was 60+/-10 kW, with flames less than 12 in. (0.35 m) high for its duration. The fire sustained itself by the rendering process for more than 6 1/2 h from ignition, at which time it was extinguished. An average mass loss rate of 1.5 g/s (5.3 kg/h) was observed during the self-sustained fire. Extensive destruction of the carcass (more than 60% by weight) included reduction of large bones to a fragile, ashen state. Other test data will demonstrate the similarity between subcutaneous fat from human and porcine sources. The implications for the reconstruction of accidental and homicidal fires involving such destruction will be discussed.


Individual psychodynamic psychotherapy and psychoanalysis for schizophrenia and severe mental illness.
People with schizophrenia and severe mental illness may require considerable support from health care professionals, in most cases over a long period of time. Research on the effects of psychotherapy for schizophrenia shows mixed results. Although pharmacological interventions remain the treatment of choice for schizophrenia patients, it is also of interest to look at the effects of treatment methods focusing on psychosocial factors affecting schizophrenia. To review the effects of individual psychodynamic psychotherapy and/or psychoanalysis for people with schizophrenia or severe mental illness. Electronic searches of Biological Abstracts (1985-1999), CINAHL (1982-1999), The Cochrane Library CENTRAL (Issue 1, 1999), The Cochrane Schizophrenia Group's Register (2000), Dissertation Abstracts On Disc (1866-1999), EMBASE (1980-1999), MEDLINE (1966-1999), National Research Register (2000), PsycLIT (1974-1999), and Sociofile (1974-1998) were made. Authors of included trials were contacted for information on further trials. All randomised trials of individual psychodynamic psychotherapy or psychoanalysis for people with schizophrenia or severe mental illness (however defined) were selected. Data were independently extracted by at least two reviewers. For dichotomous data relative risks (RR) were calculated and for continuous data weighted mean differences (WMD) between groups were calculated. No trials of a psychoanalytic approach were identified. Data are sparse for all comparisons involving a psychodynamic approach. There is no evidence of any positive effect of psychodynamic therapy and the possibility of adverse effects seems never to have been considered. The psychodynamic approach may be more acceptable to people than a more cognitive reality-adaptive therapy. Current data do not support the use of psychodynamic psychotherapy techniques for hospitalised people with schizophrenia. If psychoanalytic therapy is being used for people with schizophrenia there is an urgent need for trials.


Effect of arginine on cellular adhesion molecule expression and leukocyte transmigration in endothelial cells stimulated by biological fluid from surgical patients.
This study investigated the effect of different arginine (Arg) concentrations on adhesion molecule expression on endothelial cells (ECs) and leukocytes and the transendothelial migration of polymorphonuclear neutrophils (PMNs) through ECs stimulated by plasma or peritoneal drain fluid (PDF) from surgical patients. Human umbilical vein ECs (HUVECs) and PMNs from healthy subjects were treated with different concentrations (0, 50, 100, and 1000 micromol/L) of Arg for 24 h. After that, HUVECs were stimulated for 3 h with plasma or PDF from patients who underwent abdominal surgery, and PMNs were allowed to transmigrate through ECs for 2 h. The HUVEC expression of cellular adhesion molecules (CAMs) and integrin (CD11b) and the interleukin (IL) 8 receptor expression on PMNs were measured by flow cytometry. The PMNs transmigrating through ECs were also analyzed. The results showed that CAM and integrin expressions in PDF groups were higher than those in control groups. Among the PDF groups, IL-8 secretions from ECs and PMNs were lower with 100 and 1000 micromol/L Arg than with 0 and 50 micromol/L Arg, and this was consistent with the expression of the IL-8 receptor on PMNs. In addition, CAM expressions on ECs and CD11b expression on PMNs, as well as PMN transmigration, were lower with 100 and 1000 micromol/L Arg than with 0 and 50 micromol/L Arg. The HUVECs stimulated by plasma from surgical patients had similar effects on surface molecule expression as PDF; however, as shown in PDF stimulation, the effects were not so obvious. Inhibition of nitric oxide production results in high CAM and IL-8 expressions comparable with groups with low Arg administration. The results of this in vitro study suggest that ECs and PMNs were activated after patients' plasma or PDF stimulation. A low Arg concentration comparable with catabolic conditions resulted in higher adhesion molecule expression and greater transendothelial migration of neutrophils. Arginine administration at levels similar to or higher than physiological concentrations reduced IL-8 and CAM expression, and PMN transmigration was also decreased after stimulation with plasma or PDF from surgical patients. Inactivation of NO results in high CAM and IL-8 expression. This finding indicated that NO may be an important endogenous inhibitor for EC-PMN interaction and neutrophil transmigration.


The role of standardized protocols in unplanned extubations in a medical intensive care unit.
Many patients admitted to medical intensive care units require mechanical ventilation to assist with respiratory management. Unplanned extubations of these patients are associated with poor outcomes for patients and organizations. No previous research has investigated the role of standardized protocols in unplanned extubations when examined in conjunction with traditional risk factors. To identify risk factors associated with unplanned extubation among patients receiving mechanical ventilation and determine degree of compliance with pain, sedation, and weaning protocols. A prospective cohort study design was used. Data on all patients admitted to the medical intensive care unit who required mechanical ventilation were gathered daily. Additional data were gathered on those patients who experienced unplanned extubation. Descriptive, correlational, and regression analyses were performed. Weaning protocols were a significant predictor of unplanned extubation: patients who had weaning protocols ordered and followed were least likely to experience unplanned extubation. Only 10% of the 190 patients in the study required reintubation, resulting in a significantly shorter ventilation time and unit length of stay among the unplanned extubation group. Weaning protocols were associated with decreased incidence of unplanned extubation. Use of standardized protocols was feasible, as compliance among health care providers was high when protocols were medically prescribed. The reintubation rate in this study was low and associated with a significantly shorter ventilatory period and unit length of stay in the unplanned extubation group.


Red meat intake, NAT2, and risk of colorectal cancer: a pooled analysis of 11 studies.
Red meat intake has been associated with risk of colorectal cancer, potentially mediated through heterocyclic amines. The metabolic efficiency of N-acetyltransferase 2 (NAT2) required for the metabolic activation of such amines is influenced by genetic variation. The interaction between red meat intake, NAT2 genotype, and colorectal cancer has been inconsistently reported. We used pooled individual-level data from the Colon Cancer Family Registry and the Genetics and Epidemiology of Colorectal Cancer Consortium. Red meat intake was collected by each study. We inferred NAT2 phenotype based on polymorphism at rs1495741, highly predictive of enzyme activity. Interaction was assessed using multiplicative interaction terms in multivariate-adjusted models. From 11 studies, 8,290 colorectal cancer cases and 9,115 controls were included. The highest quartile of red meat intake was associated with increased risk of colorectal cancer compared with the lowest quartile [OR, 1.41; 95% confidence interval (CI), 1.29-1.55]. However, a significant association was observed only for studies with retrospective diet data, not for studies with diet prospectively assessed before cancer diagnosis. Combining all studies, high red meat intake was similarly associated with colorectal cancer in those with a rapid/intermediate NAT2 genotype (OR, 1.38; 95% CI, 1.20-1.59) as with a slow genotype (OR, 1.43; 95% CI, 1.28-1.61; P interaction = 0.9). We found that high red meat intake was associated with increased risk of colorectal cancer only from retrospective case-control studies and not modified by NAT2 enzyme activity. Our results suggest no interaction between NAT2 genotype and red meat intake in mediating risk of colorectal cancer.


Prognostic impact of isolated tumor cells in breast cancer axillary nodes: single tumor cell(s) versus tumor cell cluster(s) and microanatomic location.
In breast cancer, it has been shown that pN0(i+) and pN1mi have a comparable negative impact on disease-free survival, compared with pN0. However, pN0(i+) is considered to be a heterogeneous group. We determined the effect of metastatic size and microanatomic location within the pN0(i+) group on breast cancer recurrence. We included all Dutch breast cancer patients diagnosed in 1998-2005 with favorable primary tumor characteristics and a final nodal status of pN0(i+). For this analysis, only patients without adjuvant systemic therapy were eligible (n = 513). Presence of single tumor cells versus cell clusters, metastatic size and microanatomic location were recorded. Primary endpoint was disease-free survival. Analyses were adjusted for age at diagnosis, tumor size, tumor grade, axillary treatment and hormone receptor status. The 5-year disease-free survival of patients with single tumor cell(s) (n = 93) was 78.6% and with tumor cell cluster(s) (n = 404) 77.1%. The hazard ratio for disease events was 1.05 (95% CI 0.63-1.76) for cell cluster(s) compared with single cell(s). In a Cox regression model, doubling of metastatic tumor size corresponded to a hazard ratio of 1.21 (95% CI 1.02-1.43). The adjusted hazard ratio was 0.90 (95% CI 0.54-1.50) for parenchymal (n = 112) versus sinusoidal location (n = 395). Single tumor cells bear similar prognostic information as small tumor cell clusters, even though results do suggest that within the pN0(i+) group, increasing size of nodal involvement is associated with reduced survival. Microanatomic location does not seem to have prognostic relevance.


Gene × physical activity interactions in obesity: combined analysis of 111,421 individuals of European ancestry.
Numerous obesity loci have been identified using genome-wide association studies. A UK study indicated that physical activity may attenuate the cumulative effect of 12 of these loci, but replication studies are lacking. Therefore, we tested whether the aggregate effect of these loci is diminished in adults of European ancestry reporting high levels of physical activity. Twelve obesity-susceptibility loci were genotyped or imputed in 111,421 participants. A genetic risk score (GRS) was calculated by summing the BMI-associated alleles of each genetic variant. Physical activity was assessed using self-administered questionnaires. Multiplicative interactions between the GRS and physical activity on BMI were tested in linear and logistic regression models in each cohort, with adjustment for age, age(2), sex, study center (for multicenter studies), and the marginal terms for physical activity and the GRS. These results were combined using meta-analysis weighted by cohort sample size. The meta-analysis yielded a statistically significant GRS × physical activity interaction effect estimate (Pinteraction = 0.015). However, a statistically significant interaction effect was only apparent in North American cohorts (n = 39,810, Pinteraction = 0.014 vs. n = 71,611, Pinteraction = 0.275 for Europeans). In secondary analyses, both the FTO rs1121980 (Pinteraction = 0.003) and the SEC16B rs10913469 (Pinteraction = 0.025) variants showed evidence of SNP × physical activity interactions. This meta-analysis of 111,421 individuals provides further support for an interaction between physical activity and a GRS in obesity disposition, although these findings hinge on the inclusion of cohorts from North America, indicating that these results are either population-specific or non-causal.


Naphthenic Acid Mixtures from Oil Sands Process-Affected Water Enhance Differentiation of Mouse Embryonic Stem Cells and Affect Development of the Heart.
Extraction of petrochemicals from the surface mining of oil sand deposits results in generation of large volumes of oil sands process-affected water (OSPW). Naphthenic acids (NA) are generally considered to be among the most toxic components of OSPW. Previous studies have shown that NAs are toxic to aquatic organisms, however knowledge of their effects on mammalian health and development is limited. In the present study, we evaluated the developmental effects of an NA extract prepared from fresh OSPW on differentiating mouse embryonic stem cells (ESC). We found that treatment of differentiating cells with the NA extract at noncytotoxic concentrations alters expression of various lineage specification markers and development of the heart. Notably, expression of cardiac specific markers such as Nkx2.5, Gata4, and Mef2c were significantly up-regulated. Moreover, exposure to the NA extract enhanced differentiation of embryoid bodies and resulted in the early appearance of spontaneously beating clusters. Interestingly, exposure of undifferentiated mouse ESCs to the NA extract did not change the expression level of pluripotency markers (i.e., Oct4, Nanog, and Sox2). Altogether, these data identify some of the molecular pathways affected by components within this NA extract during differentiation of mammalian cells.


First-principle DFT and MP2 modeling of infrared reflection-absorption spectra of oriented helical ethylene glycol oligomers.
First-principle modeling is used to obtain a comprehensive understanding of infrared reflection absorption (RA) spectra of helical oligo(ethylene glycol) (OEG) containing self-assembled monolayers (SAMs). Highly ordered SAMs of methyl-terminated 1-thiaoligo(ethylene glycols) [HS(CH2CH2O)(n)CH3, n = 5, 6] on gold recently became accessible for systematic infrared analyses [Vanderah et al., Langmuir, 2003, 19, 3752]. We utilized the quoted experimental data to validate the first-principle modeling of infrared RA spectra of HS(CH2CH2O)(5,6)CH3 obtained by (i) DFT methods with gradient corrections (using different basis sets, including 6-311++G) and (ii) HF method followed by a Møller-Plesset (MP2) correlation energy correction. In focus are fundamental modes in the fingerprint and CH-stretching regions. The frequencies and relative intensities in the calculated spectra for a single molecule are unambiguously identified with the bands observed in the experimental RA spectra of the corresponding SAMs. In addition to confirming our earlier assignment of the dominating peak in the CH-stretching region to CH2 asymmetric stretching vibrations, all other spectral features observed in that region have received an interpretation consistent (but not in all cases coinciding) with previous investigations. The obtained results provide an improved understanding of the orientation and conformation of the molecular building blocks within OEG-containing assemblies, which, in our opinion, is crucial for being able to predict the folding and phase characteristics and interaction of OEG-SAMs with water and proteins.


Examination of the mechanisms of osteolysis in patients with metastatic breast cancer.
The benefits of bisphosphonates (BPs) in reducing skeletal-related events (SREs) in patients with bone metastases has mainly been attributed to their potent osteoclast inhibiting effect. However, despite the use of modern systemic anticancer therapy including potent BPs, many patients with bone metastases continue to have SREs. An improved understanding of the fundamental mechanisms of bone destruction allows for further development of appropriate targeted treatments. In this study, archival paraffin-embedded bone metastases specimens from patients with metastatic breast cancer were examined for the presence of osteoclasts, expression of the receptor activator of nuclear factor kappaB (RANK), RANK Ligand (RANKL), osteoprotegerin (OPG) and vascular endothelial growth factor (VEGF). Histological specimens were available for primary breast cancer, lymph node metastases, normal breast and normal bone tissues for comparison. Bone metastasis specimens were available for 20 BP naïve patients and two BP-treated patients. Osteoclasts were significantly increased in the bone metastases of the BP naïve group compared to normal bone. No osteoclasts were detected in the BP-treated group. RANKL was predominantly expressed in osteoblasts and in the stromal elements of metastatic tissue. Conversely, RANK was present in osteoclasts of bone metastases and normal bone, as well as in tumor cells of metastatic lymph nodes and bone metastases. VEGF was strongly expressed in the control bone and bone metastases regardless of BP treatment. In summary, osteoclasts may not be the singular obligatory factor for osteolysis in bone metastases. An increased expression of RANKL in stromal tissue surrounding bone metastases, RANK in osteoclasts and VEGF may serve as future targeted therapies possibly in conjunction with bisphosphonates. The mechanisms for osteoclast expression and the expression of RANKL, RANK, OPG and VEGF merit further prospective analysis, particularly in the context of BP treatment and progressive bone metastases.


Hyaluronic Acid Binding Sperm Selection for assisted reproduction treatment (HABSelect): study protocol for a multicentre randomised controlled trial.
The selection of a sperm with good genomic integrity is an important consideration for improving intracytoplasmic sperm injection (ICSI) outcome. Current convention selects sperm by vigour and morphology, but preliminary evidence suggests selection based on hyaluronic acid binding may be beneficial. The aim of the Hyaluronic Acid Binding Sperm Selection (HABSelect) trial is to determine the efficacy of hyaluronic acid (HA)-selection of sperm versus conventionally selected sperm prior to ICSI on live birth rate (LBR). The mechanistic aim is to assess whether and how the chromatin state of HA-selected sperm corresponds with clinical outcomes-clinical pregnancy rate (CPR), LBR and pregnancy loss (PL). Couples attending UK Centres will be approached, eligibility screening performed and informed consent sought. Randomisation will occur within 24 hours prior to ICSI treatment. Participants will be randomly allocated 1:1 to the intervention arm (physiological intracytoplasmic sperm injection, PICSI) versus the control arm using conventional methods (ICSI). The primary clinical outcome is LBR ≥37 weeks' gestation with the mechanistic study determining LBR's relationship with sperm DNA integrity. Secondary outcomes will determine this for CPR and PL. Only embryologists performing the procedure will be aware of the treatment allocation. Steps will be taken to militate against biases arising from embryologists being non-blinded. Randomisation will use a minimisation algorithm to balance for key prognostic variables. The trial is powered to detect a 5% difference (24-29%: p=0.05) in LBR ≥37 weeks' gestation. Selected residual sperm samples will be tested by one or more assays of DNA integrity. HABSelect is a UK NIHR-EME funded study (reg no 11/14/34; IRAS REF. 13/YH/0162). The trial was designed in partnership with patient and public involvement to help maximise patient benefits. Trial findings will be reported as per CONSORT guidelines and will be made available in lay language via the trial web site (http://www.habselect.org.uk/). ISRCTN99214271; Pre-results.


Lattice Boltzmann method for the fractional advection-diffusion equation.
Mass transport, such as movement of phosphorus in soils and solutes in rivers, is a natural phenomenon and its study plays an important role in science and engineering. It is found that there are numerous practical diffusion phenomena that do not obey the classical advection-diffusion equation (ADE). Such diffusion is called abnormal or superdiffusion, and it is well described using a fractional advection-diffusion equation (FADE). The FADE finds a wide range of applications in various areas with great potential for studying complex mass transport in real hydrological systems. However, solution to the FADE is difficult, and the existing numerical methods are complicated and inefficient. In this study, a fresh lattice Boltzmann method is developed for solving the fractional advection-diffusion equation (LabFADE). The FADE is transformed into an equation similar to an advection-diffusion equation and solved using the lattice Boltzmann method. The LabFADE has all the advantages of the conventional lattice Boltzmann method and avoids a complex solution procedure, unlike other existing numerical methods. The method has been validated through simulations of several benchmark tests: a point-source diffusion, a boundary-value problem of steady diffusion, and an initial-boundary-value problem of unsteady diffusion with the coexistence of source and sink terms. In addition, by including the effects of the skewness β, the fractional order α, and the single relaxation time τ, the accuracy and convergence of the method have been assessed. The numerical predictions are compared with the analytical solutions, and they indicate that the method is second-order accurate. The method presented will allow the FADE to be more widely applied to complex mass transport problems in science and engineering.


Highly Crystalline Near-Infrared Acceptor Enabling Simultaneous Efficiency and Photostability Boosting in High-Performance Ternary Organic Solar Cells.
The near-infrared (NIR) absorbing fused-ring electron acceptor, COi8DFIC, has demonstrated very good photovoltaic performance when combined with PTB7-Th as a donor in binary organic solar cells (OSCs). In this work, the NIR acceptor was added to state-of-the-art PBDBT-2F:IT4F-based solar cells as a third component, leading to (i) an efficiency increase of the ternary devices compared to the binary solar cells in the presence of the highly crystalline COi8DFIC acceptor and (ii) much-improved photostability under 1-sun illumination. The electron transport properties were investigated and revealed the origin of the enhanced device performance. Compared to the binary cells, the optimized ternary PBDBT-2F:COi8DFIC:IT4F blends exhibit improved electron transport properties in the presence of 10% COi8DFIC, which is attributed to improved COi8DFIC molecular packing. Furthermore, transient absorption spectroscopy revealed a slow recombination of charge carriers in the ternary blend. The improved electron transport properties were preserved in the ternary OSC upon aging, while in the binary devices they seriously deteriorated after simulated 1-sun illumination of 240 h. Our work demonstrates a simple approach to enhance both OSC efficiency and photostability.


A Case Report of Acute Cellular Rejection Following Intestinal Transplantation Managed With Adalimumab.
There is a higher incidence of acute cellular rejection (ACR) in small bowel transplantation (SBT) compared with transplantation of other solid organs. Although there are reports on the use of infliximab to successfully treat ACR refractory to other treatments, there are no reports, to our knowledge, regarding the use of adalimumab. We present a case of a female patient with a history of Crohn's disease who underwent an isolated SBT and developed an episode of severe ACR. She was initially treated with methylprednisolone, thymoglobulin, basiliximab, and a dosage adjustment of tacrolimus. Results of repeat endoscopies and biopsies revealed no significant improvement. The patient initiated treatment with adalimumab every 2 weeks for a total of 6 months, in addition to maintenance treatment with prednisone and tacrolimus. Subsequent evaluations showed gradual improvement to normal mucosa and villi without ulceration. A regimen that incorporates adalimumab can thus be used to treat ACR after intestinal transplantation. Larger multicenter studies are needed to show the full efficacy of this therapeutic regimen.


Association of working shifts, inside and outside of healthcare, with severe COVID-19: an observational study.
Health and key workers have elevated odds of developing severe COVID-19; it is not known, however, if this is exacerbated in those with irregular work patterns. We aimed to investigate the odds of developing severe COVID-19 in health and shift workers. We included UK Biobank participants in employment or self-employed at baseline (2006-2010) and with linked COVID-19 data to 31st August 2020. Participants were grouped as neither a health worker nor shift worker (reference category) at baseline, health worker only, shift worker only, or both, and associations with severe COVID-19 investigated in logistic regressions. Of 235,685 participants (81·5% neither health nor shift worker, 1·4% health worker only, 16·9% shift worker only, and 0·3% both), there were 580 (0·25%) cases of severe COVID-19. The odds of severe COVID-19 was higher in health workers (adjusted odds ratio: 2·32 [95% CI: 1·33, 4·05]; shift workers (2·06 [1·72, 2·47]); and in health workers who worked shifts (7·56 [3·86, 14·79]). Being both a health worker and a shift worker had a possible greater impact on the odds of severe COVID-19 in South Asian and Black and African Caribbean ethnicities compared to White individuals. Both health and shift work (measured at baseline, 2006-2010) were independently associated with over twice the odds of severe COVID-19 in 2020; the odds were over seven times higher in health workers who work shifts. Vaccinations, therapeutic and preventative options should take into consideration not only health and key worker status but also shift worker status.


Effects of a transient noise reduction algorithm on speech intelligibility in noise, noise tolerance and perceived annoyance in cochlear implant users.
To evaluate the validity and efficacy of a transient noise reduction algorithm (TNR) in cochlear implant processing and the interaction of TNR with a continuous noise reduction algorithm (CNR). We studied the effects of TNR and CNR on the perception of realistic sound samples with transients, using subjective ratings of annoyance, a speech-in-noise test and a noise tolerance test. Participants were 16 experienced cochlear implant recipients wearing an Advanced Bionics Naida Q70 processor. CI users rated sounds with transients as moderately annoying. Annoyance was slightly, but significantly reduced by TNR. Transients caused a large decrease in speech intelligibility in noise and a moderate decrease in noise tolerance, measured on the Acceptable Noise Level test. The TNR had no significant effect on noise tolerance or on speech intelligibility in noise. The combined application of TNR and CNR did not result in interactions. The TNR algorithm was effective in reducing annoyance from transient sounds, but was not able to prevent a decreasing effect of transients on speech understanding in noise and noise tolerance. TNR did not reduce the beneficial effect of CNR on speech intelligibility in noise, but no cumulated improvement was found either.


Morphine-evoked release of adenosine from the spinal cord occurs via a nucleoside carrier with differential sensitivity to dipyridamole and nitrobenzylthioinosine.
We have investigated the potential role of a bi-directional nucleoside carrier in the release of endogenous adenosine from spinal cord synaptosomes by examining the effects of dipyridamole and nitrobenzylthioinosine (NBI) on evoked release of adenosine. When 40 pmol adenosine were added to synaptosomes, only 70 +/- 2% was recovered, suggesting 30% uptake of adenosine. Dipyridamole (0.1-10 microM) reduced this uptake and also increased basal adenosine release, probably due to inhibition of the re-uptake of adenosine derived from released nucleotide. In contrast, NBI (0.1-10 microM) had no effect on either uptake of added adenosine or on basal release of adenosine. Addition of K+ (24 mM) and morphine (10 microM) produced a 50-60% increase in the release of adenosine, and this was reduced 35-98% by both dipyridamole and NBI (0.01-10 microM). Dipyridamole (0.01-1 microM) had no effect on the release of nucleotides (detected as adenosine) induced by noradrenaline, 5-hydroxytryptamine (5-HT) and capsaicin (50 microM each), although 10 microM dipyridamole significantly reduced release evoked by noradrenaline and 5-HT. This latter effect of dipyridamole was determined not to be due to inhibition of ATP release when measured directly. Within the spinal cord, there is a removal system for adenosine which is dipyridamole-sensitive but NBI-insensitive. Release of adenosine, but not nucleotides, appears to occur via this carrier system. The inhibition of release by NBI, but its lack of effect on uptake, suggests the involvement of heterogeneous carrier molecules in adenosine uptake and release from the spinal cord.


Contezolid can replace linezolid in a novel combination with bedaquiline and pretomanid in a murine model of tuberculosis.
Contezolid is a new oxazolidinone with in vitro and in vivo activity against Mycobacterium tuberculosis comparable to that of linezolid. Pre-clinical and clinical safety studies suggest it may be less toxic than linezolid, making contezolid a potential candidate to replace linezolid in the treatment of drug-resistant tuberculosis. We evaluated the dose-ranging activity of contezolid, alone and in combination with bedaquiline and pretomanid, and compared it with linezolid at similar doses, in an established BALB/c mouse model of tuberculosis. Contezolid had an MIC of 1 µg/mL, similar to linezolid, and exhibited similar bactericidal activity in mice. Contezolid-resistant mutants selected in vitro had 32- to 64-fold increases in contezolid MIC and harbored mutations in the mce3R gene. These mutants did not display cross-resistance to linezolid. Our results indicate that contezolid has the potential to replace linezolid in regimens containing bedaquiline and pretomanid and likely other regimens.


The modified self: family caregivers' experiences of caring for a dying family member at home.
The aim of this study was to explore situations in daily life that challenge caregivers' self-image when caring for a dying family member at home. Background. Caregiving affects the health and daily lives of family caregivers. Patterns of challenging situations may provide insight into the home caregiving experience, thus contributing to our understanding of the influence it has on the caregivers' self-image. Qualitative descriptive study. Ten family caregivers who cared for a dying family member at home with support from an advanced home care team were interviewed 6-12 months after the death of the family member. The interviews were analysed with interpretive description. Result. Three patterns characterised the experiences of caregivers' daily lives in caring for a dying family member at home: challenged ideals, stretched limits and interdependency. These patterns formed the core theme, the modified self. Situations that challenged the caregivers' self-image were connected to experiences such as 'forbidden thoughts', intimacy and decreasing personal space. The caregivers met challenging situations in their daily lives that created a modified image of self. It is important to recognise the impact of caring for a dying family member at home. This study argues for supporting family caregivers to maximise their potential to handle the demanding everyday life with a dying family member at home. This study contributes to understanding situations in the home that may challenge caregivers' self-image and points out the importance of talking about caregiving experiences. From a clinical perspective, this study emphasises the significance of creating a climate, which allows family caregivers to express thoughts and feelings. Sharing experiences such as 'forbidden thoughts' can be one way of handling the profoundly changed every day life.


A mechanically coupled reaction-diffusion model for predicting the response of breast tumors to neoadjuvant chemotherapy.
There is currently a paucity of reliable techniques for predicting the response of breast tumors to neoadjuvant chemotherapy. The standard approach is to monitor gross changes in tumor size as measured by physical exam and/or conventional imaging, but these methods generally do not show whether a tumor is responding until the patient has received many treatment cycles. One promising approach to address this clinical need is to integrate quantitative in vivo imaging data into biomathematical models of tumor growth in order to predict eventual response based on early measurements during therapy. In this work, we illustrate a novel biomechanical mathematical modeling approach in which contrast enhanced and diffusion weighted magnetic resonance imaging data acquired before and after the first cycle of neoadjuvant therapy are used to calibrate a patient-specific response model which subsequently is used to predict patient outcome at the conclusion of therapy. We present a modification of the reaction-diffusion tumor growth model whereby mechanical coupling to the surrounding tissue stiffness is incorporated via restricted cell diffusion. We use simulations and experimental data to illustrate how incorporating tissue mechanical properties leads to qualitatively and quantitatively different tumor growth patterns than when such properties are ignored. We apply the approach to patient data in a preliminary dataset of eight patients exhibiting a varying degree of responsiveness to neoadjuvant therapy, and we show that the mechanically coupled reaction-diffusion tumor growth model, when projected forward, more accurately predicts residual tumor burden at the conclusion of therapy than the non-mechanically coupled model. The mechanically coupled model predictions exhibit a significant correlation with data observations (PCC = 0.84, p < 0.01), and show a statistically significant >4 fold reduction in model/data error (p = 0.02) as compared to the non-mechanically coupled model.


Optimism and recovery after acute coronary syndrome: a clinical cohort study.
Optimism is associated with reduced cardiovascular mortality, but its impact on recovery after acute coronary syndrome (ACS) is poorly understood. We hypothesized that greater optimism would lead to more effective physical and emotional adaptation after ACS and would buffer the impact of persistent depressive symptoms on clinical outcomes. This prospective observational clinical study took place in an urban general hospital and involved 369 patients admitted with a documented ACS. Optimism was assessed with a standardized questionnaire. The main outcomes were physical health status, depressive symptoms, smoking, physical activity, and fruit and vegetable consumption measured 12 months after ACS, and composite major adverse cardiac events (cardiovascular death, readmission with reinfarction or unstable angina, and coronary artery bypass graft surgery) assessed over an average of 45.7 months. We found that optimism predicted better physical health status 12 months after ACS independently of baseline physical health, age, sex, ethnicity, social deprivation, and clinical risk factors (B = 0.65, 95% confidence interval [CI] = 0.10-1.20). Greater optimism also predicted reduced risk of depressive symptoms (odds ratio = 0.82, 95% CI = 0.74-0.90), more smoking cessation, and more fruit and vegetable consumption at 12 months. Persistent depressive symptoms 12 months after ACS predicted major adverse cardiac events over subsequent years (odds ratio = 2.56, 95% CI = 1.16-5.67), but only among individuals low in optimism (optimism × depression interaction; p = .014). Optimism predicts better physical and emotional health after ACS. Measuring optimism may help identify individuals at risk. Pessimistic outlooks can be modified, potentially leading to improved recovery after major cardiac events.


Stabilization of ion concentration polarization using a heterogeneous nanoporous junction.
We demonstrate a recycled ion-flux through heterogeneous nanoporous junctions, which induce stable ion concentration polarization with an electric field. The nanoporous junctions are based on integration of ionic hydrogels whose surfaces are negatively or positively charged for cationic or anionic selectivity, respectively. Such heterogeneous junctions can be matched up in a way to achieve continuous ion-flux operation for stable concentration gradient or ionic conductance. Furthermore, the combined junctions can be used to accumulate ions on a specific region of the device.


Di-(2-ethylhexyl) phthalate-induced tumor growth is regulated by primary cilium formation via the axis of H2O2 production-thymosin beta-4 gene expression.
Di-(2-ethylhexyl) phthalate (DEHP) that is one of the most commonly used phthalates in manufacturing plastic wares regulates tumorigenesis. Thymosin beta-4 (TB4), an actin-sequestering protein, has been reported as a novel regulator to form primary cilia that are antenna-like organelles playing a role in various physiological homeostasis and pathological development including tumorigenesis. Here, we investigated whether DEHP affects tumor growth via primary cilium (PC) formation via the axis of TB4 gene expression and the production of reactive oxygen species (ROS). Tumor growth was increased by DEHP treatment that enhanced TB4 expression, PC formation and ROS production. The number of cells with primary cilia was enhanced time-dependently higher in HeLa cells incubated in the culture medium with 0.1% fetal bovine serum (FBS). The number of cells with primary cilia was decreased by the inhibition of TB4 expression. The incubation of cells with 0.1% FBS enhanced ROS production and the transcriptional activity of TB4 that was reduced by ciliobrevin A (CilioA), the inhibitor of ciliogenesis. ROS production was decreased by catalase treatment but not by mito-TEMPO, which affected to PC formation with the same trend. H2O2 production was reduced by siRNA-based inhibition of TB4 expression. H2O2 also increased the number of ciliated cells, which was reduced by siRNA-TB4 or the co-incubation with CilioA. Tumor cell viability was maintained by ciliogenesis, which was correlated with the changes of intracellular ATP amount rather than a simple mitochondrial enzyme activity. TB4 overexpression enhanced PC formation and DEHP-induced tumor growth. Taken together, data demonstrate that DEHP-induced tumor growth might be controlled by PC formation via TB4-H2O2 axis. Therefore, it suggests that TB4 could be a novel bio-marker to expect the risk of DEHP on tumor growth.


Expanding the diversity of mycobacteriophages: insights into genome architecture and evolution.
Mycobacteriophages are viruses that infect mycobacterial hosts such as Mycobacterium smegmatis and Mycobacterium tuberculosis. All mycobacteriophages characterized to date are dsDNA tailed phages, and have either siphoviral or myoviral morphotypes. However, their genetic diversity is considerable, and although sixty-two genomes have been sequenced and comparatively analyzed, these likely represent only a small portion of the diversity of the mycobacteriophage population at large. Here we report the isolation, sequencing and comparative genomic analysis of 18 new mycobacteriophages isolated from geographically distinct locations within the United States. Although no clear correlation between location and genome type can be discerned, these genomes expand our knowledge of mycobacteriophage diversity and enhance our understanding of the roles of mobile elements in viral evolution. Expansion of the number of mycobacteriophages grouped within Cluster A provides insights into the basis of immune specificity in these temperate phages, and we also describe a novel example of apparent immunity theft. The isolation and genomic analysis of bacteriophages by freshman college students provides an example of an authentic research experience for novice scientists.


Nanotherapeutic systems for local treatment of brain tumors.
Malignant brain tumor, including the most common type glioblastoma, are histologically heterogeneous and invasive tumors known as the most devastating neoplasms with high morbidity and mortality. Despite multimodal treatment including surgery, radiotherapy, chemotherapy, and immunotherapy, the disease inevitably recurs and is fatal. This lack of curative options has motivated researchers to explore new treatment strategies and to develop new drug delivery systems (DDSs); however, the unique anatomical, physiological, and pathological features of brain tumors greatly limit the effectiveness of conventional chemotherapy. In this context, we review the recent progress in the development of nanoparticle-based DDSs aiming to address the key challenges in transporting sufficient amount of therapeutic agents into the brain tumor areas while minimizing the potential side effects. We first provide an overview of the standard treatments currently used in the clinic for the management of brain cancers, discussing the effectiveness and limitations of each therapy. We then provide an in-depth review of nanotherapeutic systems that are intended to bypass the blood-brain barrier, overcome multidrug resistance, infiltrate larger tumorous tissue areas, and/or release therapeutic agents in a controlled manner. WIREs Nanomed Nanobiotechnol 2018, 10:e1479. doi: 10.1002/wnan.1479 This article is categorized under: Implantable Materials and Surgical Technologies > Nanomaterials and Implants Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.


Tubal ligation and the risk of ovarian cancer: review and meta-analysis.
The reduction of ovarian cancer (OC) risk in women with a history of tubal ligation (TL) has been reported repeatedly, mostly on small populations. We have aimed to provide a critical overview of the studies available to date and to conduct a meta-analysis. There were 40 relevant studies identified. The studies were divided into two groups for strict and extended meta-analysis, respectively. Subgroup analysis was performed for age, time dependency since TL, histological types of OC and BReast CAncer (BRCA) mutation. Meta-analysis of 13 strictly selected studies showed a reduced risk of epithelial OC by 34%. The protective effect of TL was confirmed even in a subgroup of women 10-14 years after the procedure. The risk reduction was confirmed for the endometrioid (RR = 0.40) and serous (RR = 0.73) cancers but not for mucinous. The review of relevant articles, as well as the meta-analysis of selected studies, yields consistent data on a significant reduction of OC risk in women who had undergone TL. The results of this meta-analysis should provide an impulse for further research on the etiology of ovarian epithelial cancers, focusing particularly on the importance of retrograde transport of endometrial cells.


Carbonic anhydrase IX is a prognostic biomarker in glioblastoma multiforme.
The identification of prognostic factors in patients with glioblastoma multiforme (GBM) represents an area of increasing interest. Carbonic anhydrase IX (CA-IX), a hypoxia marker, correlates with tumor progression in a variety of human cancers. However, the role of CA-IX in GBM remains largely unknown. In the present study, we evaluated the prognostic role of CA-IX in GBM patients. In total, 66 consecutive patients with GBM who received concomitant chemoradiotherapy and adjuvant chemotherapy with temozolomide were retrospectively reviewed, and all patients received temozolomide chemotherapy for at least 3 months. Kaplan-Meier curves and log-rank tests were used for analysis of progression-free survival (PFS) and overall survival (OS), and a multivariate Cox proportional hazard model was employed to identify factors with an independent effect on survival. The median OS was longer in patients with low levels of CA-IX expression (18 months) compared to patients overexpressing CA-IX (9 months) (P = 0.004). There was not a statistically significant difference in median PFS (3.5 vs. 8 months, P = 0.054) between patients with high or low levels of CA-IX expression. In multivariate analysis, the variables that were identified as significant prognostic factors for OS were preoperative Karnofsky performance scale score (KPS) (hazard ratio (HR), 3.703; P = 0.001), CA-IX overexpression (HR, 1.967; P = 0.019), and incomplete adjuvant temozolomide treatment (HR, 2.241; P = 0.003) and gross-total resection (HR, 1.956; P = 0.034). Our findings indicated that CA-IX may be a potential prognostic biomarker in the treatment of GBM.


Substrate binding on the APC/C occurs between the coactivator Cdh1 and the processivity factor Doc1.
The anaphase-promoting complex/cyclosome (APC/C) is a 22S ubiquitin ligase complex that initiates chromosome segregation and mitotic exit. We have used biochemical and electron microscopic analyses of Saccharomyces cerevisiae and human APC/C to address how the APC/C subunit Doc1 contributes to recruitment and processive ubiquitylation of APC/C substrates, and to understand how APC/C monomers interact to form a 36S dimeric form. We show that Doc1 interacts with Cdc27, Cdc16 and Apc1 and is located in the vicinity of the cullin-RING module Apc2-Apc11 in the inner cavity of the APC/C. Substrate proteins also bind in the inner cavity, in close proximity to Doc1 and the coactivator Cdh1, and induce conformational changes in Apc2-Apc11. Our results suggest that substrates are recruited to the APC/C by binding to a bipartite substrate receptor composed of a coactivator protein and Doc1.


Cardiac parasympathetic dysfunction concurrent with cardiac sympathetic denervation in Parkinson's disease.
We aimed to characterize the relationship between cardiac sympathetic and parasympathetic dysfunction employing cardiac (123)I-meta-iodobenzylguanidine (MIBG) uptake and other autonomic function parameters in Parkinson's disease (PD). 79 PD patients were studied. We performed (123)I-MIBG myocardial scintigraphy to assess the extent of cardiac sympathetic denervation. Electrocardiogram readings at rest and postural change in blood pressure were also examined. Coefficient variation of RR intervals (CVR-R) was used as an index for cardiac parasympathetic activity. Cardiac (123)I-MIBG uptake did not vary significantly among the Hoehn-Yahr (H-Y) stages. There was a significant correlation between cardiac (123)I-MIBG uptake and CVR-R (early, r=0.457, p<0.001; late, r=0.442, p<0.001). While the correlation was present among the patients who had had the disease less than two years (early, r=0.558, p<0.001; late, r=0.530, p<0.001), the patients with the disease duration longer than two years did not have such a significant correlation. Age, disease duration, corrected QT interval, or postural blood pressure change did not correlate with cardiac (123)I-MIBG uptake. Orthostatic hypotension was observed in 13 out of 72 subjects, and reduced CVR-R was a major determinant for the development of orthostatic hypotension. We conclude that cardiac parasympathetic dysfunction occurs concurrent with sympathetic denervation as revealed by (123)I-MIBG myocardial scintigraphy in PD and contributes to the development of orthostatic hypotension.


Functional expression of an inactivating potassium channel cloned from human heart.
Recently a putative K+ channel with homology to the Shaker family of potassium channels has been cloned from human ventricular myocardium. However, proof that the cDNA encodes a K+ channel requires appropriate translation and expression of a functional ion-selective channel. Therefore, expression of this putative human K+ channel DNA was attempted by cytoplasmic injections of in vitro transcribed cRNA into Xenopus laevis oocytes and screening by two-electrode voltage-clamp methods. This resulted in expression of voltage-gated channels that rapidly inactivated (time constant of inactivation, 47.6 +/- 3.6 msec; 0 mV; n = 10) and were at least 50 times more selective for K+ than Na+ (Na+/K+ permeability ratio of 0.02). The channels showed voltage-dependent activation (half-maximal voltage, -34 +/- 0.7 mV; n = 5), and 50% of the channels were inactivated within 2 seconds when the membrane potential was clamped near -60 mV (half-maximal voltage, -62 +/- 7 mV; n = 10). The expressed protein resulted in a K+ current that had many properties similar to the 4-aminopyridine-sensitive calcium-insensitive component of the cardiac transient outward current that is observed in native cardiac myocytes and thus may serve as one molecular substrate for this current.


Induced growth of asymmetric nanocantilever arrays on polar surfaces.
We report that the Zn-terminated ZnO (0001) polar surface is chemically active and the oxygen-terminated (000(-)1) polar surface is inert in the growth of nanocantilever arrays. Longer and wider "comblike" nanocantilever arrays are grown from the (0001)-Zn surface, which is suggested to be a self-catalyzed process due to the enrichment of Zn at the growth front. The chemically inactive (0001;)-O surface typically does not initiate any growth, but controlling experimental conditions could lead to the growth of shorter and narrower nanocantilevers from the intersections between (000(-)1)-O with +/- (01(-)10) surfaces.


Incidence of genitofemoral nerve block during lumbar sympathetic block: comparison of two lumbar injection sites.
Genitofemoral nerve (GFN) block is a known side effect of a lumbar sympathetic block (LSB), although the incidence has not been well documented. Furthermore, genitofemoral neuralgia can occur following neurolytic LSB. Because the level at which the GFN exits the psoas sheath varies, this study was designed to identify differences in the incidence of GFN block following LSB at the level of the second versus the fourth lumbar vertebrae. Patients requiring LSB to evaluate chronic lower extremity pain were prospectively studied. Patients were injected at the second lumbar (L2 group) or fourth lumbar (L4 group) vertebral body depending on the location of the pain syndrome in the lower extremity. Lumbar sympathetic blocks were performed using 10 mL of a 0.5% bupivacaine solution with radiocontrast; spread of injectate was verified using fluoroscopy. An observer evaluating for presence of GFN block was blinded to the lumbar level of injection. Thirty patients were enrolled (L2 group, n = 15; L4 group, n = 15). Spread of local anesthetic/radiocontrast solution was limited to approximately one vertebral body above and one below the target level. There was no difference in the ability to achieve a LSB; success rates were 66% and 73% using L2 and L4, respectively. The incidence of GFN block was 0% (0/15) in the L2 group versus 40% (6/15) in the L4 group; this was statistically significant (P = .017, Fisher's exact test). The GFN is less likely to be blocked when the LSB is performed near the second lumbar vertebra as compared with the fourth lumbar vertebra.


Biogenesis of mitochondrial heme lyases in yeast. Import and folding in the intermembrane space.
Heme lyases are components of the mitochondrial intermembrane space facilitating the covalent attachment of heme to the apoforms of c-type cytochromes. The precursors of heme lyases are synthesized in the cytosol without the typical N-terminal mitochondrial targeting signal. Here, we have analyzed the mode of import and folding of the two heme lyases of the yeast Saccharomyces cerevisiae, namely of cytochrome c heme lyase and of cytochrome c1 heme lyase. For transport into mitochondria, both proteins use the general protein import machinery of the outer membrane. Import occurred independently of a membrane potential, delta psi, across the inner membrane and ATP in the matrix space, suggesting that the inner membrane is not required for transport along this direct sorting pathway. The presence of a large folded domain in heme lyases was utilized to study their folding in the intermembrane space. Formation of this domain occurred at the same rate as import, indicating that heme lyases fold either during or immediately after their transfer across the membrane. Folding was not affected by depletion of ATP and delta psi or by inhibitors of peptidylprolyl cis-trans isomerases, i.e. it does not involve homologs of known folding factors (like Hsp60 and Hsp70). The energy derived from folding cannot be regarded as a major driving force for import, since the folded domain could be imported into mitochondria with the same efficiency as the intact protein. We conclude that protein folding in the intermembrane space obeys principles different from those established for other subcellular compartments.