Psychotic disorders and repeat offending: systematic review and meta-analysis.
To undertake a systematic review and meta-analysis on the risk of repeat offending in individuals with psychosis and to assess the effect of potential moderating characteristics on risk estimates. A systematic search was conducted in 6 bibliographic databases from January 1966 to January 2009, supplemented with correspondence with authors. Studies that reported risks of repeat offending in individuals with psychotic disorders (n = 3511) compared with individuals with other psychiatric disorders (n = 5446) and healthy individuals (n = 71 552) were included. Risks of repeat offending were calculated using fixed- and random-effects models to calculate pooled odds ratios (ORs). Subgroup and meta-regression analyses were conducted to examine how risk estimates were affected by various study characteristics including mean sample age, study location, sample size, study period, outcome measure, duration of follow-up, and diagnostic criteria. Twenty-seven studies, which included 3511 individuals with psychosis, were identified. Compared with individuals without any psychiatric disorders, there was a significantly increased risk of repeat offending in individuals with psychosis (pooled OR = 1.6, 95% confidence interval [CI] = 1.4-1.8), although this was only based on 4 studies. In contrast, there was no association when individuals with other psychiatric disorders were used as the comparison group (pooled OR = 1.0, 95% CI = 0.7-1.3), although there was substantial heterogeneity. Higher risk estimates were found in female-only samples with psychosis and in studies conducted in the United States. The association between psychosis and repeat offending differed depending on the comparison group. Despite this, we found no support for the findings of previous reviews that psychosis is associated with a lower risk of repeat offending.


Physicochemical characterization of airborne particulate matter at a mainline underground railway station.
Underground railway stations are known to have elevated particulate matter (PM) loads compared to ambient air. As these particles are derived from metal-rich sources and transition metals may pose a risk to health by virtue of their ability to catalyze generation of reactive oxygen species (ROS), their potential enrichment in underground environments is a source of concern. Compared to coarse (PM10) and fine (PM2.5) particulate fractions of underground railway airborne PM, little is known about the chemistry of the ultrafine (PM0.1) fraction that may contribute significantly to particulate number and surface area concentrations. This study uses inductively coupled plasma mass spectrometry and ion chromatography to compare the elemental composition of size-fractionated underground PM with woodstove, roadwear generator, and road tunnel PM. Underground PM is notably rich in Fe, accounting for greater than 40% by mass of each fraction, and several other transition metals (Cu, Cr, Mn, and Zn) compared to PM from other sources. Importantly, ultrafine underground PM shows similar metal-rich concentrations as the coarse and fine fractions. Scanning electron microscopy revealed that a component of the coarse fraction of underground PM has a morphology indicative of generation by abrasion, absent for fine and ultrafine particulates, which may be derived from high-temperature processes. Furthermore, underground PM generated ROS in a concentration- and size-dependent manner. This study suggests that the potential health effects of exposure to the ultrafine fraction of underground PM warrant further investigation as a consequence of its greater surface area/volume ratio and high metal content.


An Analysis of Endocannabinoid Concentrations and Mood Following Singing and Exercise in Healthy Volunteers.
The euphoric feeling described after running is, at least in part, due to increased circulating endocannabinoids (eCBs). eCBs are lipid signaling molecules involved in reward, appetite, mood, memory and neuroprotection. The aim of this study was to investigate whether activities other than running can increase circulating eCBs. Nine healthy female volunteers (mean 61 years) were recruited from a local choir. Circulating eCBs, haemodynamics, mood and hunger ratings were measured before and immediately after 30 min of dance, reading, singing or cycling in a fasted state. Singing increased plasma levels of anandamide (AEA) by 42% (P < 0.05), palmitoylethanolamine (PEA) by 53% (P < 0.01) and oleoylethanolamine (OEA) by 34% (P < 0.05) and improved positive mood and emotions (P < 0.01), without affecting hunger scores. Dancing did not affect eCB levels or hunger ratings, but decreased negative mood and emotions (P < 0.01). Cycling increased OEA levels by 26% (P < 0.05) and tended to decrease how hungry volunteers felt, without affecting mood. Reading increased OEA levels by 28% (P < 0.01) and increased the desire to eat. Plasma AEA levels were positively correlated with how full participants felt (P < 0.05). Plasma OEA levels were positively correlated with positive mood and emotions (P < 0.01). All three ethanolamines were positively correlated with heart rate (HR; P < 0.0001). These data suggest that activities other than running can increase plasma eCBs associated with changes in mood or appetite. Increases in eCBs may underlie the rewarding and pleasurable effects of singing and exercise and ultimately some of the long-term beneficial effects on mental health, cognition and memory.


Toll-like receptors and atherosclerosis: key contributors in disease and health?
The identification of Toll-like receptors (TLRs) as key patternrecognition receptors of innate immunity has opened inquiries into previously unknown disease mechanisms. The ability of TLRs to detect a spectrum of pathogen-derived molecules defines their importance in innate immunity and provides a mechanistic link between infection and disease. Atherosclerosis is a chronic inflammatory disease where immune and metabolic factors interact to initiate and propagate arterial lesions. An understanding of TLRs in atherosclerosis could clarify the etiology of this complex process. Furthermore, the existence of host-derived endogenous TLR ligands may implicate TLR involvement in disease mechanisms beyond innate immunity, such as a role in homeostatic mechanisms to resolve injury. Our current knowledge of TLRs in atherosclerosis is discussed in this review with emphasis on experimental studies in atherosclerosis-susceptible mouse models. Highlights from studies of TLR involvement in other disease processes have demonstrated that TLR-dependent mechanisms probably parallel those found in atherosclerosis, some of which could be important in mitigating atherosclerotic injury. Finally, an appreciation of the pro- and anti-atherosclerotic mechanisms of TLR activation over the entire lifetime of an organism will provide clues to the role of TLRs in both health and disease.


Use of colonoscopy to screen asymptomatic adults for colorectal cancer. Veterans Affairs Cooperative Study Group 380.
The role of colonoscopy in screening for colorectal cancer is uncertain. At 13 Veterans Affairs Medical Centers, we performed colonoscopy to determine the prevalence and location of advanced colonic neoplasms and the risk of advanced proximal neoplasia in asymptomatic patients (age range, 50 to 75 years) with or without distal neoplasia. Advanced colonic neoplasia was defined as an adenoma that was 10 mm or more in diameter, a villous adenoma, an adenoma with high-grade dysplasia, or invasive cancer. In patients with more than one neoplastic lesion, classification was based on the most advanced lesion. Of 17,732 patients screened for enrollment, 3196 were enrolled; 3121 of the enrolled patients (97.7 percent) underwent complete examination of the colon. The mean age of the patients was 62.9 years, and 96.8 percent were men. Colonoscopic examination showed one or more neoplastic lesions in 37.5 percent of the patients, an adenoma with a diameter of at least 10 mm or a villous adenoma in 7.9 percent, an adenoma with high-grade dysplasia in 1.6 percent, and invasive cancer in 1.0 percent. Of the 1765 patients with no polyps in the portion of the colon that was distal to the splenic flexure, 48 (2.7 percent) had advanced proximal neoplasms. Patients with large adenomas (> or = 10 mm) or small adenomas (< 10 mm) in the distal colon were more likely to have advanced proximal neoplasia than were patients with no distal adenomas (odds ratios, 3.4 [95 percent confidence interval, 1.8 to 6.5] and 2.6 (95 percent confidence interval, 1.7 to 4.1], respectively). However, 52 percent of the 128 patients with advanced proximal neoplasia had no distal adenomas. Colonoscopic screening can detect advanced colonic neoplasms in asymptomatic adults. Many of these neoplasms would not be detected with sigmoidoscopy.


A new species of Corydalus Latreille from Venezuela (Megaloptera, Corydalidae).
A new species of dobsonfly, Corydalus wanningeri, from Venezuela, is described and illustrated. It superficially resembles Corydalus neblinensis Contreras-Ramos, with a uniform reddish coloration of body and wings. Yet, because of male genitalic structure it might be closely related to Corydalus crossi Contreras-Ramos. Specimens were collected from a rain forest transitional zone between the Orinoco lowlands and the Gran Sabana plateau, in Bolívar state. This is the 15(th) species of Corydalus to be recorded from Venezuela, rendering this the country with the highest number of documented Corydalus species. A key to the sexually dimorphic, long-mandibled Venezuelan species of the genus is provided.


Treatment of Philadelphia-positive chronic myeloid leukemia with imatinib: importance of a stable molecular response.
The achievement of a major molecular response (MMolR) at 12 months is a surrogate marker of progression-free survival in chronic myeloid leukemia patients treated with imatinib. We evaluated the prognostic value of the long-term evolution of the molecular response based on a retrospective analysis of 130 late chronic phase chronic myeloid leukemia patients who achieved a complete cytogenetic response (CCgR) with 400 mg/d imatinib and have now a median follow-up of 72 months (range, 48-77). In 71 (55%) patients, molecular response was consistently major (stable MMolR); in 19 (15%) patients, molecular response was occasionally less than major (unstable MMolR); in 40 (30%) patients, MMolR was never achieved (never MMolR) during all the course of CCgR. Patients with stable MMolR had a longer CCgR duration and a significantly better progression-free survival compared with patients with absent or unstable MMolR. The achievement of a MMolR, if maintained continuously, conferred a marked long-term stability to the CCgR: patients with a stable MMolR have a significantly lower risk of losing the CCgR than patients with unstable and never MMolR (4% versus 21%, P = 0.03, and 4% versus 33%, P < 0.0001, respectively). Finally, if a MMolR is not maintained consistently, the risk of losing the CCgR is higher but not significantly than if it is never achieved (33% versus 21%, P = 0.5). These data confirm that achieving a MMolR is prognostically important but point out that the prognostic value of achieving a MMolR is greater if the response is confirmed and stable.


The role of fearless dominance in psychopathy: confusions, controversies, and clarifications.
Based on their 2011 meta-analysis of the correlates of the Psychopathic Personality Inventory (PPI), Miller and Lynam (An examination of the Psychopathic Personality Inventory's nomological network: A meta-analytic review, Personality Disorders: Theory, Research, and Treatment, 3, 305-326) conclude that its Fearless Dominance (PPI-FD) higher-order dimension exhibits weak construct validity, leading them to question the relevance of boldness to the conceptualization and assessment of psychopathy. We examine their assertions in light of the clinical, conceptual, and empirical literatures on psychopathy. We demonstrate that Miller and Lynam's assertions (a) are sharply at odds with evidence that well-validated psychopathy measures detect both secondary and primary subtypes, the latter of which is linked to social poise and immunity to psychological distress, (b) are inconsistent with most classic clinical descriptions of psychopathy, in which fearless dominance plays a key role, (c) presume an a priori nomological network of psychopathy that leaves scant room for adaptive functioning and renders psychopathy largely equivalent to antisocial personality disorder as defined by the Diagnostic and Statistical Manual of Mental Disorders, (d) are premised on a misunderstanding of the role of Cleckley's "mask" of healthy adjustment in psychopathy, and (e) are contradicted by data-some reported elsewhere by Miller and Lynam themselves-that PPI-FD is moderately to highly associated with scores on several well-validated psychopathy measures, as well as with personality traits and laboratory markers classically associated with psychopathy. A scientific approach to psychopathy requires the question of whether its subdimensions are linked to adaptive functioning to be adjudicated by data, not by fiat.


Neurodevelopmental and perinatal correlates of simple brain metrics in very preterm infants.
To explore perinatal correlates of 3 simple measures of brain size, known as metrics, in very preterm infants at term-equivalent age and their relationship to 2-year neurodevelopmental outcomes. Prospective cohort study of preterm infants born at a gestational age of less than 30 weeks or a weight of less than 1250 g between April 1, 2001, and December 31, 2003, and followed up at 2 years of corrected age. The Royal Women's Hospital and the magnetic resonance imaging unit at the Royal Children's Hospital. Two hundred thirty-six preterm infants. Brain metrics--biparietal, bifrontal, and transverse cerebellar diameters--on magnetic resonance imaging for preterm infants at term-equivalent age and neurodevelopmental assessments at 2 years of corrected age. Mental Development Index and the Psychomotor Development Index of the Bayley Scales of Infant Development-Revised. Higher birth weight z score, shorter duration of assisted ventilation, and postmenstrual age at magnetic resonance imaging were independently associated with increases in the 3 brain metrics, and male sex was associated with larger bifrontal and biparietal diameters. Only the biparietal diameter was predictive of cognitive and motor indices after adjustment for perinatal variables and social risk. This study provides further evidence of altered brain growth in preterm infants, relating to growth restriction and severity of illness, that in turn relate to neurodevelopmental outcome.


IL-6 blockade inhibits the induction of myelin antigen-specific Th17 cells and Th1 cells in experimental autoimmune encephalomyelitis.
The development of Th17 cells is a key event in the pathogenesis of experimental autoimmune encephalomyelitis (EAE), a murine model of human multiple sclerosis (MS). Previous studies have demonstrated that an IL-6-dependent pathway is involved in the differentiation of Th17 cells from naïve CD4-positive T cells in vitro. However, the role of IL-6 in vivo in the development of Th17 cells in EAE has remained unclear. In the present study, we found that IL-6 blockade by treatment with an anti-IL-6 receptor monoclonal antibody (anti-IL-6R mAb) inhibited the development of EAE and inhibited the induction of myelin oligodendrocyte glycoprotein (MOG) peptide-specific CD4-positive, CD8-positive, and Th17 T cells, in inguinal lymph nodes. Thus, the protective effect of IL-6 blockade in EAE is likely to be mediated via the inhibition of the development of MOG-peptide-specific Th17 cells and Th1 cells, which in turn leads to reduced infiltration of T cells into the CNS. These findings indicate that anti-IL-6R mAb treatment might represent a novel therapy for human MS.


Resource utilization and convalescent care cost in neonatal opioid withdrawal syndrome.
Neonatal opioid withdrawal syndrome (NOWS) is a growing public health problem associated with complex and prolonged medical care and a significant resource utilization burden. The objective of this study was to compare the cost of different convalescent care settings for infants with NOWS. Retrospective comparison study of infants with NOWS discharged directly from NICU, transferred to an acute care pediatric floor (PPCU) or rehabilitation hospital (PRH). Primary outcomes were length of stay (LOS) and cost of stay (COS). Infants had 1.3 (95% CI: 1.1,1.6) times and 2.5 (95% CI: 2.1,3.1) times significantly longer mean LOS for PPCU and RH discharges compared to NICU discharges. NICU discharged infants had the lowest mean COS ($25,745.00) and PRH the highest ($60,528.00), despite PRH having a lower cost per day. PRH discharged infants had higher rates of methadone and benzodiazepine and less buprenorphine exposure than NICU/PPCU discharged. Infants born to mothers on marijuana and buprenorphine had a 28% lower mean COS compared to unexposed infants. Median treatment cumulative morphine doses were six-fold higher for PRH than NICU discharge. Infants transferred to convalescence care facilities had longer and more costly admissions and received more medication. However, there may be a role for earlier transfer of a subset of infants at-risk for longer LOS as those exposed to methadone and/or benzodiazepines. Further studies exploring differences in resource utilization, convalescent care delivery and cost expenditure are recommended.


Attachment anxiety benefits from security priming: Evidence from working memory performance.
The present study investigates the relationship between the attachment dimensions (anxious vs. avoidance) and the cognitive performance of individuals, specifically whether the attachment dimensions would predict the working memory (WM) performance. In the n-back task, reflecting the WM capacity, both attachment related and non-attachment related words were used. Participants were randomly assigned into two groups that received either the secure or the neutral subliminal priming. In the secure priming condition, the aim was to induce sense of security by presenting secure attachment words prior to the n-back task performance. In neutral priming condition, neutral words that did not elicit sense of security were presented. Structural equation modeling revealed divergent patterns for attachment anxiety and avoidance dimensions under the different priming conditions. In neutral priming condition, WM performance declined in terms of capacity in the n-back task for individuals who rated higher levels of attachment anxiety. However in the secure priming condition, WM performance was boosted in the n-back task for individuals who rated higher levels of attachment anxiety. In other words, the subliminal priming of the security led to increased WM capacity of individuals who rated higher levels of attachment anxiety. This effect, however, was not observed for higher levels of attachment avoidance. Results are discussed along the lines of hyperactivation and deactivation strategies of the attachment system.


Development and functional analysis of novel genetic promoters using DNA shuffling, hybridization and a combination thereof.
Development of novel synthetic promoters with enhanced regulatory activity is of great value for a diverse range of plant biotechnology applications. Using the Figwort mosaic virus full-length transcript promoter (F) and the sub-genomic transcript promoter (FS) sequences, we generated two single shuffled promoter libraries (LssF and LssFS), two multiple shuffled promoter libraries (LmsFS-F and LmsF-FS), two hybrid promoters (FuasFScp and FSuasFcp) and two hybrid-shuffled promoter libraries (LhsFuasFScp and LhsFSuasFcp). Transient expression activities of approximately 50 shuffled promoter clones from each of these libraries were assayed in tobacco (Nicotiana tabacum cv. Xanthi) protoplasts. It was observed that most of the shuffled promoters showed reduced activity compared to the two parent promoters (F and FS) and the CaMV35S promoter. In silico studies (computer simulated analyses) revealed that the reduced promoter activities of the shuffled promoters could be due to their higher helical stability. On the contrary, the hybrid promoters FuasFScp and FSuasFcp showed enhanced activities compared to F, FS and CaMV 35S in both transient and transgenic Nicotiana tabacum and Arabidopsis plants. Northern-blot and qRT-PCR data revealed a positive correlation between transcription and enzymatic activity in transgenic tobacco plants expressing hybrid promoters. Histochemical/X-gluc staining of whole transgenic seedlings/tissue-sections and fluorescence images of ImaGene Green™ treated roots and stems expressing the GUS reporter gene under the control of the FuasFScp and FSuasFcp promoters also support the above findings. Furthermore, protein extracts made from protoplasts expressing the human defensin (HNP-1) gene driven by hybrid promoters showed enhanced antibacterial activity compared to the CaMV35S promoter. Both shuffled and hybrid promoters developed in the present study can be used as molecular tools to study the regulation of ectopic gene expression in plants.


Functional imaging of proteolysis: stromal and inflammatory cells increase tumor proteolysis.
The underlying basement membrane is degraded during progression of breast and colon carcinoma. Thus, we imaged degradation of a quenched fluorescent derivative of basement membrane type IV collagen (DQ-collagen IV) by living human breast and colon tumor spheroids. Proteolysis of DQ-collagen IV by HCT 116 and HKh-2 human colon tumor spheroids was both intracellular and pericellular. In contrast, proteolysis of DQ-collagen IV by BT20 human breast tumor spheroids was pericellular. As stromal elements can contribute to proteolytic activities associated with tumors, we also examined degradation of DQ-collagen IV by human monocytes/macrophages and colon and breast fibroblasts. Fibroblasts themselves exhibited a modest amount of pericellular degradation. Degradation was increased 4-17-fold in cocultures of fibroblasts and tumor cells as compared to either cell type alone. Inhibitors of matrix metalloproteinases, plasmin, and the cysteine protease, cathepsin B, all reduced degradation in the cocultures. Monocytes did not degrade DQ-collagen IV; however, macrophages degraded DQ-collagen IV intracellularly. In coculture of tumor cells, fibroblasts, and macrophages, degradation of DQ-collagen IV was further increased. Imaging of living tumor and stromal cells has, thus, allowed us to establish that tumor proteolysis occurs pericellularly and intracellularly and that tumor, stromal, and inflammatory cells all contribute to degradative processes.


Fine structure of virus chromatin in thin sections of SV40-infected cells: a cytochemical and autoradiographical study.
The ultrastructural organization of virus chromatin was studied within nuclei prepared from CV1 cells (cultured monkey kidney cells) lytically infected with SV40 virus (simian virus 40) by a procedure which allows a mild loosening of nucleoproteins. In addition to dispersed host components, DNA-containing nucleoplasmic structures could be identified as virus chromatin. Both standard staining for structure and specific staining for DNA clearly revealed in thin sections the nucleosomal structure of well-extended virus chromatin as well as alignments of virions on host chromatin. In addition, replicating and transcribing virus chromatins were abundant as revealed by high-resolution autoradiography. Therefore, the procedure of loosening of nucleoproteins used in this report also preserves the active SV40 chromatin and allows the in situ visualization in Epon sections of transcription and replication of the virus genome.


A detailed study of patients and tumor characteristics of epithelial ovarian cancer in Saudi women.
The Saudi population is characterized by high parity and intermarriages that may impact ovarian carcinogenesis. Herein, we analyzed the tumor characteristics and outcomes in Saudi patients with epithelial ovarian cancer (EOC). Patients with EOC treated at King Faisal Specialist Hospital and Research Center during 1995-2007 were identified retrospectively through a review of their medical records. Patients' and tumor characteristics were collected including age at diagnosis, marital status, parity, histology, stage, treatment rendered, and follow-up data. One hundred-ninety-three patients with EOC were identified in this cohort. The mean age of the patients was 55 ± 15 years, the mean ± SD body mass index was 27.0 ± 5.6 kg/m, and the median parity was approximately 7.0. Whereas 4 patients reported a family history of cancer, 164 women reported negative family history; and it was unknown in 27 cases. Tumor distribution by International Federation of Gynecology and Obstetrics stage was the following: 12 patients (6.2%) had stage I disease at diagnosis, 1 patient (0.5%) stage II disease, 130 patients (67.4%) stage III disease, 39 patients (20.2%) stage IV disease, and that of 11 patients (5.7%) was unknown. Information on residual disease after surgery was available on 98 patients with optimal debulking (<1 cm) achieved in 61 cases. Median progression-free survival from end of chemotherapy to recurrence/progression was 11.9 months (95% confidence interval, 9.4-15.2). Tumor histology, size of residual disease, and stage at diagnosis were significant prognostic factors. The patients' age, body mass index, tumor histology, and grade had no impact on survival. Patients presenting with advanced-stage disease are higher among Saudis than those reported in global literature. Despite high intermarriage rates, reported family history for related cancers was quite low in this cohort. Notably, this is the first study evaluating EOC in Saudi patients.


Can passive mobilization provide clinically-relevant brain stimulation? A pilot EEG and NIRS study on healthy subjects.
Lower limb rehabilitation is a fundamental part of post-acute care in neurological disease. Early commencement of active workout is often prevented by paresis, thus physical treatment may be delayed until patients regain some voluntary command of their muscles. Passive mobilization of the affected joints is mostly delivered in order to safeguard tissue properties and shun circulatory problems. The present paper investigates the potential role of early passive motion in stimulating cortical areas of the brain devoted to the control of the lower limb. An electro-mechanical mobilizer for the ankle joint (Toe-Up!) was implemented utilizing specially-designed shape-memory-alloy-based actuators. This device was constructed to be usable by bedridden subjects. Besides, the slowness and gentleness of the imparted motion, make it suitable for patients in a very early stage of their recovery. The mobilizer underwent technical checks to confirm reliability and passed the required safety tests for electric biomedical devices. Four healthy volunteers took part in the pre-clinical phase of the study. The protocol consisted in measuring of brain activity by EEG and NIRS in four different conditions: rest, active dorsiflexion of the ankle, passive mobilization of the ankle, and assisted motion of the same joint. The acquired data were processed to obtain maps of cortical activation, which were then compared. The measurements collected so far show that there is a similar pattern of activity between active and passive/assisted particularly in the contralateral premotor areas. This result, albeit based on very few observations, might suggest that passive motion provides somatosensory afferences that are processed in a similar manner as for voluntary control. Should this evidence be confirmed by further trials on healthy individuals and neurological patients, it could form a basis for a clinical use of early passive exercise in supporting central functional recovery.


Current trends in the management of difficult urinary catheterizations.
Routine urinary catheter placement may cause trauma and poses a risk of infection. Male catheterization, in particular, can be difficult, especially in patients with enlarged prostate glands or other potentially obstructive conditions in the lower urinary tract. Solutions to problematic urinary catheterization are not well known and when difficult catheterization occurs, the risk of failed catheterization and concomitant complications increase. Repeated and unsuccessful attempts at urinary catheterization induce stress and pain for the patient, injury to the urethra, potential urethral stricture requiring surgical reconstruction, and problematic subsequent catheterization. Improper insertion of catheters also can significantly increase healthcare costs due to added days of hospitalization, increased interventions, and increased complexity of follow-up evaluations. Improved techniques for catheter placement are essential for all healthcare personnel involved in the management of the patient with acute urinary retention, including attending emergency physicians who often are the first physicians to encounter such patients. Best practice methods for blind catheter placement are summarized in this review. In addition, for progressive clinical practice, an algorithm for the management of difficult urinary catheterizations that incorporates technology enabling direct visualization of the urethra during catheter insertion is presented. This algorithm will aid healthcare personnel in decision making and has the potential to improve quality of care of patients.


Arterial stiffness throughout pregnancy: Arteriograph device-specific reference ranges based on a low-risk population.
The maternal cardiovascular system undergoes significant adaptation during pregnancy. We aimed to examine the changes in arterial stiffness parameters during normal pregnancy and establish reference ranges for the general population. We performed a prospective cross-sectional observational study at the University Hospitals of Leicester. We included low-risk healthy pregnant women with singleton and viable pregnancies with no evidence of foetal abnormality or aneuploidy. Smokers, women with pre-existing or gestational hypertensive disorders and diabetes, booking BMI at least 30, on medication that could affect cardiac function and/or those who delivered before 37 completed weeks of gestation, and/or a neonate with birthweight less than 10th centile were excluded. Brachial (BrAIx) and aortic augmentation indices (AoAIx), and pulse wave velocity (PWV) were assessed using the Arteriograph. Data were analysed using a linear mixed model. We analysed a total of 571 readings from 259 women across different gestational ages and present the 10th, 25th, 50th, 75th and 90th centiles for BrAIx, AoAIx and PWV from 12+0 to 42+0 weeks' gestation. All haemodynamic variables were significantly associated with maternal heart rate. BrAIx, AoAIx and PWV demonstrated significant change with gestation, with all reaching their lowest value in the second trimester. The current study presents reference ranges for BrAIx, AoAIx and PWV in low-risk singleton pregnancies. Further work is required to establish if women in whom measures of arterial stiffness lie above the 90th centile could be at increased risk of adverse pregnancy outcomes and to identify the optimum time for screening.


Functional substructure of antigen molecules.
It has been firmly established that helper T lymphocytes respond to antigen only when it is presented in the context of class II major histocompatibility complex molecules. This has fostered the concept that the nominal antigen becomes physically associated with class II molecules on antigen-presenting cells (APCs). However, the structural components of antigen molecules that actually interact with class II molecules on APCs (agretopes) and with antigen receptors of T lymphocytes (epitopes) have not been precisely defined. This question was addressed using murine T cell clones specific for the model synthetic antigen L-tyrosine-p-azobenzenearsonate (ABA-tyr), which induces T cell responses despite its small size and simple structure, and a series of analogues of the homologous immunogen. Two experimental approaches were taken. First, APCs were pulsed with analogues and used to stimulate T cell proliferation. The patterns of stimulation segregated the clones into two specificity groups and indicated that the epitope recognized by the T cell included the arsonate group and elements of the side chain of tyrosine. Second, analogues that failed to stimulate were used to block the presentation of ABA-tyr in an effort to define the agretope. The blocking protocol involved serially pulsing APCs with analogue and with ABA-tyr prior to culturing with T cells. Compounds containing the core azo-linked ring structure blocked presentation of ABA-tyr in a dose-dependent fashion, whereas p-arsanilic acid and L-tyrosine were ineffective. The blocking was specific inasmuch as the compounds had no effect on the antigen-induced proliferative responses of unrelated T cell clones.(ABSTRACT TRUNCATED AT 250 WORDS)


[Effect of moderate protein-calorie deprivation on cell-mediated immunity in mice].
Mild protein-calorie deprivation in mice decreases their early nonspecific inflammatory response to an injection of BCG or tuberculin into the footpad. After an injection of BCG, the size of the granuloma and the delayed hypersensitivity reaction to tuberculin significantly decreased. This decrease in cell-mediated immunity was paradoxically accompanied by a fall in bacillus multiplication at the popliteal ganglion, i.e. the site of BCG injection. A reduction in microbial multiplication was also observed in the spleen after intraperitoneal injection of Listeria and in the liver after intravenous injection.


Minimal positional substring cover is a haplotype threading alternative to Li and Stephens model.
The Li and Stephens (LS) hidden Markov model (HMM) models the process of reconstructing a haplotype as a mosaic copy of haplotypes in a reference panel. For small panels, the probabilistic parameterization of LS enables modeling the uncertainties of such mosaics. However, LS becomes inefficient when sample size is large, because of its linear time complexity. Recently the PBWT, an efficient data structure capturing the local haplotype matching among haplotypes, was proposed to offer a fast method for giving some optimal solution (Viterbi) to the LS HMM. Previously, we introduced the minimal positional substring cover (MPSC) problem as an alternative formulation of LS whose objective is to cover a query haplotype by a minimum number of segments from haplotypes in a reference panel. The MPSC formulation allows the generation of a haplotype threading in time constant to sample size (O(N)). This allows haplotype threading on very large biobank-scale panels on which the LS model is infeasible. Here, we present new results on the solution space of the MPSC. In addition, we derived a number of optimal algorithms for MPSC, including solution enumerations, the length maximal MPSC, and h-MPSC solutions. In doing so, our algorithms reveal the solution space of LS for large panels. We show that our method is informative in terms of revealing the characteristics of biobank-scale data sets and can improve genotype imputation.


In vitro pharmacokinetics of anti-psoriatic fumaric acid esters.
Psoriasis is a chronic inflammatory skin disease that can be successfully treated with a mixture of fumaric acid esters (FAE) formulated as enteric-coated tablets for oral use. These tablets consist of dimethylfumarate (DMF) and salts of monoethylfumarate (MEF) and its main bioactive metabolite is monomethylfumarate (MMF). Little is known about the pharmacokinetics of these FAE. The aim of the present study was to investigate the hydrolysis of DMF to MMF and the stability of MMF, DMF and MEF at in vitro conditions representing different body compartments. DMF is hydrolyzed to MMF in an alkaline environment (pH 8), but not in an acidic environment (pH 1). In these conditions MMF and MEF remained intact during the period of analysis (6 h). Interestingly, DMF was hardly hydrolyzed to MMF in a buffer of pH 7.4, but was rapidly hydrolyzed in human serum having the same pH. Moreover, in whole blood the half-life of DMF was dramatically reduced as compared to serum. The concentrations of MMF and MEF in serum and whole blood decreased with increasing time. These data indicate that the majority of the FAE in the circulation are metabolized by one or more types of blood cells. Additional experiments with purified blood cell fractions resuspended in phosphate buffered saline (pH 7.4) revealed that at concentrations present in whole blood monocytes/lymphocytes, but not granulocytes and erythrocytes, effectively hydrolyzed DMF to MMF. Furthermore, in agreement with the data obtained with the pure components of the tablet, the enteric-coated tablet remained intact at pH 1, but rapidly dissolved at pH 8. Together, these in vitro data indicate that hydrolysis of DMF to MMF rapidly occurs at pH 8, resembling that within the small intestines, but not at pH 1 resembling the pH in the stomach. At both pHs MMF and MEF remained intact. These data explain the observation that after oral FAE intake MMF and MEF, but not DMF, can be readily detected in the circulation of human healthy volunteers and psoriasis patients.


Neuroticism, depressive symptoms and white-matter integrity in the Lothian Birth Cohort 1936.
Clinical depression is associated with reductions in white-matter integrity in several long tracts of the brain. The extent to which these findings are localized or related to depressive symptoms or personality traits linked to disease risk remains unclear. Method Members of the Lothian Birth Cohort 1936 (LBC936) were assessed in two waves at mean ages of 70 and 73 years. At wave 1, they underwent assessments of depressive symptoms and the personality traits of neuroticism and extraversion. Brain diffusion magnetic resonance imaging (MRI) data were obtained at the second wave and mood assessments were repeated. We tested whether depressive symptoms were related to reduced white-matter tract fractional anisotropy (FA), a measure of integrity, and then examined whether high neuroticism or low extraversion mediated this relationship. Six hundred and sixty-eight participants provided useable data. Bilateral uncinate fasciculus FA was significantly negatively associated with depressive symptoms at both waves (standardized β=0.12-0.16). Higher neuroticism and lower extraversion were also significantly associated with lower uncinate FA bilaterally (standardized β=0.09-0.15) and significantly mediated the relationship between FA and depressive symptoms. Trait liability to depression and depressive symptoms are associated with reduced structural connectivity in tracts connecting the prefrontal cortex with the amygdala and anterior temporal cortex. These effects suggest that frontotemporal disconnection is linked to the etiology of depression, in part through personality trait differences.


The impact of bleeding complications in patients receiving target-specific oral anticoagulants: a systematic review and meta-analysis.
Vitamin K antagonists (VKAs) have been the standard of care for treatment of thromboembolic diseases. Target-specific oral anticoagulants (TSOACs) have been developed and found to be at least noninferior to VKAs with regard to efficacy, but the risk of bleeding with TSOACs remains controversial. We performed a systematic review and meta-analysis of phase-3 randomized controlled trials (RCTs) to assess the bleeding side effects of TSOACs compared with VKAs in patients with venous thromboembolism or atrial fibrillation. We searched MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials; conference abstracts; and www.clinicaltrials.gov with no language restriction. Two reviewers independently performed study selection, data extraction, and study quality assessment. Twelve RCTs involving 102 607 patients were retrieved. TSOACs significantly reduced the risk of overall major bleeding (relative risk [RR] 0.72, P < .01), fatal bleeding (RR 0.53, P < .01), intracranial bleeding (RR 0.43, P < .01), clinically relevant nonmajor bleeding (RR 0.78, P < .01), and total bleeding (RR 0.76, P < .01). There was no significant difference in major gastrointestinal bleeding between TSOACs and VKAs (RR 0.94, P = .62). When compared with VKAs, TSOACs are associated with less major bleeding, fatal bleeding, intracranial bleeding, clinically relevant nonmajor bleeding, and total bleeding. Additionally, TSOACs do not increase the risk of gastrointestinal bleeding.


Gene expression profiling of cutaneous wound healing.
Although the sequence of events leading to wound repair has been described at the cellular and, to a limited extent, at the protein level this process has yet to be fully elucidated. Genome wide transcriptional analysis tools promise to further define the global picture of this complex progression of events. This study was part of a placebo-controlled double-blind clinical trial in which basal cell carcinomas were treated topically with an immunomodifier--toll-like receptor 7 agonist: imiquimod. The fourteen patients with basal cell carcinoma in the placebo arm of the trial received placebo treatment consisting solely of vehicle cream. A skin punch biopsy was obtained immediately before treatment and at the end of the placebo treatment (after 2, 4 or 8 days). 17.5K cDNA microarrays were utilized to profile the biopsy material. Four gene signatures whose expression changed relative to baseline (before wound induction by the pre-treatment biopsy) were identified. The largest group was comprised predominantly of inflammatory genes whose expression was increased throughout the study. Two additional signatures were observed which included preferentially pro-inflammatory genes in the early post-treatment biopsies (2 days after pre-treatment biopsies) and repair and angiogenesis genes in the later (4 to 8 days) biopsies. The fourth and smallest set of genes was down-regulated throughout the study. Early in wound healing the expression of markers of both M1 and M2 macrophages were increased, but later M2 markers predominated. The initial response to a cutaneous wound induces powerful transcriptional activation of pro-inflammatory stimuli which may alert the host defense. Subsequently and in the absence of infection, inflammation subsides and it is replaced by angiogenesis and remodeling. Understanding this transition which may be driven by a change from a mixed macrophage population to predominantly M2 macrophages, may help the interpretation of the cellular and molecular events occurring in the microenvironment of serially biopsied tissues.


Mode of action of butoxyethanol-induced mouse liver hemangiosarcomas and hepatocellular carcinomas.
Chronic exposure to 2-butoxyethanol resulted in an increase in liver hemangiosarcomas and hepatic carcinomas in male mouse liver. No increase in liver neoplasia was observed in similarly exposed male and female rats or female mice. We have proposed that the production of liver neoplasia in the male mouse is the result of oxidative damage secondary to the hemolytic deposition of iron in the liver. Our working hypothesis is that the mode of action of butoxyethanol-induced mouse liver hemangiosarcomas and hepatic neoplasia involves the metabolism of 2-butoxyethanol to butoxyacetic acid which results in the induction of RBC hemolysis. This hemolytic response is translated into the accumulation of iron in both liver hepatocytes and Kupffer cells. The Kupffer cell response to this insult is two-fold: (1) the production of oxidative species-through both Kupffer cell activation and through the Fenton reaction involving iron and (2) the production of cytokines (for example TNF alpha). The induction of reactive oxygen species can, if not scavenged, produce oxidative DNA damage (the formation of OH8dG), as well as increase cell growth through modulation of gene expression. While the reactive oxygen species generation would occur in the both rats and mice, the ability of the rat to detoxify the reactive oxygen species would preclude the remaining steps from occurring. In contrast, in the mouse, the reactive oxygen species would override antioxidant defense mechanisms and allow the proposed mode of action to move forward. Our results to date in male B6C3F1 mice and male F344 rats treated with 2-butoxyethanol (via daily gavage; five times per week) at doses of 0, 225, 450, and 900 mg/kg/day (mice) and 0, 225, 450 mg/kg/day (rats), respectively, showed: an increase in hemolysis in 2-butoxyethanol treated rats and mice in a dose-dependent manner, in addition, an increase in the percent of iron stained Kupffer cells in the liver was observed following treatment with 450 and 900 mg/kg of 2-butoxyethanol in mice and 225 and 450 mg/kg of 2-butoxyethanol in rat. With the iron deposition, a biphasic increase in oxidative damage (OH8dG and malondialdehyde) was seen in mouse liver after treatment with 2-butoxyethanol. In contrast, no increase in oxidative damage was observed in the rat liver at any of the doses examined. Concomitant with the increase in oxidative damage, Vitamin E levels were similarly reduced by 2-butoxyethanol in both mice and rat liver. However, the basal level of Vitamin E in rat liver was 2.5-fold greater than in mouse liver. A biphasic induction of DNA synthesis was seen following 2-butoxyethanol in the mouse. In mouse liver, increased DNA synthesis was observed in hepatocytes at 90 days and in endothelial cells at 7 and 14 days at all doses. No change in DNA synthesis was seen in 2-butoxyethanol treated rat liver. No apparent differences in apoptosis and mitosis in the liver were observed in mouse and rat liver between 2-butoxyethanol treatment groups and untreated controls. These results suggest that the induction of DNA synthesis, possibly from oxidative stress and/or Kupffer cell activation, occurs selectively in the mouse liver, in endothelial cells and in hepatocytes following exposure to 2-butoxyethanol, and support the hypothesis proposed above.


Automatic attention lateral asymmetry in visual discrimination tasks.
There is evidence that automatic visual attention favors the right side. This study investigated whether this lateral asymmetry interacts with the right hemisphere dominance for visual location processing and left hemisphere dominance for visual shape processing. Volunteers were tested in a location discrimination task and a shape discrimination task. The target stimuli (S2) could occur in the left or right hemifield. They were preceded by an ipsilateral, contralateral or bilateral prime stimulus (S1). The attentional effect produced by the right S1 was larger than that produced by the left S1. This lateral asymmetry was similar between the two tasks suggesting that the hemispheric asymmetries of visual mechanisms do not contribute to it. The finding that it was basically due to a longer reaction time to the left S2 than to the right S2 for the contralateral S1 condition suggests that the inhibitory component of attention is laterally asymmetric.


Computational Characterizations of the Interactions Between the Pontacyl Violet 6R and Exoribonuclease as a Potential Drug Target Against SARS-CoV-2.
We report a molecular-docking and virtual-screening-based identification and characterization of interactions of lead molecules with exoribonuclease (ExoN) enzyme in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). From previously identified DEDDh/DEEDh subfamily nuclease inhibitors, our results revealed strong binding of pontacyl violet 6R (PV6R) at the catalytic active site of ExoN. The binding was found to be stabilized via two hydrogen bonds and hydrophobic interactions. Molecular dynamics simulations further confirmed the stability of PV6R at the active site showing a shift in ligand to reach a more stabilized binding. Using PV6R as the lead molecule, we employed virtual screening to identify potential molecular candidates that form strong interactions at the ExoN active site. Our study paves ways for evaluating the ExoN as a novel drug target for antiviral treatment against SARS-CoV-2.


Endoscopic submucosal dissection for colorectal neoplasms.
Although endoscopic submucosal dissection (ESD) gains acceptance as one of the standard treatments for esophageal and stomach neoplasms in Japan, it is still in the developing stage for colorectal neoplasms. In terms of indications, little likelihood of nodal metastasis and technical resectability are principally considered. Some of intramucosal neoplasms, carcinomas with minute submucosal invasion, and carcinoid tumors, which are technically unresectable by conventional endoscopic treatments, may become good candidates for ESD, considering substantial risks and obtained benefits. ESD as a staging measure to obtain histological information of the invasion depth and lymphovascular infiltration is acceptable because preoperative prediction is difficult in some cases. In terms of techniques, advantages of ESD in comparison with other endoscopic treatments are to be controllable in size and shape, and to be resectable even in large and fibrotic neoplasms. The disadvantages may be longer procedure time, heavier bleeding, and higher possibility of perforation. However, owing to refinement of the techniques, invention of devices, and the learning curve, acceptable technical safety has been achieved. Colorectal ESD is very promising and become one of the standard treatments for colorectal neoplasms in the near future.


Arthritis in children: comparison of clinical and biological characteristics of septic arthritis and juvenile idiopathic arthritis.
Childhood arthritis arises from several causes. The aim of this observational study is to compare the clinical and biological features and short-term outcome of different types of arthritis because they have different treatment and prognoses. Children <16 years of age hospitalised in a French tertiary care centre for a first episode of arthritis lasting for less than 6 weeks who underwent joint aspiration were retrospectively included. We performed non-parametrical tests to compare groups (septic arthritis (SA), juvenile idiopathic arthritis (JIA) and arthritis with no definitive diagnosis). The time before apyrexia or C reactive protein (CRP) <10 mg/L was analysed using the Kaplan-Meier method. We studied 125 children with a sex ratio (M/F) of 1.1 and a median age of 2.2 years (range 0.3 to 14.6). SA was associated with a lower age at onset (1.5 years, IQR 1.2-3.0 vs 3.6 years, IQR 2.2-5.6), shorter duration of symptoms before diagnosis (2 days, IQR 1-4 vs 7 days, IQR 1-19) and higher synovial white blood cell count (147 cells ×103/mm3, IQR 71-227, vs 51 cells ×103/mm3, IQR 12-113), than JIA. Apyrexia occurred later in children with JIA (40% after 2 days, 95% CI 17% to 75%) than children with SA (82%, 95% CI 68% to 92%), as did CRP<10 mg/L (18% at 7 days, 95% CI 6.3% to 29.6% vs 82.1%, 95% CI 76.1% to 89.7%, p=0.01). There were no sufficiently reliable predictors for differentiating between SA and JIA at onset. The outcomes were different; JIA should be considered in cases of poor disease evolution after antibiotic treatment and joint aspiration.


Denitration of 2,4,6-trinitrotoluene by Pseudomonas savastanoi.
Past disposal of wastewaters containing 2,4,6-trinitrotoluene (TNT) at the former Nebraska Ordnance Plant has resulted in numerous acres of TNT-contaminated soil. Examining the microbial population of these soils revealed several TNT-tolerant Pseudomonas spp. We selected one species, P. savastanoi, to determine its ability to transform TNT. Pure culture experiments were performed in pseudomonas minimal medium containing 0.31 mM TNT (70 mg TNT . L(-1)) under varied nutrient and cell density regimes. Experiments with TNT as a sole C or N source showed that P. savastanoi has the ability to denitrate TNT, as evidenced by production of 2,4-dinitrotoluene (2,4-DNT) and NO2- with time. TNT denitration and formation of 2,4-DNT were enhanced by removing NH4+ and adding NO2- to the growth medium. In all experiments, 2-amino-4,6-dinitrotoluene (2-ADNT) and 4-amino-2,6-dinitrotoluene (4-ADNT) appeared as incidental reduction products. Glucose addition to the medium enhanced 2-ADNT and 4-ADNT production and decreased denitration of TNT. Mid-log phase cells rapidly transformed [ring-14C(U)]TNT but were unable to mineralize significant quantities of TNT, as evidenced by conversion of less than 1% of the label to 14CO2. These results indicate that P. savastanoi is a TNT-tolerant pseudomonad that can promote TNT degradation through reductive denitration and nitro moiety reduction.


alpha-Tocopherol binding activity of red blood cells in smokers.
Despite high plasma levels of vitamin E, red blood cell membranes contain relatively low levels of vitamin E. This suggests the existence of a selective vitamin E uptake/regeneration system in human red blood cell membranes. alpha-Tocopherol binding sites on human red blood cells are thought to be involved in the uptake of alpha-tocopherol from the plasma. To understand the role of the uptake system we have compared the alpha-tocopherol content and binding activity of red blood cells from smokers and non-smokers. The specific binding of [3H] alpha-tocopherol to pure red blood cell preparations from smokers (n = 7, 28.4 +/- 2.8 years) was 30.6 +/- 3.2 fmoles per 3 x 10(8) red blood cells and for non-smokers (n = 17, 27.9 +/- 1.3 years) was 41.7 +/- 3.7 fmoles per 3 x 10(8) red blood cells. Thus alpha-tocopherol uptake activity was significantly lower in smokers (P = 0.05). Red blood cells from smokers contained less (1.8 +/- 0.4 micrograms/gHb) alpha-tocopherol than non-smokers (2.8 +/- 0.3 micrograms/gHb), (P < 0.05), despite plasma levels of alpha-tocopherol being similar: 12.9 +/- 0.8 microM in non-smokers vs. 12.7 +/- 0.5 microM in smokers. However, adjusting plasma alpha-tocopherol for total plasma cholesterol plus triacylglycerols showed alpha-tocopherol levels were higher (P < 0.01) in non-smokers (2.84 +/- 0.10 mumol alpha-tocopherol/ mmol [cholesterol+triacylglycerol]) than in smokers (2.36 +/- 0.11 mumol alpha-tocopherol/mmol [cholesterol+triacylglycerol]). The reduced alpha-tocopherol levels in red blood cells from smokers may be due to impairment of alpha-tocopherol uptake activity. The reduced levels of alpha-tocopherol in smokers red blood cells was not associated with any changes in cell membrane fluidity. At present it is not known whether supplementation of smokers with vitamin E would normalise the alpha-tocopherol uptake activity of red blood cells.


Production and regulation of leptin in bovine mammary epithelial cells.
Previously, leptin has been found in human and rodent mammary tissue. The present research was conducted to determine (1) if leptin is produced by bovine mammary epithelial cells and (2) if leptin production in bovine mammary epithelial cells is hormonally regulated. Western blot analysis indicated the presence of leptin in bovine milk, while reverse transcription-polymerase chain reaction (RT-PCR) indicated the presence of leptin mRNA in mammary tissue and cultured bovine mammary epithelial cells (MAC-T cell line). A real time RT-PCR method was developed that allowed quantitative assessment of bovine leptin mRNA over approximately 3 orders of magnitude. Time course studies indicated a rapid increase in leptin mRNA in response to insulin or insulin-like growth factor-I (IGF-I). When normalized against bovine GAPDH as an internal control, 0.5 or 1h treatment with 10 ng/mL insulin gave 39+/-4 and 64+/-2-fold increase in leptin mRNA compared with 0 h control. Leptin mRNA was increased 257+/-9 and 75+/-23-fold by 0.5 or 1h treatment with 10 ng/mL IGF-I. Dose response studies indicated significant increases in leptin mRNA in response to as little as 1 ng/mL insulin or 0.1 ng/mL IGF-I. Maximum increase in leptin mRNA was observed in response to 10 ng/mL insulin and 10 ng/mL IGF-I. These results indicate that production of leptin by bovine mammary epithelial cells can be regulated by factors known to alter mammary function and nutrient partitioning. This suggests that leptin may be an autocrine/paracrine signal in the bovine mammary gland.


Complementary AIDS therapies: the good, the bad and the ugly.
HIV-infected/AIDS patients seem to frequently use complementary therapies, yet definitive information in this area is difficult to obtain. The aim of this systematic review is therefore to assess the published data on the use of complementary medicine by HIV-infected/AIDS patients. A computerized systematic literature search was carried out. Data on prevalence of complementary medicine (CM) use, effectiveness, risks and costs were extracted. The prevalence of CM use ranges between 27 and 100%. Users perceived complementary therapies as beneficial, however, no data exist to suggest that these treatments are specifically effective. They are generally perceived as 'safe', but there is evidence to suggest that risks do exist. The costs for complementary therapies seem to be high and financial exploitation of patients may not be infrequent. It is concluded that complementary therapies for HIV-infected/AIDS patients are popular. Their potential for doing either harm or good requires more detailed study.


Increasing hip fracture volume following repeated lockdowns: an Irish multicentre study of periods pre-Covid, during Covid lockdown and following vaccination.
Older age groups were identified as a high-risk cohort for Covid-19 and thus were a focus of lockdown measures enacted internationally. Resultant decreased social mobility and physical activity levels are associated with sarcopenia, which may lead to increased risk of hip fracture upon resuming social integration and physical activities after easing of lockdown restrictions. Our aim was to compare the incidence of hip fractures during the period following vaccination with subsequent relaxation of restrictions, to those prior to and during the Covid pandemic. A multicentre retrospective cohort study was performed consisting of all patients presenting with a "hip" fracture to 3 regional trauma units over the relevant time periods in 2019, 2020 and 2021. Tallaght, Galway and Waterford University Hospitals are large academic teaching hospitals with a combined mixed urban and rural catchment of over 1 million people. Four-hundred-fourteen patients in total were included in the final analysis, with 133 eligible hip fractures observed proceeding to operative treatment across the study period in 2019, 132 in 2020 and 149 in 2021, representing a 12.88% increase. Demographic data revealed similar patient cohorts with respect to age and gender, fracture pattern and treatment. An increase in hip fracture volume was observed during the period post vaccination with subsequent relaxation of restrictions and increased social mobility, compared to those prior to and during the Covid pandemic. These findings have implications for hospital planning and orthopaedic resourcing as we navigate our way forward past the Covid-19 Pandemic.


A novel triplex quantitative PCR strategy for quantification of toxigenic and nontoxigenic Vibrio cholerae in aquatic environments.
Vibrio cholerae is a severe human pathogen and a frequent member of aquatic ecosystems. Quantification of V. cholerae in environmental water samples is therefore fundamental for ecological studies and health risk assessment. Beside time-consuming cultivation techniques, quantitative PCR (qPCR) has the potential to provide reliable quantitative data and offers the opportunity to quantify multiple targets simultaneously. A novel triplex qPCR strategy was developed in order to simultaneously quantify toxigenic and nontoxigenic V. cholerae in environmental water samples. To obtain quality-controlled PCR results, an internal amplification control was included. The qPCR assay was specific, highly sensitive, and quantitative across the tested 5-log dynamic range down to a method detection limit of 5 copies per reaction. Repeatability and reproducibility were high for all three tested target genes. For environmental application, global DNA recovery (GR) rates were assessed for drinking water, river water, and water from different lakes. GR rates ranged from 1.6% to 76.4% and were dependent on the environmental background. Uncorrected and GR-corrected V. cholerae abundances were determined in two lakes with extremely high turbidity. Uncorrected abundances ranged from 4.6×10(2) to 2.3×10(4) cell equivalents liter(-1), whereas GR-corrected abundances ranged from 4.7×10(3) to 1.6×10(6) cell equivalents liter(-1). GR-corrected qPCR results were in good agreement with an independent cell-based direct detection method but were up to 1.6 log higher than cultivation-based abundances. We recommend the newly developed triplex qPCR strategy as a powerful tool to simultaneously quantify toxigenic and nontoxigenic V. cholerae in various aquatic environments for ecological studies as well as for risk assessment programs.


Dynamic evaluation method for planning sustainable landfills using GIS and multi-criteria in areas of urban sprawl with land-use conflicts.
Landfill site selection is problematic in many countries, especially developing nations where there is rapid population growth, which leads to high levels of inadequate waste disposal. To find sustainable landfill sites in sprawling cities, this study presents an approach that combines geographic information system (GIS) with multi-criteria (social, environmental and, technical criteria) and the population growth projection. The greater Maputo area in Mozambique was selected as a representative city for the study, which is undergoing rapid urbanization. Six criteria, i.e., land use, transport networks, hydrology, conservation reserve, geology and slope, were considered and overlaid in the GIS using an analytic hierarchy process (AHP). The arithmetic projection of the population trend suggests that the greater Maputo area is experiencing a rapid and uncontrolled population growth, especially in Matola city. These pronounced changes in population then significantly change the landfill placement decision making. Dynamic and static scenarios were created, based on the analysis of multi-criteria and the areas likely to undergo future increased population growth. A comparative evaluation in a scenario of dynamic behavior considering future population showed that suitable areas for landfill sites have been drastically modified due to social and environmental factors affected by population distribution in some regions. The results indicate that some suitable areas can generate land use conflicts due to population growth with unplanned land use expansion. Finally, the western part of Matola city is recognized as the most recommendable landfill site, which can serve both Maputo and Matola city with affordable costs. This study provides an effective landfill placement decision making approach, which is possible to be applied anywhere, especially in developing countries to improve sustainable municipal solid waste management systems.


Endogenous cannabinoids mediate retrograde signals from depolarized postsynaptic neurons to presynaptic terminals.
Endogenous cannabinoids are considered to function as diffusible and short-lived modulators that may transmit signals retrogradely from postsynaptic to presynaptic neurons. To evaluate this possibility, we have made a paired whole-cell recording from cultured hippocampal neurons with inhibitory synaptic connections. In about 60% of pairs, a cannabinoid agonist greatly reduced the release of the inhibitory neurotransmitter GABA from presynaptic terminals. In most of such pairs but not in those insensitive to the agonist, depolarization of postsynaptic neurons and the resultant elevation of intracellular Ca2+ concentration caused transient suppression of inhibitory synaptic currents, which is mainly due to reduction of GABA release. This depolarization-induced suppression was completely blocked by selective cannabinoid antagonists. Our results reveal that endogenous cannabinoids mediate retrograde signals from depolarized postsynaptic neurons to presynaptic terminals to cause the reduction of transmitter release.


Identification of Gray Leaf Spot Disease Candidate Gene in Narrow-Leafed Lupin (Lupinus angustifolius L.).
Selection for resistance against gray leaf spot (GLS) is a major objective in the lupin breeding programs. A segregation ratio of 1:1 (resistant:susceptible) in F8 recombinant inbred lines (RIL8) derived from a cross between a breeding line 83A:476 (resistant to GLS) and a wild accession P27255 (susceptible to GLS) indicated that GLS was controlled by a single major gene. To develop molecular markers linked to GLS, in the beginning, only 11 resistant lines and six susceptible lines from the 83A:476 and P27255 population were genotyped with MFLP markers, and three MFLP markers were identified to be co-segregated with GLS. This method was very efficient, but the markers were located outside of the gene, and could not be used in other germplasms. Then QTL analysis and fine mapping were conducted to identify the gene. Finally, the gene was narrowed down to a 241-kb region containing two disease resistance genes. To further identify the candidate gene, DNA variants between accessions Tanjil (resistant to GLS) and Unicrop (susceptible to GLS) were analyzed. The results indicated that only one SNP was detected in the 241 kb region. This SNP was located in the TMV resistance protein N-like gene region and also identified between 83A:476 and P27255. Genotyping the Tanjil/Unicrop RIL8 population showed that this SNP co-segregated with GLS resistance. The phylogenetic tree analysis of this gene among 18 lupin accessions indicates that Australian resistant breeding line/varieties were clustered into one group and carry two resistant alleles, while susceptible accessions were clustered into different groups.


Management of bleeding in patients with advanced cancer.
Bleeding occurs in up to 10% of patients with advanced cancer. It can present in many different ways. This article provides a qualitative review of treatment options available to manage visible bleeding. Local modalities, such as hemostatic agents and dressings, radiotherapy, endoscopic ligation and coagulation, and transcutaneous arterial embolization, are reviewed in the context of advanced cancer, as are systemic treatments such as vitamin K, vasopressin/desmopressin, octreotide/somatostatin, antifibrinolytic agents (tranexamic acid and aminocaproic acid), and blood products. Considerations at the end of life are described.


Nrf2-AKT interactions regulate heme oxygenase 1 expression in kidney epithelia during hypoxia and hypoxia-reoxygenation.
Ischemia-reperfusion (IR)-induced kidney injury is a major clinical problem, but its underlying mechanisms remain unclear. The transcription factor known as nuclear factor, erythroid 2-like 2 (NFE2L2 or Nrf2) is crucial for protection against oxidative stress generated by pro-oxidant insults. We have previously shown that Nrf2 deficiency enhances susceptibility to IR-induced kidney injury in mice and that its upregulation is protective. Here, we examined Nrf2 target antioxidant gene expression and the mechanisms of its activation in both human and murine kidney epithelia following acute (2 h) and chronic (12 h) hypoxia and reoxygenation conditions. We found that acute hypoxia modestly stimulates and chronic hypoxia strongly stimulates Nrf2 putative target HMOX1 expression, but not that of other antioxidant genes. Inhibition of AKT1/2 or ERK1/2 signaling blocked this induction; AKT1/2 but not ERK1/2 inhibition affected Nrf2 levels in basal and acute hypoxia-reoxygenation states. Unexpectedly, chromatin immunoprecipitation assays revealed reduced levels of Nrf2 binding at the distal AB1 and SX2 enhancers and proximal promoter of HMOX1 in acute hypoxia, accompanied by diminished levels of nuclear Nrf2. In contrast, Nrf2 binding at the AB1 and SX2 enhancers significantly but differentially increased during chronic hypoxia and reoxygenation, with reaccumulation of nuclear Nrf2 levels. Small interfering-RNA-mediated Nrf2 depletion attenuated acute and chronic hypoxia-inducible HMOX1 expression, and primary Nrf2-null kidney epithelia showed reduced levels of HMOX1 induction in response to both acute and chronic hypoxia. Collectively, our data demonstrate that Nrf2 upregulates HMOX1 expression in kidney epithelia through a distinct mechanism during acute and chronic hypoxia reoxygenation, and that both AKT1/2 and ERK1/2 signaling are required for this process.


[Counselling for erectile dysfunction during inpatient rehabilitation after radical prostatectomy].
For men erectile function is essential for quality of life. Besides urine incontinence postsurgical erectile dysfunction (ED) following radical prostatectomy (RPE) represents a significant and prevalent problem. One of the first approaches to this condition should be a consultation performed by professionals in a rehabilitation clinic.A total of 149 patients post RPE participated in this prospective study. All patients were questioned about their understanding of postoperative surgical ED after RPE and if affected they were asked about their own psychological burden as well as their knowledge of possible therapy options. The qualities of presurgical patient information as well as the modules of information pertaining to ED during the rehabilitation were evaluated. Of the patients, 53% expressed that they experienced a considerable burden due to postsurgical ED during their follow-up rehabilitation (AR group) and 70% of the patients during oncological rehabilitation treatment (rehab group). Men who were sexually more active prior to surgery suffered more from postsurgical ED than their less active counterparts. A negative correlation between psychological burden and age was found in the AR group, which however was levelled in the rehab group. Particularly in older patients the burden of ED increases with more time elapsing after the operation. The medical information on ED therapy options provided during the inpatient rehabilitation was considered to be essential by 60% of the men in the AR group and 48% of the patients in the rehab group.Therapeutic possibilities for postsurgical ED following RPE cannot always be given to patients in the preoperative phase or during their stay in the hospital. Since however a large majority of men suffer from postoperative ED following RPE a specialized inpatient urological rehabilitation is suited for a comprehensive consultation.


Eggcrate UV: a whole ceiling upper-room ultraviolet germicidal irradiation system for air disinfection in occupied rooms.
A novel whole ceiling upper-room ultraviolet germicidal irradiation (UVGI) system [eggcrate ultraviolet (UV)] has been developed that incorporates open-cell 'eggcrate'-suspended ceiling panels and bare UV lamps with a ceiling fan. Upper-room UVGI is more effective for air disinfection than mechanical ventilation at much lower installation and operating costs. Conventional upper-room UVGI fixtures employ multiple tightly spaced horizontal louvers to confine UV to the upper-room. These louvered fixtures protect occupants in the lower-room from UV-induced eye and skin irritation, but at a major cost to fixture efficiency. Using a lamp and ballast from a conventional upper-room UVGI fixture in the eggcrate UV system, the germicidal efficacy was markedly improved even though the UV radiation emitted by the lamp was unchanged. This fundamental change in the application of upper-room UVGI air disinfection should permit wider, more effective application of UVGI globally to reduce the spread of airborne infection.


R&D investments and quality of life in Turkey.
The standards of development and life quality of cities play an important role in the investment and career planning of the investors and the qualified people who will work in R&D and Technoparks. Also, all the leading cities in the world are the most developed cities in the regions and countries in terms of R&D and innovation. Therefore, all cities in Turkey are compared by using the R&D investment data and TurkStat "Quality of Life Index for Cities". The criteria are weighted by the Fuzzy Analytic Hierarchy Process (FAHP). Then 81 cities are compared with the TOPSIS (Technique for Order Preference by Similarity to Ideal Solution) method. The article aims to provide information about the current situation of Turkey's cities regarding R&D, Technology Development Zones and quality of life. According to the results, the quality of life and socio-economic development has a very close relationship with the existence of R&D investments. If the current development policy continues, the regions with low quality of life will continue to lag behind the other cities in terms of development. The study indicates that there are remarkable differences between eastern and western Turkey in terms of living standards and the contribution of R&D and Technoparks to economic development.


Tryptophan catabolism in Bacillus megaterium.
Bacillus megaterium grows in a medium containing L-tryptophan as the sole carbon, nitrogen, and energy source. Kynurenine, anthranilic acid, and catechol are metabolic intermediates, suggesting that this organism used the anthranilic acid pathway for tryptophan degradation. Cells that grow on L-tryptophan oxidize kynurenine, alanine, and anthranilic acid and the presence of tryptophan oxygenase (EC 220.127.116.11), kynureninase (EC 126.96.36.199), and catechol oxygenase (EC 220.127.116.11) in cell extracts provide additional evidence for the degradative pathway in B. megaterium. Tryptophan oxygenase is inhibited by sodium azide, potassium cyanide, and hydroxylamine, indicating that the enzyme has a functional heme group. D-Tryptophan is not a substrate for tryptophan oxygenase, and the D-isomer does not inhibit this enzyme. Formamidase (EC 184.108.40.206) and anthranilate hydroxylase are not detectable in extracts. Tryptophan catabolism is inducible in B megaterium and is subject to catabolite repression by glucose and glutamate. Arginine does not cause repression, and kynurenine induces both tryptophan oxygenase and kynureninase.


Case Report: Birth Outcome and Neurodevelopment in Placental Malaria Discordant Twins.
Maternal infection during pregnancy can have lasting effects on neurodevelopment, but the impact of malaria in pregnancy on child neurodevelopment is unknown. We present a case of a 24-year-old gravida three woman enrolled at 14 weeks 6 days of gestation in a clinical trial evaluating malaria prevention strategies in pregnancy. She had two blood samples test positive for Plasmodium falciparum using loop-mediated isothermal amplification before 20 weeks of gestation. At 31 weeks 4 days of gestation, the woman presented with preterm premature rupture of membranes, and the twins were delivered by cesarean section. Twin A was 1,920 g and Twin B was 1,320 g. Both placentas tested negative for malaria by microscopy, but the placenta of Twin B had evidence of past malaria by histology. The twins' development was assessed using the Bayley Scales of Infant and Toddler Development-Third Edition. At 1 year chronologic age, Twin B had lower scores across all domains (composite scores: cognitive, Twin A [100], Twin B [70]; motor, Twin A [88], Twin B [73]; language, Twin A [109], Twin B [86]). This effect persisted at 2 years chronologic age (composite scores: cognitive, Twin A [80], Twin B [60]; motor, Twin A [76], Twin B [67]; language, Twin A [77], Twin B [59]). Infant health was similar over the first 2 years of life. We report differences in neurodevelopmental outcomes in placental malaria-discordant dizygotic twins. Additional research is needed to evaluate the impact of placental malaria on neurodevelopmental complications. Trial registration number: ClinicalTrials.gov number, NCT02163447. Registered: June 2014, https://clinicaltrials.gov/ct2/show/NCT02163447.


Hypericin-Based Photodynamic Therapy Displays Higher Selectivity and Phototoxicity towards Melanoma and Squamous Cell Cancer Compared to Normal Keratinocytes In Vitro.
The aim of this study was to explore the potential of hypericin, a naturally occurring photosensi-tizer, for photodynamic therapy (PDT) in skin cancer, investigating its phototoxic effects and mechanisms of action in cancer cells compared to normal skin keratinocytes, squamous cell cancer (SCC-25) cells and melanoma (MUG-Mel2) cells. Hypericin was applied at concentrations ranging from 0.1-40 μM to HaCaT, SCC-25, and MUG-Mel2 cells. After 24 h of incubation, the cells were exposed to orange light at 3.6 J/cm2 or 7.2 J/cm2. Phototoxicity was assessed using MTT and SRB tests. Cellular uptake was measured by flow cytometry. Apoptosis-positive cells were estimated through TUNEL for apoptotic bodies' visualization. Hypericin exhibited a higher phototoxic reaction in cancer cells compared to normal keratinocytes after irradiation. Cancer cells demonstrated increased and selective uptake of hypericin. Apoptosis was observed in SCC-25 and MUG-Mel2 cells following PDT. Our findings suggest that hypericin-based PDT is a promising and less invasive approach for treating skin cancer. The higher phototoxic reaction, selective uptake by cancer cells, and observed proapoptotic properties support the promising role of hypericin-based PDT in skin cancer treatment.


The Relationship between Preoperative Echocardiographic Evaluation and Spinal Deformity in Patients with Neuromuscular Scoliosis.
Echocardiography is an important component of perioperative cardiac risk stratification in patients with neuromuscular scoliosis (NMS). However, there are little data regarding the relationship between preoperative echocardiographic findings and spinal deformity. We retrospectively reviewed preoperative echocardiographic data to investigate the relationship between echocardiographic evaluation and spinal deformity in NMS. We reviewed 73 NMS patients (mean age: 13.3 years, male 66%) who underwent spinal correction surgery between 2008 and 2016. Echocardiographic data including ejection fraction (EF), valvar disease, and inferior vena cava diameter were collected from the preoperative exam. Demographic and radiographic data were also collected. Preoperative diagnoses included Duchenne muscular dystrophy, Fukuyama congenital muscular dystrophy, other dystrophy, spinal muscular atrophy, and congenital myopathies. Mean Body Mass Index (BMI) was 15.6 kg/m2. Mean major Cobb angle before surgery was 86.6 ± 28.2°. Because of technical difficulty, complete echocardiographic data could only be collected and evaluated in 49.3% of patients. Neither right nor left sided cardiac evaluation could be completed in 20.5%. Patients in whom complete echocardiographic data could not be collected had significantly more extensive thoracic scoliosis with a more rigid curve and hypokyphosis, and were of lower weight and BMI than patients in whom complete data could be collected. Ten cases (13.7%) were diagnosed as having minor heart-related complications immediately after surgery, and they had higher right atrial pressures preoperatively. Echocardiography can be technically difficult in NMS patients with extensive spinal deformities. We found that perioperative cardiac function could only be evaluated by echocardiogram in about half of NMS patients undergoing spinal correction surgery. The absence of an adequate preoperative cardiac evaluation could render these patients more susceptible to perioperative heart-related complications. Echocardiography may not be sufficient to evaluate cardiac conditions in children with extensive NMS.


Long-Term Outcome of Inflammatory Breast Cancer Compared to Non-Inflammatory Breast Cancer in the Setting of High-Dose Chemotherapy with Autologous Hematopoietic Cell Transplantation.
Introduction: Inflammatory breast cancer (IBC) is a rare aggressive form of breast cancer. It is well known that the long-term survival and progression-free survival of IBC are worse than that of non-IBC. We report the long term outcomes of patients with IBC and non-IBC who had undergone high-dose chemotherapy (HDC) with autologous hematopoietic cell transplantation (AHCT). Methods: All 3387 patients with IBC or non-IBC who underwent HDC with AHCT between1990-2002 and registered with CIBMTR were included in this analysis. Transplant-related mortality (TRM), disease relapse/progression, progression-free survival (PFS) and overall survival (OS) were compared between the two cohorts. Multivariate Cox regression model was used to determine the independent impact of stage on outcomes. Results: 527 patients with IBC and 2,860 patients with non-IBC were included; the median age at transplantation (47 vs 46 years old) and median follow-up period in the 2 groups (167 vs 168 months) were similar. The most common conditioning regimen was cyclophosphamide and carboplatin based in both groups (54% in IBC and 50% in non-IBC). AHCT was well tolerated in both groups. TRM was similar in both groups (one year TRM was 2% for IBC and 3% for non-IBC, p=0.16). The most common cause of death was disease progression or relapse (81% in IBC and 75% in non-IBC). The median survival for both IBC and non-IBC was the same at 40 months. The PFS at 10 years was 27% (95% CI: 23-31%) for IBC and 24% (95% CI: 22-26%) for non-IBC (p=0.21), and the OS at 10 years was 31% (95% CI: 27-35%) for IBC and 28% (95% CI: 26-30%) for non-IBC (p=0.16). In univariate analysis, patients with stage III IBC and no active diseases at transplantation had lower PFS and OS than that in non-IBC. In multivariate analysis, controlling for age, disease status at AHCT, hormonal receptor status, time from diagnosis to AHCT, and performance status at AHCT, patients with stage III IBC had higher mortality (HR 1.16, 95% CI: 1-1.34, p= 0.0459), worse PFS (HR: 1.17, 95% CI: 1.01-1.36, p= 0.0339) and higher risk of disease relapse/progression (HR: 1.24, 95% CI: 1.06-1.45, p= 0.0082) as compared to stage III non-IBC. Amongst all patients a higher stage disease was associated with worse PFS, OS and disease relapse/progression. Conclusions: Long-term outcomes of stage III IBC patients who underwent AHCT were poorer than that in non-IBC patients confirming that the poor prognosis of IBC even in the setting of HDC with AHCT.


Evaluation of verapamil in the treatment of hypertension.
Two separate randomized double-blind, crossover trials were carried out in hypertensive patients to evaluate the antihypertensive efficacy and safety of verapamil. In the first study, verapamil, in doses of 120 mg three times daily, was compared with pindolol, in doses of 7.5 mg twice daily. A thiazide diuretic was given with both drugs. In another study, verapamil, in doses of 160 mg twice daily, was compared with 200 mg twice daily of labetalol in hypertensive patients with coexisting chronic obstructive lung disease. Blood pressure fell equally with these drugs, and neither of the drugs caused significant side effects. Labetalol significantly reduced both forced expiration volume at 1s (FEV1) and forced vital capacity (FVC), suggesting a bronchoconstrictor effect. Verapamil was devoid of any such effect. Verapamil did not affect plasma renin concentration.


Pharmacist recommendations to improve the quality of diabetes care: a randomized controlled trial.
Diabetes mellitus continues to result in substantial morbidity and mortality despite receiving much attention from health care providers. Automated clinician reminder systems have been developed to improve adherence to diabetes care guidelines, but these reminder systems do not always provide actionable information and may be unable to detect relevant, subjective patient information that affects clinical decision making. Face-to-face visits with pharmacists, who have knowledge of care guidelines and medication management strategies, may assist in improving diabetes care. It is unknown if the combination of pharmacist chart review and clinician reminders could improve diabetes care without requiring face-to-face visits. To assess the effects of a comprehensive, pharmacistdelivered, primary care, physician-focused intervention in a large hospital based primary care practice to improve the quality of care for patients with diabetes including rates of semiannual hemoglobin A1c testing and other biomarker and process measures. This was a prospective, randomized, controlled study conducted in a hospital-based, primary care practice, composed of 37 faculty primary care physicians (PCPs) and 95 internal medicine residents. The initial sample included 346 patients with diabetes and 72 PCPs caring for them. PCPs were randomized to receive either a personalized letter from a practicing pharmacist containing treatment recommendations for patients with upcoming primary care visits (intervention, n = 33) or to usual care without the letters (control, n = 39). The letter included patient-specific recommendations regarding overdue testing as well as drug therapy to achieve diabetes-related treatment targets. The intervention included addition of the letter to the electronic medical record (EMR) and presentation of the letter to the PCP at the time of the index primary care visit that occurred between November 2003 and August 2004. Follow-up chart review was performed after the primary care visit to determine changes in 5 process and 3 biomarker outcome measures of diabetes care within 30 days of the index visit. The primary study outcome was a process measure, change in rates of semiannual A1c testing from baseline to 30-day follow-up. Baseline differences were tested for statistical significance using Pearson chisquare. The statistical significance of the intervention's effect was tested using logistic regression models predicting achievement of each study outcome, with randomization status (intervention vs. control) as the predictor variable of interest, controlling for baseline performance for each measure. 171 patients were in the 4 medical clinic suites with 33 PCPs who received the intervention, and 175 patients were in the 4 suites with 39 PCPs in usual care. 30-day outcomes were analyzed for 301 patients (87.0%) who attended their scheduled index primary care visit. Of these 301 patients, 44.5% were black, 65.8% were female, and the mean age was 63 years. At baseline, there were no significant differences between the intervention group (n = 150) and the usual care (control) group (n = 151) in the 3 biomarker measures (proportion with A1c less than 7%, proportion with low-density lipoprotein cholesterol [LDL-C] less than 100 milligrams per deciliter [mg per dL], or blood pressure less than 130/80 millimeters mercury [mm Hg]). There were no significant baseline differences in 4 of the 5 process measures; however, the rate of annual LDL-C testing was significantly higher for the intervention than for the control group at baseline (86.0% vs. 74.8%, respectively, P = 0.015). In logistic regression analysis, rates of semiannual A1c testing were not significantly different between the intervention and control groups, increasing from baseline to follow-up by 16% in the intervention group and 9% in the control group (P = 0.146). The proportion of patients with A1c less than 7% at follow-up was 43.3% in the intervention group versus 37.7% in the control group (intervention effect P = 0.099). The only statistically significant difference between the 2 groups in the 8 outcome measures was a higher proportion with an annual eye exam at follow-up in the intervention group (60.0%) versus the usual care group (50.3%, intervention effect P = 0.017). Pharmacist-generated recommendations delivered by letter to PCPs in an academic medical practice were not associated with statistically significant improvements in most quality measures for diabetes care assessed at 30 days following the intervention. Further research is needed with more patients and a longer follow-up time to determine how best to improve the quality of care of patients with diabetes using focused recommendations for therapy changes and reminder notices to clinicians.


A survey of equine abortion and perinatal foal losses in Hungary during a three-year period (1998-2000).
Cases of equine abortion and perinatal foal losses were investigated in Hungary during a three-year period (1998-2000). Samples from aborted equine fetuses and newborn foals (total n = 96) were examined using bacteriological, virological, pathological, immunohistochemical (IHC), molecular biological and serological methods. The cause of abortion and perinatal foal loss was identified in 67/96 cases (70%); viral infection was found in 22 (23%), viral and bacterial coinfection in 1 (1%), bacterial infection in 23 (24%), protozoan infection in 1 (1%) and fungal infection in 2 cases (2%). Morphological lesions suggestive of infection were recorded in 2 (2%) and non-infectious causes in 16 cases (17%).


Left atrial function and maximal exercise capacity in heart failure with preserved and mid-range ejection fraction.
Exercise intolerance is the leading manifestation of heart failure with preserved or mid-range ejection fraction (HFpEF or HFmrEF), and left atrial (LA) function might contribute to modulating left ventricular filling and pulmonary venous pressures. We aim to assess the association between LA function and maximal exercise capacity in patients with HFpEF or HFmrEF. Sixty-five patients, prospectively enrolled in the German HFpEF Registry, were analysed. Inclusion criteria were New York Heart Association functional class ≥ II, left ventricular ejection fraction > 40%, structural heart disease or diastolic dysfunction, and elevated levels of N terminal pro brain natriuretic peptide (NT-proBNP). LA function was evaluated through speckle-tracking echocardiography by central reading in the Charité Academic Echocardiography core lab. All patients underwent maximal cardiopulmonary exercise test and were classified according to a peak VO2 cut-off of prognostic value (14 mL/kg/min). NT-pro-BNP was measured. Twenty-nine patients (45%) reached a peak VO2 < 14 mL/kg/min (mean value 12.4 ± 1.5) and 36 patients (55%) peak VO2 ≥ 14 mL/kg/min (mean value 19.4 ± 3.9). There was no significant difference in left ventricular ejection fraction (60 ± 9 vs. 59 ± 8%), left ventricular mass (109 ± 23 vs. 112 ± 32 g/m2 ), LA volume index (45 ± 17 vs. 47 ± 22 mL/m2 ), or E/e´ (13.1 ± 4.7 vs. 13.0 ± 6.0) between these groups. In contrast, all LA strain measures were impaired in patients with lower peak VO2 (reservoir strain 14 ± 5 vs. 21 ± 9%, P = 0.002; conduit strain 9 ± 2 vs. 13 ± 4%, P = 0.001; contractile strain 7 ± 4 vs. 11 ± 6%, P = 0.02; reported lower limits of normality for LA reservoir, conduit and contractile strains: 26.1%, 12.0%, and 7.7%). In linear regression analysis, lower values of LA reservoir strain were associated with impaired peak VO2 after adjustment for age, sex, body mass index, heart rhythm (sinus/AFib), and log-NTproBNP [β 0.29, 95% confidence interval (CI) 0.02-0.30, P = 0.02], with an odds ratio 1.22 (95% CI 1.05-1.42, P = 0.01) for peak VO2 < 14 mL/kg/min for LA reservoir strain decrease after adjustment for these five covariates. Adding left ventricular ejection fraction, it did not influence the results. On the other hand, the addition of LA strain to the adjustment parameters alone described above provided a significant increase of the predictive value for lower peak VO2 values (R2 0.50 vs. 0.45, P = 0.02). With receiver operating characteristic curve analysis, we identified LA reservoir strain < 22% to have 93% sensitivity and 49% specificity in predicting peak VO2 < 14 mL/kg/min. Using this cut-off, LA reservoir strain < 22% was associated with peak VO2 < 14 mL/kg/min in logistic regression analysis after comprehensive adjustment for age, sex, body mass index, heart rhythm, and log-NTproBNP [odds ratio 95% CI 10.4 (1.4-74), P = 0.02]. In this HFpEF and HFmrEF cohort, a reduction in LA reservoir strain was a sensible marker of decreased peak exercise capacity. Therefore, LA reservoir strain might be of clinical value in predicting exercise capacity in patients with HFpEF or HFmrEF.


DC-SIGN and L-SIGN can act as attachment receptors for alphaviruses and distinguish between mosquito cell- and mammalian cell-derived viruses.
C-type lectins such as DC-SIGN and L-SIGN, which bind mannose-enriched carbohydrate modifications of host and pathogen proteins, have been shown to bind glycoproteins of several viruses and facilitate either cis or trans infection. DC-SIGN and L-SIGN are expressed in several early targets of arbovirus infection, including dendritic cells (DCs) and cells of the reticuloendothelial system. In the present study, we show that DC-SIGN and L-SIGN can function as attachment receptors for Sindbis (SB) virus, an arbovirus of the Alphavirus genus. Human monocytic THP-1 cells stably transfected with DC-SIGN or L-SIGN were permissive for SB virus replication, while untransfected controls were essentially nonpermissive. The majority of control THP-1 cells were permissive when attachment and entry steps were eliminated through electroporation of virus transcripts. Infectivity for the DC-SIGN/L-SIGN-expressing cells was largely blocked by yeast mannan, EDTA, or a DC-SIGN/L-SIGN-specific monoclonal antibody. Infection of primary human DCs by SB virus was also dependent upon SIGN expression by similar criteria. Furthermore, production of virus particles in either C6/36 mosquito cells or CHO mammalian cells under conditions that limited complex carbohydrate content greatly increased SB virus binding to and infection of THP-1 cells expressing these lectins. C6/36-derived virus also was much more infectious for primary human DCs than CHO-derived virus. These results suggest that (i) lectin molecules such as DC-SIGN and L-SIGN may represent common attachment receptor molecules for arthropod-borne viruses, (ii) arbovirus particles produced in and delivered by arthropod vectors may preferentially target vertebrate host cells bearing these or similar lectin molecules, and (iii) a cell line has been identified that can productively replicate alphaviruses but is deficient in attachment receptors.


Potent Anti-Inflammatory and Antiadipogenic Properties of Bamboo (Sasa coreana Nakai) Leaves Extract and Its Major Constituent Flavonoids.
The pro-inflammatory response and recruitment of macrophages into adipose tissue contribute to metabolic dysfunction. Here, we reported the anti-inflammatory and antiadipogenic effects of the methanol (MeOH) extract and ethyl acetate (EtOAc) fraction of bamboo leaf and its molecular mechanism in RAW264.7 cells and 3T3-L1 adipocytes, respectively. Functional macrophage migration assays also were performed. Surprisingly, the EtOAc fraction of MeOH extracts from native Korean plant species Sasa coreana Nakai (SCN) has shown potent anti-inflammatory properties; SCN pretreatment inhibited nitric oxide (NO) production (p < 0.01) and inducible nitric oxide synthase (iNOS) expression in lipopolysaccharide (LPS)-stimulated macrophages. Inflammatory genes induced by LPS, including TNFα, IL-1β, and IL-6, were significantly attenuated by SCN (p < 0.01). Pretreatment with SCN antagonized NF-κB nuclear translocation and the simultaneous degradation of inhibitory κB protein. Furthermore, SCN selectively inhibited the LPS-induced phosphorylation of JNK (p < 0.01) and p38 (p < 0.05) but not ERK (p > 0.05). Similar to leaf extracts of other bamboo species, we identified that SCN contained several flavonoids including orientin, isoorientin, and vitexin; these compounds inhibited LPS-induced NO production (p < 0.05) and iNOS expression. In addition, SCN inhibited adipocyte differentiation in a dose-dependent manner, as demonstrated by Oil Red O staining and the protein expression of mature adipogenic marker genes. Treatment with the major flavonoids of SCN also inhibited adipogenesis. Furthermore, conditioned medium obtained from adipocytes stimulated macrophage chemotaxis, whereas medium from adipocytes treated with SCN significantly inhibited macrophage migration. Therefore, SCN is a potential therapeutic agent for the prevention of inflammation and obesity.


Influence of extent of muscle shortening and heart rate on work from frog heart trabeculae.
Shortening, lengthening, and net work done by frog (Rana pipiens) heart trabeculae were measured over a range of strain amplitudes (length change) and cycle frequencies. Net work, the product of muscle strain and force over a full lengthening/shortening cycle, increased with strain to strains well over 25% of the muscle's rest length, a value greater than optimum strains reported for most skeletal muscles. A distinct optimum strain for net work was not found. Maximum net work per cycle averaged 7.5 J/kg for ventricular muscle and 2.0 J/kg for atrial muscle. Isometric twitch stress was maximal at 0.4-0.6 Hz twitch frequency in ventricular trabeculae (average 51 kN/m2) and 0.6-1.4 Hz in the atrium (average 14 kN/m2). The twitch duration decreased with increasing twitch frequency. Shortening and net work were maximal at 0.7-Hz cycle frequency in ventricular trabeculae and 0.9 to 1.4 Hz in the atrium. The decline in work per cycle at slower frequencies was due in part to a decline in twitch force. Maximum power for the ventricle was approximately 5 W/kg and occurred at 0.8 Hz and 26% strain, and was 1/3 to 1/4 the power of most skeletal muscles studied at similar temperatures.