Correlates of Physical Activity in Urban African American Adults and Older Adults: Testing the Social Cognitive Theory.
Older adults, especially ethnic minorities continue to be the least active segment of the U.S. population. Health disparities are evident in that African Americans participate in less physical activity (PA) and are less likely to meet PA guidelines compared with non-Hispanic Caucasians. Using the social cognitive theory (SCT), this study examined the individual, social, and physical environmental correlates of PA behavior. Participants (N = 110, females = 96, mean age = 64.8 ± 5.7 years) were urban, community-dwelling African American adults and older adults who completed demographics and psychosocial questionnaires assessing (SCT) constructs of self-efficacy, outcome expectations, social support, and perceptions of the physical environment. A latent factor PA construct represented self-report (Godin Leisure-time Exercise Questionnaire, Physical Activity Scale for the Elderly) and objective (accelerometer worn for 7 days) PA. The direct and indirect effects of SCT constructs on PA were tested using structural equation modeling, and the overall model fit was adequate (comparative fit index = 0.94, root mean square error of approximation = 0.04, standardized root mean square residual = 0.05, chi square = 67.03, p = .17). Results indicated that: (a) self-efficacy was the strongest direct predictor of PA (β = 0.79) and also influenced outcome expectations (β = 0.457, p < .001); and (b) outcome expectations directly (β = 0.36) predicted PA. Among demographic moderators, only age was inversely associated with outcome expectations (β = -0.28). Social support or physical environment did not influence PA. Our findings suggest that self-efficacy and outcome expectations are important correlates of PA for African American adults and older adults. Future studies should examine the direct and indirect impact of PA interventions targeting self-efficacy and outcomes expectations to promote behavior change.


Dietary cysteine and other amino acids and stroke incidence in women.
Cysteine could potentially lower the risk of stroke through antihypertensive and antioxidant effects. Our aim was to evaluate the hypothesis that cysteine intake is inversely associated with stroke incidence. We used data from the Swedish Mammography Cohort, a population-based prospective cohort of 34 250 women who were free of cardiovascular disease and cancer and had completed a food-frequency questionnaire about diet and other risk factors for stroke in the autumn of 1997. Stroke cases were identified by linkage of the study population with the Swedish Inpatient Register and the Swedish Cause of Death Register. Relative risks (RR) with 95% confidence intervals, adjusted for potential confounders, were estimated by using Cox proportional hazards regression model. We ascertained 1751 incident cases of stroke during 10.4 years of follow-up. Dietary cysteine intake (mean, 635 mg/d) was inversely associated with stroke risk. The multivariable RR of total stroke comparing the highest with the lowest quintile of cysteine intake was 0.79 (95% confidence interval, 0.65-0.97; P for trend=0.04). The corresponding RR was 0.82 (95% confidence interval, 0.65-1.03; P for trend=0.12) for cerebral infarction and 0.54 (95% confidence interval, 0.29-1.03; P for trend=0.08) for intracerebral hemorrhage. Dietary intake of other amino acids showed no independent (after adjustment for cysteine intake) association with stroke risk. These findings suggest that dietary cysteine intake may be inversely associated with risk of stroke. URL: http://www.clinicaltrials.gov. Unique identifier: NCT01127698.


Measuring gender norms about relationships in early adolescence: Results from the global early adolescent study.
Gender norms are increasingly recognized as drivers of health and wellbeing. While early adolescence constitutes a critical window of development, there is limited understanding about how adolescents perceive gender relations across different cultural settings. This study used a mixed-method approach, grounded in the voices of young people around the world, to construct and test a cross-cultural scale assessing the perceptions of gender norms regulating romantic relationships between boys and girls in early adolescence. The study draws on the Global Early Adolescent study (GEAS), a study focusing on gender norms and health related outcomes over the course of adolescence in urban poor settings worldwide. In-depth interviews were first conducted among approximately 200 adolescents between 10-14 years in seven sites across 4 continents to identify common scripts guiding romantic relations in early adolescence. These scripts were then transformed into a multidimensional scale. The scale was tested among 120 adolescents in each of 14 GEAS sites, followed by a second pilot among 75 adolescents in six sites. We evaluated the psychometric criteria of each sub-scale using principal component analysis, and parallel analysis, followed by exploratory factor analysis to guide the selection of a more parsimonious set of items. Results suggested a two-factor structure, consisting of an "adolescent romantic expectations" subscale and a "Sexual Double Standard" subscale. Both subscales yielded high internal validity in each site, with polychoric Cronbach alpha values above 0.70 with the exception of Kinshasa for the adolescent romantic expectations scale (0.64) and Hanoi for the sexual double standard scale (0.61). This study reveals common perceptions of gendered norms about romantic engagement in early adolescence, normative for both sexes, but socially valued for boys while devaluated for girls. The findings illustrate that social hierarchies of power in romantic relationships form early in adolescence, regardless of cultural setting.


Parkinson's Disease With Visual Hallucinations Is Associated With Epileptiform Activity on EEG.
Background: Visual hallucinations (VHs) in Parkinson's disease (PD) are the cardinal symptoms which declare the onset of PD psychosis (PDP). The anthropomorphic and zoomorphic VHs of PD resemble those of Charles Bonnet syndrome and temporal lobe epilepsy. In both of these disorders electroencephalography (EEG) abnormalities have been described. We therefore sought to examine whether VHs in PD were associated with similar EEG abnormalities. Methods: This retrospective observational study searched the medical records of 300 PD patients and filtered for those containing clinical 20-min scalp EEGs. Remaining records were separated into two groups: patients with reported VHs and those without. The prevalence of epileptiform discharges in the EEGs of both groups was identified. Results: Epileptiform discharges were present in 5 of 13 (38.5%) PD patients with VHs; all localized to the temporal lobe. No epileptiform discharges were observed in the EEGs of the 31 PD patients without VHs. Conclusion: The significantly high incidence of temporal lobe epileptiform discharges in PD patients with VHs as compared to those without VHs lends to the possibility of an association visual cortex epileptogenic focus. Accordingly, for treatment-refractory patients, antiepileptic drugs might be considered, as in the case of Charles Bonnet syndrome, temporal lobe epilepsy and migraine with visual aura. Future prospective studies involving larger samples and multi-center cohorts are required to validate these observational findings.


Animal models of chronic obstructive pulmonary disease.
Chronic obstructive pulmonary disease (COPD) is a leading global cause of mortality and chronic morbidity. Inhalation of cigarette smoke is the principal risk factor for development of this disease. COPD is a progressive disease that is typically characterised by chronic pulmonary inflammation, mucus hypersecretion, airway remodelling and emphysema that collectively reduce lung function. There are currently no therapies that effectively halt or reverse disease progression. It is hoped that the development of animal models that develop the hallmark features of COPD, in a short time frame, will aid in the identifying and testing of new therapeutic approaches. The authors review the recent developments in mouse models of chronic cigarette smoke-induced COPD as well as the principal findings. Furthermore, the authors discuss the use of mouse models to understand the pathogenesis and the contribution of infectious exacerbations. They also discuss the investigations of the systemic co-morbidities of COPD (pulmonary hypertension, cachexia and osteoporosis). Recent advances in the field mark a point where animal models recapitulate the pathologies of COPD patients in a short time frame. They also reveal novel insights into the pathogenesis and potential treatment of this debilitating disease.


Exploiting parallel corpora to scale up multilingual biomedical terminologies.
Creating and maintaining biomedical terminologies for multiple natural languages is a resource-expensive task, typically carried out by human domain experts. We here report on efforts to computationally support this process by treating term acquisition as a machine translation-guided classification problem capitalizing on parallel corpora. We report on experiments for French, German, Spanish and Dutch parts of a UMLS-derived terminology for which we generated 18 k, 23 k, 19 k and 12 k new terms and synonyms, respectively. Based on expert assessments of a novel German terminology segment about 80% of the newly acquired terms were judged as bio-medically reasonable and terminologically valid.


HOXB5 Overexpression Is Associated with Neuroendocrine Differentiation and Poor Prognosis in Prostate Cancer.
Homeobox genes function as master regulatory transcription factors during embryogenesis. HOXB5 is known to play an important role in several cancers. However, the biological role of HOXB5 in prostate cancer (PCa) is not fully elucidated. This study aimed to analyze the expression and function of HOXB5 and involvement of HOXB5 in neuroendocrine differentiation in PCa. Immunohistochemistry showed that 56 (43.8%) of 128 cases of localized PCa were positive for HOXB5. HOXB5-positive cases were associated with poor prostate-specific antigen recurrence-free survival after prostatectomy. Among 74 cases of metastatic PCa, 43 (58.1%) were positive for HOXB5. HOXB5 expression was higher in metastatic PCa than that in localized PCa. HOXB5 knockdown suppressed cell growth and invasion, but HOXB5 overexpression increased cell growth and invasion in PCa cell lines. Furthermore, HOXB5 regulated RET expression. Gene set enrichment analysis revealed that Nelson androgen response gene set was enriched in low HOXB5 expression group. RB1 knockout increased HOXB5 expression. Of note, additional p53 knockdown further increased HOXB5 expression in RB1 knockout cells. In silico analysis showed that HOXB5 expression was increased in neuroendocrine PCa (NEPC). These results suggest that HOXB5 may be a promising prognostic marker after prostatectomy and is involved in progression to NEPC.


Alcohol outlet business hours and violent crime in New York state.
Alcohol-related harm places a significant strain on victims, perpetrators and society. The present research reports on how licensed alcohol outlet business hours may influence the reported incidence of interpersonal violence and the associated burden of disease. We examined the relationship between alcohol outlet business hours and violent crime in 2009 in New York State (excluding New York City). Regression analyses modeled the burden of disease for the violence associated with outlet business hours. Every 1 h increase in weekly outlet business hours was associated with a greater reported incidence of violent crimes generally, more reported aggravated assaults and more reported non-gun violence. The estimated cost from having licensed premises open after 1 a.m. was $194 million in 2009. The findings suggest that alcohol outlet business hours affect the incidence of reported violence even in regions that would not be considered to have severe problems with alcohol-fueled violence.


Synthetic aperture imaging using sources with finite aperture: deconvolution of the spatial impulse response.
A method for ultrasonic synthetic aperture imaging using finite-sized transducers is introduced that is based on a compact, linear, discrete model of the ultrasonic measurement system developed using matrix formalism. Using this model a time-domain algorithm for deconvolution of the transducer's spatial impulse responses (SIRs) is developed that is based on a minimum mean square error (MMSE) criterion. The algorithm takes the form of a spatiotemporal filter that compensates for the SIRs associated with a finite-sized transducer at every point of the processed image. A major advantage of the proposed method is that it can be used for any transducer, provided that its associated SIRs are known. This is in contrast to the synthetic aperture focusing technique (SAFT), which treats the transducer as a point source. The performance of the method is evaluated with simulations and experiments, performed in water using a linear phased array. The results obtained using the proposed method are compared to those obtained with a classical time-domain SAFT algorithm. For a finite aperture source, it is clearly shown that the resolution obtained using the proposed method is superior to that obtained using the SAFT algorithm.


Cost-effective criteria for glucose screening.
To study cost-effective screening criteria for gestational diabetes, a prospective study of 1012 patients was completed. All patients underwent a glucose screen between 26 and 30 weeks of gestation, consisting of a 50-g oral glucose load followed by a one-hour plasma glucose determination. Patients with a glucose screen greater than or equal to 130 mg/dL were studied with a standard three-hour oral glucose tolerance test. The incidence of gestational diabetes was 2.4% (24 of 1012). Only one gestational diabetic was identified with a glucose screen below 150 mg/dL. Twenty-two of the 24 cases were at least 24 years old. Twenty-one of the 24 (88%) gestational diabetes had a glucose screen greater than or equal to 150 mg/dL and were 24 years old or greater. The cost of the diagnosis in these latter patients was 40% of the cost of diagnosis of universal screening with a threshold of 130 mg/dL. It is concluded that screening with a threshold of 150 mg/dL only patients who are at least 24 years old should be considered an alternative to universal screening.


Exploring the binding mechanism of Guaijaverin to human serum albumin: fluorescence spectroscopy and computational approach.
The Guaijaverin (Gua) is a polyphenolic substance which exhibits some pharmacological activities such as antibacterial and antioxidant activities. Here we have investigated the binding of Gua with human serum albumin (HSA) at physiological pH 7.0. In this study, the fluorescence spectroscopy, ab initio and molecular modeling calculations were applied. The Stern-Volmer quenching constant (K(SV)) and its modified form (K(a)) were calculated at 298, 303 and 308 K, with the corresponding thermodynamic parameters ΔH, ΔG and ΔS as well. The fluorescence quenching method was used to determine the number of binding sites (n) and binding constants (K(b)) values at 298, 303 and 308 K. The distance between donor (HSA) and acceptor (Gua) was estimated according to fluorescence resonance energy transfer. The geometry optimization of Gua was performed in its ground state by using ab initio DFT/B3LYP functional with a 6-31G(d,p) basis set used in calculations. Molecular modeling calculation indicated that the Gua is located within the hydrophobic pocket of the subdomain IIA of HSA. The theoretical results obtained by molecular modeling were corroborated by fluorescence spectroscopy data.


Compensatory Increase in Heart Rate Is Responsible for Exercise Tolerance among Male Patients with Permanent Atrial Fibrillation.
Atrial fibrillation (AF) is an exacerbating factor for exercise tolerance due to the loss of atrial kick. However, many patients with permanent AF, which lasts for at least a year without interruption, and preserved left ventricular ejection fraction (LVEF ≥ 50%) are asymptomatic and have good exercise tolerance. In such cases, the possible mechanism that compensates for the decrease in cardiac output accompanying the loss of atrial kick is a sufficient increase in heart rate (HR) during exercise. We investigated the relationship between exercise tolerance and peak HR during exercise using cardiopulmonary exercise testing in 242 male patients with preserved LVEF, 214 with sinus rhythm (SR) and 28 with permanent AF. Peak HR was significantly higher in the AF group than the SR group (148.9 ± 41.9 vs. 132.0 ± 22.0 beats/min, p = 0.001). However, oxygen uptake at peak exercise did not differ between the AF and SR groups (19.4 ± 5.7 vs. 21.6 ± 6.0 mL/kg/min, p = 0.17). In multiple regression analysis, peak HR (β, 0.091; p < 0.001) and the interaction term constructed by peak HR and presence of permanent AF (β, 0.05; p = 0.04) were selected as determinants for peak VO2; however, presence of permanent AF was not selected (β, -0.38; p = 0.31). Therefore, the impact of peak HR on exercise tolerance differed between the AF and SR groups, suggesting that a sufficient increase in HR during exercise is an important factor to preserve exercise tolerance among patients with AF.


The effects of (2R,6R)-hydroxynorketamine on oxycodone withdrawal and reinstatement.
Despite the thousands of lives lost during the ongoing opioid crisis, a scarcity of new and effective clinical treatments for opioid use disorder (OUD) remains. To address this unmet need, some researchers have turned to dissociative and psychedelic drugs to treat multiple psychiatric conditions. In particular, low doses of ketamine have been shown to attenuate opioid withdrawal and drug use in clinical and preclinical studies. However, ketamine has misuse liability and dissociative side effects that may limit its widespread application as a treatment for OUD. More recently, (2R,6R)-hydroxynorketamine (HNK), a ketamine metabolite that lacks misuse potential, has gained attention for its effectiveness in depression and stress models. To uncover its role in OUD, we tested the time-dependent effects of (2R,6R)-HNK on oxycodone withdrawal and reinstatement of oxycodone conditioned place preference (CPP). In male and female oxycodone-dependent mice, we found that 24h pretreatment with (2R,6R)-HNK (10 or 30mg/kg, s.c.) reduced the frequency of withdrawal-like behaviors and global withdrawal scores during naloxone-precipitated withdrawal, whereas 1h pretreatment with (2R,6R)-HNK only reduced paw tremors and the sum of global withdrawal scores but not GWS Z-scores. In other experiments, both 1h and 24h pretreatment with (2R,6R)-HNK (30mg/kg, s.c.) blocked drug-induced reinstatement of oxycodone CPP. Finally, we found (2R,6R)-HNK (30mg/kg, sc) had no effect on locomotor activity and thigmotaxis. Together, these results indicate that acute (2R,6R)-HNK has efficacy in some preclinical models of OUD without producing locomotor or anxiety-like side effects.


Distinct Actions of the Thyroid Hormone Transporters Mct8 and Oatp1c1 in Murine Adult Hippocampal Neurogenesis.
Inactivating mutations in the thyroid hormone (TH) transporter monocarboxylate transporter 8 (MCT8) result in Allan-Herndon-Dudley Syndrome, a severe form of psychomotor retardation, while inactivating mutations in another TH transporter, organic anion transporting polypeptide 1c1 (OATP1C1), are linked to juvenile neurodegeneration. These diseases point to essential roles for TH transporters in CNS function. We recently defined the presence of Mct8 in adult hippocampal progenitors and mature granule cell neurons and unraveled cell-autonomous and indirect requirements for Mct8 in adult hippocampal neurogenesis. Here, we investigated whether Oatp1c1 is involved in the hippocampal neurogenic process in concert with Mct8. We detected Oatp1c1 gene expression activity and transcripts in subsets of progenitors, neurons and niche cells in the dentate gyrus. Absence of Oatp1c1 resulted in increased neuroblast and reduced immature neuron numbers in 6-month-old Oatp1c1ko and Mct8/Oatp1c1 double knockout (M/Odko) mice. Reduced EdU-label retention in Mct8ko and M/Odko mice confirmed the impact of Mct8 on neuron formation. In contrast, no significant effect of Oatp1c1 loss on granule cell neuron production and anxiety-like behavior in the open field arena were seen. Together, our results reinforce that distinct actions of each TH transporter are required at multiple stages to ensure proper adult hippocampal neurogenesis.


Function of various intestinal bacteria in converting germfree mice to the normal state.
Earlier work had shown that a collection of anaerobic bacteria, in conjunction with facultative anaerobes, may be implanted into germfree mice, thereby rendering the animals "normal" with respect to a variety of parameters tested. The present experiments indicate that a different collection of anaerobic bacteria, isolated from the cecum of normal mice, was necessary to convert germfree mice to the "normal" state when the animals were fed a crude diet, rather than the refined food which had been used in the earlier work. The nature and level of short-chain fatty acids associated with various natural or synthetic "normal" floras in the ceca of mice did not always correlate with the Escherichia coli population present, indicating that fatty acids were not the sole agents inhibiting bacterial populations in the intestine. Experiments are reported which indicate that intestinal anaerobes may under certain circumstances be sufficient to control the populations of other intestinal bacteria such as E. coli. In other instances, such as control of Shigella populations in the mouse intestine, intestinal anaerobes appeared to act synergistically with an E. coli strain, in spite of the fact that the population of the latter was itself suppressed by the anaerobes.


Radioiodine therapy accelerates apoptosis in peripheral blood lymphocytes of patients with differentiated thyroid cancer.
Both apoptosis and micronuclei formation reflect cytogenetic damage in cells and could contribute to cell homeostasis. The aim of this study was to evaluate apoptosis in peripheral blood lymphocytes (PBLs) of patients with differentiated thyroid cancer (DTC) before and after 131-iodine (131-I)-therapy and its correlation with micronuclei (MN) frequency. The study population included 18 DTC patients and 18 healthy donors. Apoptotic cells were detected using the Annexin V-FITC/7-AAD kit and MN frequency by cytokinesis-block MN assay. The difference between early apoptosis in PBLs of DTC patients before therapy and controls (9.88 ± 4.99% vs. 6.64 ± 2.07%, p = 0.003) was significant, as well as between early apoptosis in PBLs of DTC patients before and after 131-I-therapy (9.88 ± 4.99% vs. 13.53 ± 6.57%, p = 0.008). The MN frequency and early apoptosis in PBLs of DTC patients was positively correlated before (r = 0.540, p= 0.021) and after 131-I-therapy (r = 0.585, p= 0.014). Thyroid cancer patients had a significantly increased early apoptosis in PBLs, which further increased after 131-I-therapy in association with MN frequency.


Identification of UvrY as the cognate response regulator for the BarA sensor kinase in Escherichia coli.
BarA is a membrane-associated protein that belongs to a subclass of tripartite sensors of the two-component signal transduction system family. In this study, we report that UvrY is the cognate response regulator for BarA of Escherichia coli. This conclusion is based upon homologies with analogous two-component systems and demonstrated by both biochemical and genetic means. We show that the purified BarA protein is able to autophosphorylate when incubated with [gamma-(32)P]ATP but not with [alpha-(32)P]ATP or [gamma-(32)P]GTP. Phosphorylated BarA, in turn, acts as an efficient phosphoryl group donor to UvrY but not to the non-cognate response regulators ArcA, PhoB, or CpxR. The specificity of the transphosphorylation reaction is further supported by the fact that UvrY can receive the phosphoryl group from BarA-P but not from the non-cognate tripartite sensor ArcB-P or ATP. In addition, genetic evidence that BarA and UvrY mediate the same signal transduction pathway is provided by the finding that both uvrY and barA mutant strains exhibit the same hydrogen peroxide hypersensitive phenotype. These results provide the first biochemical evidence as well as genetic support for a link between BarA and UvrY, suggesting that the two proteins constitute a new two-component system for gene regulation in Escherichia coli.


β-Cyclodextrin-threaded biocleavable polyrotaxanes ameliorate impaired autophagic flux in Niemann-Pick type C disease.
Niemann-Pick type C (NPC) disease is characterized by the lysosomal accumulation of cholesterols and impaired autophagic flux due to the inhibited fusion of autophagosomes to lysosomes. We have recently developed β-cyclodextrin (β-CD)-threaded biocleavable polyrotaxanes (PRXs), which can release threaded β-CDs in response to intracellular environments as a therapeutic for NPC disease. The biocleavable PRXs exhibited effective cholesterol reduction ability and negligible toxic effect compared with hydroxypropyl-β-CD (HP-β-CD). In this study, we investigated the effect of biocleavable PRX and HP-β-CD on the impaired autophagy in NPC disease. The NPC patient-derived fibroblasts (NPC1 fibroblasts) showed an increase in the number of LC3-positive puncta compared with normal fibroblasts, even in the basal conditions; the HP-β-CD treatment markedly increased the number of LC3-positive puncta and the levels of p62 in NPC1 fibroblasts, indicating that autophagic flux was further perturbed. In sharp contrast, the biocleavable PRX reduced the number of LC3-positive puncta and the levels of p62 in NPC1 fibroblasts through an mTOR-independent mechanism. The mRFP-GFP-LC3 reporter gene expression experiments revealed that the biocleavable PRX facilitated the formation of autolysosomes to allow for autophagic protein degradation. Therefore, the β-CD-threaded biocleavable PRXs may be promising therapeutics for ameliorating not only cholesterol accumulation but also autophagy impairment in NPC disease.


An Application for the Quantitative Analysis of Pharmaceutical Tablets Using a Rapid Switching System Between a Near-Infrared Spectrometer and a Portable Near-Infrared Imaging System Equipped with Fiber Optics.
We present a rapid switching system between a newly developed near-infrared (NIR) spectrometer and its imaging system to select the spot size of a diffuse reflectance (DR) probe. In a previous study, we developed a portable NIR imaging system, known as D-NIRs, which has significant advantages over other systems. Its high speed, high spectral resolution, and portability are particularly useful in the process of monitoring pharmaceutical tablets. However, the spectral accuracies relating to the changes in the formulation of the pharmaceutical tablets have not been fully discussed. Therefore, we improved the rapid optical switching system and present a new model of D-NIRs (ND-NIRs) here. This system can automatically switch the optical paths of the DR and NIR imaging probes, greatly contributing to the simultaneous measurement of both the imaging and spot. The NIR spectra of the model tablets, including 0-10% ascorbic acid, were measured and simultaneous NIR images of the tablets were obtained. The predicted results using spot sizes for the DR probe of 1 and 5 mm diameter, resulted in concentrations of R2 = 0.79 and 0.94, with root mean square errors (RMSE) of 1.78 and 0.89, respectively. For tablets with a high concentration of ascorbic acid, the NIR imaging results showed inhomogeneity in concentration. However, the predicted values for the low concentration samples appeared higher than the known concentration of the tablets, although the homogeneity of the concentration was confirmed. In addition, the optimal spot size using NIR imaging data was estimated to be 5-7 mm. The results obtained in this study show that the spot size of the fiber probe, attached to a spectrometer, is important in developing a highly reliable model to determine the component concentration of a tablet.


Population genetic structure of Phytophthora cinnamomi associated with avocado in California and the discovery of a potentially recent introduction of a new clonal lineage.
Phytophthora root rot (PRR) of avocado (Persea americana), caused by Phytophthora cinnamomi, is the most serious disease of avocado worldwide. Previous studies have determined that this pathogen exhibits a primarily clonal reproductive mode but no population level studies have been conducted in the avocado-growing regions of California. Therefore, we used amplified fragment length polymorphism based on 22 polymorphic loci and mating type to investigate pathogen diversity from 138 isolates collected in 2009 to 2010 from 15 groves from the Northern and Southern avocado-growing regions. Additional isolates collected from avocado from 1966 to 2007 as well as isolates from other countries and hosts were also used for comparative purposes. Two distinct clades of A2 mating-type isolates from avocado were found based on neighbor joining analysis; one clade contained both newer and older collections from Northern and Southern California, whereas the other clade only contained isolates collected in 2009 and 2010 from Southern California. A third clade was also found that only contained A1 isolates from various hosts. Within the California population, a total of 16 genotypes were found with only one to four genotypes identified from any one location. The results indicate significant population structure in the California avocado P. cinnamomi population, low genotypic diversity consistent with asexual reproduction, potential evidence for the movement of clonal genotypes between the two growing regions, and a potential introduction of a new clonal lineage into Southern California.


Cross-species analysis of the mammalian beta-defensin gene family: presence of syntenic gene clusters and preferential expression in the male reproductive tract.
Mammalian beta-defensins are an important family of innate host defense peptides with pleiotropic activities. As a first step to study the evolutionary relationship and biological role of the beta-defensin family, we identified their complete repertoires in the human, chimpanzee, mouse, rat, and dog following systemic, genome-wide computational searches. Although most beta-defensin genes are composed of two exons separated by an intron of variable length, some contain an additional one or two exons encoding an internal pro-sequence, a segment of carboxy-terminal mature sequences or untranslated regions. Alternatively, spliced isoforms have also been found with several beta-defensins. Furthermore, all beta-defensin genes are densely clustered in four to five syntenic chromosomal regions, with each cluster spanning <1.2 Mb across the five species. Phylogenetic analysis indicated that, although the majority of beta-defensins are evolutionarily conserved across species, subgroups of gene lineages exist that are specific in certain species, implying that some beta-defensins originated after divergence of these mammals from each other, while most others arose before the last common ancestor of mammals. Surprisingly, RT-PCR revealed that all but one rat beta-defensin transcript are preferentially expressed in the male reproductive tract, particularly in epididymis and testis, except that Defb4, a human beta-defensin-2 ortholog, is more restricted to the respiratory and upper gastrointestinal tracts. Moreover, most beta-defensins expressed in the reproductive tract are developmentally regulated, with enhanced expression during sexual maturation. Existence of such a vast array of beta-defensins in the male reproductive tract suggests that these genes may play a dual role in both fertility and host defense.


The hibernating South American marsupial, Dromiciops gliroides, displays torpor-sensitive microRNA expression patterns.
When faced with adverse environmental conditions, the marsupial Dromiciops gliroides uses either daily or seasonal torpor to support survival and is the only known hibernating mammal in South America. As the sole living representative of the ancient Order Microbiotheria, this species can provide crucial information about the evolutionary origins and biochemical mechanisms of hibernation. Hibernation is a complex energy-saving strategy that involves changes in gene expression that are elicited in part by microRNAs. To better elucidate the role of microRNAs in orchestrating hypometabolism, a modified stem-loop technique and quantitative PCR were used to characterize the relative expression levels of 85 microRNAs in liver and skeletal muscle of control and torpid D. gliroides. Thirty-nine microRNAs were differentially regulated during torpor; of these, 35 were downregulated in liver and 11 were differentially expressed in skeletal muscle. Bioinformatic analysis predicted that the downregulated liver microRNAs were associated with activation of MAPK, PI3K-Akt and mTOR pathways, suggesting their importance in facilitating marsupial torpor. In skeletal muscle, hibernation-responsive microRNAs were predicted to regulate focal adhesion, ErbB, and mTOR pathways, indicating a promotion of muscle maintenance mechanisms. These tissue-specific responses suggest that microRNAs regulate key molecular pathways that facilitate hibernation, thermoregulation, and prevention of muscle disuse atrophy.


Multiple domains of Ruk/CIN85/SETA/CD2BP3 are involved in interaction with p85alpha regulatory subunit of PI 3-kinase.
Ruk/CIN85/SETA/CD2BP3 and CD2AP/CMS/METS-1 comprise a new family of proteins involved in such fundamental processes as clustering of receptors and rearrangement of the cytoskeleton in regions of specialised cell-cell contacts, ligand-activated internalisation and targeting to lysosome degradation pathway of receptor tyrosine kinases, and apoptotic cell death. As typical adapter proteins they execute these functions by interacting with other signalling molecules via multiple protein-protein interaction interfaces: SH3 domains, Pro-rich region and coiled-coil domain. It has been previously demonstrated that Ruk is able to interact with the p85alpha regulatory subunit of PI 3-kinase and that the SH3 domain of p85alpha is required for this interaction. However, later observations hinted at a more complex mechanism than simple one-way SH3-Pro-rich interaction. Because interaction with p85alpha was suggested to be important for pro-apoptotic activity of the long isoform of Ruk, Ruk(l)/CIN85, we carried out detailed studies of the mechanism of this interaction and demonstrated that multiple domains are involved; SH3 domains of Ruk are required and sufficient for efficient interaction with full-length p85alpha but the SH3 domain of p85alpha is vital for their "activation" by ousting them from intramolecular interaction with the Pro-rich region of Ruk. Our data also suggest that homodimerisation via C-terminal coiled-coil domain affects both intra- and intermolecular interactions of Ruk proteins.


Is patient education helpful in providing care for patients with rheumatoid arthritis? A qualitative study involving French nurses.
This French study explored nurses' involvement in patient education for patients with rheumatoid arthritis. The study design was qualitative. Semistructured interviews were conducted with 16 hospital nurses. Data analysis was performed according to Giorgi's descriptive phenomenological method, and supported by specific qualitative analysis software (Sphinx). The results showed the important role of hospital nurses in rheumatoid arthritis care. Patient education is a core part of nurses' work, allowing them to give patients information and emotional support. The interviewees displayed skills in helping patients learn to care for themselves. However, patient education mostly concerned patients who are already committed to their health care. Non-adherent patients warrant special attention; their acceptance of their disease, perceptions about disease and treatment, motivation, and autonomy should be specifically addressed. French nurses could benefit from more training, and could be aided by psychologists. Ambulatory services could also be developed for patient education in France, based on examples from other countries.


[Efficacy of domiciliary noninvasive positive pressure ventilation in chronic obstructive pulmonary disease patients].
The aim of this study was to assess the clinical features and efficacy of domiciliary noninvasive positive pressure ventilation (NPPV) in patients with chronic obstructive pulmonary disease (COPD). We conducted a retrospective study of 16 patients with COPD who received NPPV between March 1996 and April 2005. The patient characteristics, clinical features, a change in arterial PaCO2 and prognoses were evaluated. The study population consisted of 15 males and 1 female, mean age 68.4 +/- 9.9 yrs. The mean values of pulmonary function tests were as follows; FEV1 = 0.73L, FEV1% = 29.8%, VC = 2.49L, %VC = 77.5%, RV/ TLC 55.4%, PaO2 59.8 Torr, PaCO2 71.4 Torr (on admission). Fourteen of 16 patients presented desaturation in the night and 6 patients had sleep apnea syndrome. Eight of the 16 patients received NPPV during acute exacerbation. NPPV yielded dramatic improvement in daytime hypercapnia and clinical symptoms. However, arterial PaCO2 gradually elevated during the long-term clinical course. The duration of treatment was from 2 months to 9 years, with a mean value of 2.3 years. The cause of death of 7 patients was respiratory failure in 5 cases and lung cancer in 2, respectively, and the mortality was significantly higher in patients who received NPPV during acute exacerbation than stable COPD patients receiving NPPV. Long-term improvement in daytime clinical symptoms and arterial blood gas tensions can be achieved by NPPV in patients with COPD.


Inhibition of xanthine dehydrogenase from Triatoma infestans by some purine analogues.
Xanthine dehydrogenase (EC 22.214.171.124) activity was determined in the fat body of the Chagas' disease vector Triatoma infestans using a system in which phenazine methosulphate was associated with p-iodonitrotetrazolium violet as electron acceptors for the oxidation of the substrate xanthine. Under the standard conditions used, xanthine was the substrate of choice. The apparent Michaelis-Menten constant (Km) for xanthine was found to be 0.217 +/- 0.020 mM (mean +/- standard deviation of four independent determinations) in the absence of the inhibitors. In the presence of the purine derivatives used the average apparent Km varied from 0.216 mM to 0.219 mM, using the same enzyme preparation. In the presence of the inhibitors tested, competitive inhibition was observed with 8-azaxanthine (Ki = 0.160 mM), adenine hemisulphate (Ki = 0.184 mM) and 6-mercaptopurine (Ki = 0.008 mM). Noncompetitive inhibition was obtained with 8-azaguanine (Ki = 0.077 mM) most probably due to the formation of a dead-end complex between the enzyme, the substrate and the inhibitor.


Closing the Wearable Gap-Part II: Sensor Orientation and Placement for Foot and Ankle Joint Kinematic Measurements.
The linearity of soft robotic sensors (SRS) was recently validated for movement angle assessment using a rigid body structure that accurately depicted critical movements of the foot-ankle complex. The purpose of this study was to continue the validation of SRS for joint angle movement capture on 10 participants (five male and five female) performing ankle movements in a non-weight bearing, high-seated, sitting position. The four basic ankle movements-plantar flexion (PF), dorsiflexion (DF), inversion (INV), and eversion (EVR)-were assessed individually in order to select good placement and orientation configurations (POCs) for four SRS positioned to capture each movement type. PF, INV, and EVR each had three POCs identified based on bony landmarks of the foot and ankle while the DF location was only tested for one POC. Each participant wore a specialized compression sock where the SRS could be consistently tested from all POCs for each participant. The movement data collected from each sensor was then compared against 3D motion capture data. R-squared and root-mean-squared error averages were used to assess relative and absolute measures of fit to motion capture output. Participant robustness, opposing movements, and gender were also used to identify good SRS POC placement for foot-ankle movement capture.


A dynamic scaffolding mechanism for rhodopsin and transducin interaction in vertebrate vision.
The early steps in vertebrate vision require fast interactions between Rh (rhodopsin) and Gt (transducin), which are classically described by a collisional coupling mechanism driven by the free diffusion of monomeric proteins on the disc membranes of rod and cone cells. Recent findings, however, point to a very low mobility for Rh and support a substantially different supramolecular organization. Moreover, Rh-G(t) interactions seem to possibly occur even prior to light stimuli, which is also difficult to reconcile with the classical scenario. We investigated the kinetics of interaction between native Rh and G(t) in different conditions by surface plasmon resonance and analysed the results in the general physiological context by employing a holistic systems modelling approach. The results from the present study point to a mechanism that is intermediate between pure collisional coupling and physical scaffolding. Such a 'dynamic scaffolding', in which prevalently dimeric Rh and G(t) interact in the dark by forming transient complexes (~25% of G(t) is precoupled to Rh), does not slow down the phototransduction cascade, but is compatible with the observed photoresponses on a broad scale of light stimuli. We conclude that Rh molecules and Rh-G(t) complexes can both absorb photons and trigger the visual cascade.


Incidental extracolonic findings at CT colonography.
To determine the frequency of extracolonic findings at computed tomographic (CT) colonography and the effect of these findings on subsequent patient treatment and cost. Conventional transverse CT colonographic scans in 264 consecutive patients were evaluated independently by two radiologists. Extracolonic findings were classified as having high, moderate, or low clinical importance. The effect of CT findings on patient treatment was assessed with chart review. The cost of additional examinations was calculated by using 1999 Medicare reimbursements. Thirty (11%) patients had highly important extracolonic findings, which resulted in further examinations in 18 (7%) patients, including ultrasonography in 10, CT in 13, and intravenous pyelography in one. Six patients underwent surgery because of incidentally discovered CT colonographic findings. Two patients with findings of moderate or low importance underwent additional imaging. A total of $7,324 was required for work-up for extracolonic findings (mean of an additional $28 per examination). Three extracolonic malignancies were overlooked at CT colonography. Additional work-up of extracolonic CT colonographic findings was relatively infrequent but was often worthwhile when performed for lesions classified as highly important. The evaluation of extracolonic structures at CT colonography has definite limitations with regard to solid organs but can help detect serious disease without substantially increasing the cost per patient.


Selectivity of Human TLR9 for Double CpG Motifs and Implications for the Recognition of Genomic DNA.
TLR9 acts as a first-line host defense against pathogens recognizing DNA comprising unmethylated CpG motifs present in bacteria and viruses. Species- and sequence-specific recognition differences were demonstrated for TLR9 receptors. Activation of human (h)TLR9 requires a pair of closely positioned CpG motifs within oligodeoxyribonucleotides (ODNs), whereas mouse TLR9 is effectively activated by an ODN with a single CpG motif. Molecular model-directed mutagenesis identified two regions, site A and site B, as important for receptor activation. Amino acid residues Gln346 and Arg348 within site A contribute to the sequence-specific recognition by hTLR9 in determining the bias for two appropriately spaced CpG motifs within immunostimulatory ODNs. Mutation of Gln562 at site B, in combination with Gln346 and Arg348 mutations of mouse counterparts, increased activation of hTLR9 by mouse-specific ODN, mammalian genomic DNA, and bacterial DNA. We propose that the double CpG motif sequence-specificity of hTLR9 results in decreased activation by ODNs with a lower frequency of CpG motifs, such as from mammalian genomic DNA, which increases hTLR9 selectivity for pathogen versus host DNA.


Altered hyperlipidemia, hepatic steatosis, and hepatic peroxisome proliferator-activated receptors in rats with intake of tart cherry.
Elevated plasma lipids, glucose, insulin, and fatty liver are among components of metabolic syndrome, a phenotypic pattern that typically precedes the development of Type 2 diabetes. Animal studies show that intake of anthocyanins reduces hyperlipidemia, obesity, and atherosclerosis and that anthocyanin-rich extracts may exert these effects in association with altered activity of tissue peroxisome proliferator-activated receptors (PPARs). However, studies are lacking to test this correlation using physiologically relevant, whole food sources of anthocyanins. Tart cherries are a rich source of anthocyanins, and whole cherry fruit intake may also affect hyperlipidemia and/or affect tissue PPARs. This hypothesis was tested in the Dahl Salt-Sensitive rat having insulin resistance and hyperlipidemia. For 90 days, Dahl rats were pair-fed AIN-76a-based diets supplemented with either 1% (wt:wt) freeze-dried whole tart cherry or with 0.85% additional carbohydrate to match macronutrient and calorie provision. After 90 days, the cherry-enriched diet was associated with reduced fasting blood glucose, hyperlipidemia, hyperinsulinemia, and reduced fatty liver. The cherry diet was also associated with significantly enhanced hepatic PPAR-alpha mRNA, enhanced hepatic PPAR-alpha target acyl-coenzyme A oxidase mRNA and activity, and increased plasma antioxidant capacity. In conclusion, physiologically relevant tart cherry consumption reduced several phenotypic risk factors that are associated with risk for metabolic syndrome and Type 2 diabetes. Tart cherries may represent a whole food research model of the health effects of anthocyanin-rich foods and may possess nutraceutical value against risk factors for metabolic syndrome and its clinical sequelae.


Self-assembly of Mutant Huntingtin Exon-1 Fragments into Large Complex Fibrillar Structures Involves Nucleated Branching.
Huntingtin (HTT) fragments with extended polyglutamine tracts self-assemble into amyloid-like fibrillar aggregates. Elucidating the fibril formation mechanism is critical for understanding Huntington's disease pathology and for developing novel therapeutic strategies. Here, we performed systematic experimental and theoretical studies to examine the self-assembly of an aggregation-prone N-terminal HTT exon-1 fragment with 49 glutamines (Ex1Q49). Using high-resolution imaging techniques such as electron microscopy and atomic force microscopy, we show that Ex1Q49 fragments in cell-free assays spontaneously convert into large, highly complex bundles of amyloid fibrils with multiple ends and fibril branching points. Furthermore, we present experimental evidence that two nucleation mechanisms control spontaneous Ex1Q49 fibrillogenesis: (1) a relatively slow primary fibril-independent nucleation process, which involves the spontaneous formation of aggregation-competent fibrillary structures, and (2) a fast secondary fibril-dependent nucleation process, which involves nucleated branching and promotes the rapid assembly of highly complex fibril bundles with multiple ends. The proposed aggregation mechanism is supported by studies with the small molecule O4, which perturbs early events in the aggregation cascade and delays Ex1Q49 fibril assembly, comprehensive mathematical and computational modeling studies, and seeding experiments with small, preformed fibrillar Ex1Q49 aggregates that promote the assembly of amyloid fibrils. Together, our results suggest that nucleated branching in vitro plays a critical role in the formation of complex fibrillar HTT exon-1 aggregates with multiple ends.


Social media use and prospective suicidal thoughts and behaviors among adolescents at high risk for suicide.
To examine the relationship between social media use and suicidal thoughts and behaviors among adolescents in the first 30 days of an intensive outpatient program (IOP) for depression and suicidality. Participants included 100 adolescents who enrolled in an IOP for depression and suicidality and completed baseline measures of social media and weekly measures of depression and suicidal thoughts and behaviors at clinical visits over the next month. Lower levels of social media use (overall and messaging) were associated with a greater likelihood of having suicidal ideation with plan over the next 30 days. There was no effect on suicidal behavior. Multilevel modeling indicated no main effects of social media use on depression or average days of suicidal thoughts. However, individuals with lower levels of social media use maintained more depression symptoms and days with passive death wish across the first month of treatment. Among adolescents at high risk for suicide, less engagement in social media may reflect social anhedonia or withdrawal, which may heighten risk for more severe suicidal ideation or impede initial treatment. Findings highlight the importance of considering social media as an additional context when assessing social dysfunction in treatment for depression and suicidality.


Adipose differentiation-related protein regulates lipids and insulin in pancreatic islets.
The excess accumulation of lipids in islets is thought to contribute to the development of diabetes in obesity by impairing beta-cell function. However, lipids also serve a nutrient function in islets, and fatty acids acutely increase insulin secretion. A better understanding of lipid metabolism in islets will shed light on complex effects of lipids on beta-cells. Adipose differentiation-related protein (ADFP) is localized on the surface of lipid droplets in a wide range of cells and plays an important role in intracellular lipid metabolism. We found that ADFP was highly expressed in murine beta-cells. Moreover, islet ADFP was increased in mice on a high-fat diet (3.5-fold of control) and after fasting (2.5-fold of control), revealing dynamic changes in ADFP in response to metabolic cues. ADFP expression was also increased by addition of fatty acids in human islets. The downregulation of ADFP in MIN6 cells by antisense oligonucleotide (ASO) suppressed the accumulation of triglycerides upon fatty acid loading (56% of control) along with a reduction in the mRNA levels of lipogenic genes such as diacylglycerol O-acyltransferase-2 and fatty acid synthase. Fatty acid uptake, oxidation, and lipolysis were also reduced by downregulation of ADFP. Moreover, the reduction of ADFP impaired the ability of palmitate to increase insulin secretion. These findings demonstrate that ADFP is important in regulation of lipid metabolism and insulin secretion in beta-cells.


Highlights on endothelins: a review.
The endothelins (ET) are a family of contractile peptides made up of 21 amino acids. They are synthesised from larger precursors and they are expressed in different tissues. ET-1 is synthesised in endothelial cells by means of a specific endothelin converting enzyme and it is assumed that most of it is secreted into the basolateral compartment. It acts in a paracrine manner on the ETA and ETB2 receptors located on the surface of the vascular smooth muscle to elicit an increase in intracellular calcium and vasoconstriction. The circulating ET-1 can also activate endothelial ETC and ETB1 receptors releasing vascular smooth muscle relaxing factors, such as nitric oxide and prostacyclin. At present, it is generally accepted that ET-1 is a vasodilator in physiological conditions acting on endothelium ETB1 receptors. Nevertheless, in pathological situations such as hypertension, heart failure, acute myocardial infarction, acute renal failure and vasospastic conditions (Raynaud's disease and subarachnoid haemorrhage), ET-1 levels increase and it binds to the receptors present in vascular smooth muscle in such a way that its vasoconstrictor effect is manifested. Currently, experimental and clinical evidence exists to support the importance of the development of drugs that block the production or actions of ET for use in cardiovascular medicine, particularly in conditions in which these peptides are clearly implicated.


Serum atropine concentrations after inhalation of atropine sulfate.
Six male subjects with chronic bronchitis were given a single aerosol dose of atropine sulfate (0.05 mg/kg). Spirometry and venous blood samples were obtained before and at 0.25, 0.5, 1.0, 1.5, 2.0, and 4.0 h after inhalation of drug. All subjects had a satisfactory bronchodilator response and detectable serum concentrations of atropine within 15 min. Measurable serum concentrations persisted for 4 h with apparent continued slow absorption occurring throughout the entire time interval. The maximal concentrations achieved ranged from 1.3 to 5.8 ng/ml in five subjects. A sixth subject achieved much higher concentrations (as high as 21 ng/ml) and experienced systemic side effects. This latter concentration is comparable to those achieved with doses of 1.5 to 2.0 mg of parenteral atropine. Significant systemic absorption may occur after inhalation of atropine sulfate, although the degree of absorption is variable.


The healing power of intercessory prayer.
Arising from an emerging world view in philosophy, it is argued that the mind can function beyond the individual and is not constrained by time and distance; it is in fact non-local. Prayer is cited as an example of non-local manifestation of consciousness. Dossey describes three distinct eras of medicine. The hallmark of Era 3 is the non-local mind and unexplained discoveries of distant healing and intercessory prayer. In researching the medical literature, Dossey discovered 130 studies dealing with the efficacy of prayer as a healing treatment. Those studies disclosed that prayer had a remarkable effect not only on human beings, but also on many other things including bacteria, germinating seeds and animals. Some cases of distant manifestation of consciousness on non-humans are discussed en passant, but the focus of this paper is the healing power of intercessory prayer on humans. Two case studies are offered in support of the evidence for non-local healing and the question is asked whether there is no place in medicine for a multiple approach to healing. Further, if these reported studies of prayer therapies are meaningful, are physicians not using these additional treatments withholding something curative from their patients?


A natural product YSK-A blocks SARS-CoV-2 propagation by targeting multiple host genes.
Natural products and herbal medicine have been widely used in drug discovery for treating infectious diseases. Recent outbreak of COVID-19 requires various therapeutic strategies. Here, we used YSK-A, a mixture of three herbal components Boswellia serrata, Commiphora myrrha, and propolis, to evaluate potential antiviral activity against SARS-CoV-2. We showed that YSK-A inhibited SARS-CoV-2 propagation with an IC50 values of 12.5 µg/ml and 15.42 µg/ml in Vero E6 and Calu-3 cells, respectively. Using transcriptome analysis, we further demonstrated that YSK-A modulated various host gene expressions in Calu-3 cells. Among these, we selected 9 antiviral- or immune-related host genes for further study. By siRNA-mediated knockdown experiment, we verified that MUC5AC, LIF, CEACAM1, and GDF15 host genes were involved in antiviral activity of YSK-A. Therefore, silencing of these genes nullified YSK-A-mediated inhibition of SARS-CoV-2 propagation. These data indicate that YSK-A displays an anti-SARS-CoV-2 activity by targeting multiple antiviral genes. Although the exact antiviral mechanism of each constituent has not been verified yet, our data indicate that YSK-A has an immunomodulatory effect on SARS-CoV-2 and thus it may represent a novel natural product-derived therapeutic agent for treating COVID-19.


Ametropia and Emmetropization in CNGB3 Achromatopsia.
Emmetropization is the process of adjusting ocular growth to the focal plane in order to achieve a clear image. Chromatic light may be involved as a cue to guide this process. Achromats are color blind and lack normal cone function; they are often described as being hyperopic, indicating a failure to emmetropize. We aim to describe the refraction and refractive development in a population of genetically characterized achromats. Refractive error data were collected retrospectively from 28 medical records of CNGB3 c.1148delC homozygous achromats. The distribution of spherical equivalent refractive error (SER) and spherical error was analyzed in adults. The refractive development in children was analyzed by documenting astigmatic refractive error and calculating median SER in 1-year age groups and by analyzing the individual development when possible. The distribution of SER and spherical error resembled a Gaussian distribution, indicating that emmetropization was disturbed in achromats, but we found indication of some decrease in SER during the first years of childhood. The prevalence of refractive errors was high and broadly distributed. Astigmatic refractive errors were frequent but did not seem to increase with age. Refractive development in achromats is more complicated than a complete failure to emmetropize. The spread of refractive errors is larger than previously documented. Results presented here support the theory that chromatic cues and cone photoreceptors may play a role in emmetropization in humans but that it is not essential.


Radiolabeled dendritic probes as tools for high in vivo tumor targeting: application to melanoma.
In bioimaging, targeting allows refining the diagnosis by improving the sensitivity and especially the specificity for an earlier diagnosis. Two 111In-radiolabeled dendritic nanoprobes (DPs) (111In-2, 111In-3) and their model counterparts (111In-1, 111In-4) are designed and assessed for in vitro and in vivo tumor targeting efficiency in a murine melanoma models. Tumor uptake is correlated to dendrimer multivalency and reaches values as high as 12.7 ± 1.6% ID g-1 at 4 h post intravenous injection for 111In-3vs. 1.5 ± 0.5% ID g-1 for the unfunctionalized DP, and over 11% ID g-1 for any tumor weight whatsoever.


SOX18 Promotes the Proliferation of Dermal Papilla Cells via the Wnt/β-Catenin Signaling Pathway.
SRY-box transcription factor 18 (SOX18) is known to play a crucial role in the growth and development of hair follicles (HF) in both humans and mice. However, the specific effect of SOX18 on sheep hair follicles remains largely unknown. In our previous study, we observed that SOX18 was specifically expressed within dermal papilla cells (DPCs) in ovine hair follicles, leading us to investigate its potential role in the growth of hair follicles in sheep. In the present study, we aimed to examine the effect of SOX18 in DPCs and preliminarily study its regulatory mechanism through RNA-seq. We initially found that the overexpression of SOX18 promoted the proliferation of DPCs compared to the negative control group, while the interference of SOX18 had the opposite effect. To gain further insight into the regulatory mechanism of SOX18, we conducted RNA-seq analysis after knocking down SOX18 in Hu sheep DPCs. The result showed that the Wnt/β-Catenin signaling pathway was involved in the growth process of DPC after SOX18 knockdown. Subsequently, we investigated the effect of SOX18 on the Wnt/β-Catenin signaling pathway in DPCs using TOP/FOP-flash, qRT-PCR, and Western blot (WB) analysis. Our data demonstrated that SOX18 could activate the Wnt/β-Catenin signaling pathway in DPCs. Additionally, we observed that SOX18 could rescue the proliferation of DPCs after inhibiting the Wnt/β-Catenin signaling pathway. These findings underscore the essential role of SOX18 as a functional molecule governing the proliferation of DPCs. Additionally, these findings also greatly enhance our understanding of the role of SOX18 in the proliferation of DPCs and the growth of wool in Hu sheep.


Diagnostic and treatment challenges in traumatic brain injury patients with severe neuropsychiatric symptoms: insights into psychiatric practice.
Traumatic brain injury (TBI) causes a variety of neuropsychiatric problems that pose diagnostic and treatment challenges for providers. In this report, we share our experience as a referral neuropsychiatry program to assist the general psychiatrist when adult TBI patients with psychiatric symptoms present for evaluation and treatment. We completed a retrospective study of patients with moderate-to-severe TBI and severe neuropsychiatric impairments. We collected information on demographics, nature of injury, symptomatology, diagnoses, and treatments. Data analysis indicates that mood stabilization was a key concern, often requiring aggressive pharmacological management. Cognitive dysfunction was a problem for the majority of patients, but was only medicated in a third, due to poor efficacy or behavioral side effects. The co-occurrence of multiple TBI-related symptoms and diagnoses in this patient cohort emphasizes the need for individualized psychopharmacological approaches and interventions.


Optimizing the restored chemotactic behavior of anticancer agent Salmonella enterica serovar Typhimurium VNP20009.
Bacteria, including strains of Salmonella, have been researched and applied as therapeutic cancer agents for centuries. Salmonella are particularly of interest due to their facultative anaerobic nature, facilitating colonization of differentially oxygenated tumor regions. Additionally, Salmonella can be manipulated with relative ease, resulting in the ability to attenuate the pathogen or engineer vectors for drug delivery. It was recently discovered that the anti-cancer Salmonella enterica serovar Typhimurium strain VNP20009 is lacking in chemotactic ability, due to a non-synonymous single nucleotide polymorphism in cheY. Replacing the mutated copy of cheY with the wild-type sequence restored chemotaxis to 70% of the parental strain. We aimed to investigate further if chemotaxis of VNP20009 can be optimized. By restoring the gene msbB in VNP20009 cheY+, which confers attenuation by lipid A modification, we observed a 9% increase in swimming speed, 13% increase in swim plate performance, 19% increase in microfluidic device partitioning towards the attractant at the optimum concentration gradient, and mitigation of a non-motile cell subpopulation. We conclude that chemotaxis can be enhanced further but at the cost of changing one defining characteristic of VNP20009. A less compromised strain might be needed to employ for investigating bacterial chemotaxis in tumor interactions.


Characteristics and Outcomes of Patients Discharged Home from an Emergency Department with AKI.
Patients discharged home from an emergency department with AKI are not well described. This study describes their characteristics and outcomes and compares these outcomes to two referent groups. We conducted a population-based retrospective cohort study in Ontario, Canada from 2003 to 2012 of 6346 patients aged ≥40 years who were discharged from the emergency department with AKI (defined using serum creatinine values). We analyzed the risk of all-cause mortality, receipt of acute dialysis, and hospitalization within 30 days after discharge. We used propensity score methods to compare all-cause mortality to two referent groups. We matched 4379 discharged patients to 4379 patients who were hospitalized from the emergency department with similar AKI stage. We also matched 6188 discharged patients to 6188 patients who were discharged home from the emergency department with no AKI. There were 6346 emergency department discharges with AKI. The mean age was 69 years and 6012 (95%) had stage 1, 290 (5%) had stage 2, and 44 (0.7%) had stage 3 AKI. Within 30 days, 149 (2%) (AKI stage 1: 127 [2%]; stage 2: 15 [5%]; stage 3: seven [16%]) died, 22 (0.3%) received acute dialysis, and 1032 (16%) were hospitalized. An emergency department discharge versus hospitalization with AKI was associated with lower mortality (3% versus 12%; relative risk, 0.3; 95% confidence interval, 0.2 to 0.3). An emergency department discharge with AKI versus no AKI was associated with higher mortality (2% versus 1%; relative risk, 1.6; 95% confidence interval, 1.2 to 2.0). Patients discharged home from the emergency department with AKI are at risk of poor 30-day outcomes. A better understanding of care in this at-risk population is warranted, as are testing strategies to improve care.


Molecular characterization of the boron adducts of the proteasome inhibitor bortezomib with epigallocatechin-3-gallate and related polyphenols.
The green tea polyphenol epigallocatechin-3-gallate (EGCG) was reported to effectively antagonize the ability of Bortezomib (BZM) to induce apoptosis in cancer cells. This interaction was attributed to the formation of a covalent adduct between a phenolic moiety of EGCG with the boronic acid group of Bortezomib. However, the structural details of this boron adduct and the molecular factors that contribute to its formation and its ability to inhibit Bortezomib's activity remain unclear. This paper describes the use of NMR spectroscopy and cell assays to characterize the structures and properties of the boron adducts of EGCG and related polyphenols. The observed boron adducts included both boronate and borate derivatives, and their structural characteristics were correlated with cell-based evaluation of the ability of EGCG and other phenols to antagonize the anticancer activity of Bortezomib. The enhanced stability of the BZM/EGCG adduct was attributed to electronic and steric reasons, and a newly identified intramolecular interaction of the boron atom of BZM with the adjacent amide bond. The reported approach provides a useful method for determining the potential ability of polyphenols to form undesired adducts with boron-based drugs and interfere with their actions.


Altered reactivity of resistance vasculature contributes to hypertension in elastin insufficiency.
Elastin (Eln) insufficiency in mice and humans is associated with hypertension and altered structure and mechanical properties of large arteries. However, it is not known to what extent functional or structural changes in resistance arteries contribute to the elevated blood pressure that is characteristic of Eln insufficiency. Here, we investigated how Eln insufficiency affects the structure and function of the resistance vasculature. A functional profile of resistance vasculature in Eln(+/-) mice was generated by assessing small mesenteric artery (MA) contractile and vasodilatory responses to vasoactive agents. We found that Eln haploinsufficiency had a modest effect on phenylephrine-induced vasoconstriction, whereas ANG II-evoked vasoconstriction was markedly increased. Blockade of ANG II type 2 receptors with PD-123319 or modulation of Rho kinase activity with the inhibitor Y-27632 attenuated the augmented vasoconstriction, whereas acute Y-27632 administration normalized blood pressure in Eln(+/-) mice. Sodium nitroprusside- and isoproterenol-induced vasodilatation were normal, whereas ACh-induced vasodilatation was severely impaired in Eln(+/-) MAs. Histologically, the number of smooth muscle layers did not change in Eln(+/-) MAs; however, an additional discontinuous layer of Eln appeared between the smooth muscle layers that was absent in wild-type arteries. We conclude that high blood pressure arising from Eln insufficiency is due partly to permanent changes in vascular tone as a result of increased sensitivity of the resistance vasculature to circulating ANG II and to impaired vasodilatory mechanisms arising from endothelial dysfunction characterized by impaired endothelium-dependent vasodilatation. Eln insufficiency causes augmented ANG II-induced vasoconstriction in part through a novel mechanism that facilitates contraction evoked by ANG II type 2 receptors and altered G protein signaling.


Controlling the 2D Magnetism of CrBr3 by van der Waals Stacking Engineering.
The manipulation of two-dimensional (2D) magnetic order is of significant importance to facilitate future 2D magnets for low-power and high-speed spintronic devices. van der Waals stacking engineering makes promises for controllable magnetism via interlayer magnetic coupling. However, directly examining the stacking order changes accompanying magnetic order transitions at the atomic scale and preparing device-ready 2D magnets with controllable magnetic orders remain elusive. Here, we demonstrate the effective control of interlayer stacking in exfoliated CrBr3 via thermally assisted strain engineering. The stable interlayer ferromagnetic (FM), antiferromagnetic (AFM), and FM-AFM coexistent ground states confirmed by the magnetic circular dichroism measurements are realized. Combined with the first-principles calculations, the atomically resolved imaging technique reveals the correlation between magnetic order and interlayer stacking order in CrBr3 flakes unambiguously. A tunable exchange bias effect is obtained in the mixed phase of FM and AFM states. This work will introduce new magnetic properties by controlling the stacking order and sequence of 2D magnets, providing ample opportunities for their application in spintronic devices.


Electroacupuncture pretreatment alleviates spasticity after stroke in rats by inducing the NF-κB/NLRP3 signaling pathway and the gut-brain axis.
Spasticity is one of the most prevalent ischemic stroke sequelae and the leading cause of disability after stroke. Although electroacupuncture pretreatment has been shown to be effective in the treatment of ischemic stroke, its therapeutic effect and mechanism on post-stroke spasm remain unknown. The purpose of this study was to look into the potential mechanism of electroacupuncture pretreatment in inducing the NF-κB/NLRP3 signaling pathway and the gut-brain axis in the therapy of spasm after stroke. After electroacupuncture treatment at Baihui (DU20) and Qubin (G87), the rat model of middle cerebral artery occlusion (MCAO) was first established. HE, Nissl, and TUNEL staining were used to detect pathological alterations in the rat brain. The relative levels of IL-4, IL-6, TNF-α, and TMAO were determined by ELISA. qRT-PCR and Western blot were used to evaluate the mRNA and protein levels of NF-κB p65, NLRP3, caspase3 and caspase9. Gas chromatography-mass spectrometry (GC-MS) was used to determine the levels of short-chain fatty acids (SCFAs) in rat gut. Hippocampal cells from rats with spasticity following stroke in the MCAO group were chaotic and loosely distributed with an unclear border, a blurred nucleolus, and vanished cytoplasm when compared to those from the sham operation group. Furthermore, the number of surviving neurons decreased while the number of apoptotic cells increased. In the I/R group, relative levels of IL-6, TNF-α, and TMAO increased considerably, while NF-κB p65, NLRP3, caspase3, and caspase9 were dramatically downregulated. The intestinal contents of n-propyl acetate and propyl butyrate were lowered in rats with spasticity following stroke. Electroacupuncture treatments miraculously remedied all of the foregoing pathogenic alterations. Pretreatment with electroacupuncture relieves spasticity after stroke by decreasing the inflammatory response, suppressing the NF-κB/NLRP3 signaling pathway, and modulating the gut-brain axis by increasing n-propyl acetate and propyl butyrate levels in the bowel. Our findings establish a new molecular mechanism and theoretical foundation for electroacupuncture therapy of ischemic stroke.


Depletion of Scleraxis-lineage cells during tendon healing transiently impairs multi-scale restoration of tendon structure during early healing.
Tendons are composed of a heterogeneous cell environment, with Scleraxis-lineage (ScxLin) cells being the predominant population. Although ScxLin cells are required for maintenance of tendon homeostasis, their functions during tendon healing are unknown. To this end, we first characterized the spatiotemporal dynamics of ScxLin cells during tendon healing, and identified that the overall ScxLin pool continuously expands up to early remodeling healing phase. To better define the function of ScxLin cells during the late proliferative phase of healing, we inducibly depleted ScxLin cells from day 14-18 post-surgery using the Scx-Cre; Rosa-DTR mouse model, with local administration of diphtheria toxin inducing apoptosis of ScxLin cells in the healing tendon. At D28 post-surgery, ScxLin cell depleted tendons (DTRScxLin) had substantial impairments in structure and function, relative to WT, demonstrating the importance of ScxLin cells during tendon healing. Next, bulk RNAseq was utilized to identify the underlying mechanisms that were impaired with depletion and revealed that ScxLin depletion induced molecular and morphological stagnation of the healing process at D28. However, this stagnation was transient, such that by D56 tendon mechanics in DTRScxLin were not significantly different than wildtype repairs. Collectively, these data offer fundamental knowledge on the dynamics and roles of ScxLin cells during tendon healing.


Medical aspects of haematuria.
Haematuria is always a significant finding that requires proper evaluation, and investigations may need to be initiated based on an adequate history. A careful urine microscopy of the urine using phase contrast microscopy is essential, and may predict the source of the haematuria based on red cell morphology, and point the direction that appropriate investigation should take. Infection tumours, obstruction; and calculi account for most cases of gross haematuria in adults. In paediatric patients, the causes of gross haematuria are readily apparent in half of the cases, but further investigations are necessary in the other half. All cases of haematuria require prompt evaluation and appropriate investigations to ensure correct and early treatment.


[Stromal bone marrow cells and the hematopoietic microenvironment].
Stromal clonogenic fibroblasts of the bone marrow possessing osteogenic potential are responsible for hemopoietic bone marrow microenvironment. These cells may be recovered from the bone marrow by cloning in cell cultures; their progeny cells upon retransplantation into the body form new bone marrow organs. Microenvironmental cells are histogenetically independent of hemopoietic cells. In bone marrow cell suspensions prepared by bone marrow tissues trypsinization stromal clonogenic cells are present in greater concentrations than in those prepared by mechanical mincing of the bone marrow tissue. New ectopic bone marrow organs may be created by transplantation of trypsinized suspensions in porous sponges.


Interdisciplinary team leadership: a revisionist approach for an old problem?
Understanding of interdisciplinary teamwork is evolving. During health care restructuring, leaders across organizations have challenging responsibilities when work groups must integrate changing organizational values with new modes of service delivery. In this environment, a well-functioning interdisciplinary team in which clinicians work as member-leaders has the potential to further organizational change and foster improvements in patient outcomes. In this paper it is argued that the term interdisciplinary team leadership should be embraced cautiously as it may be a revisionist approach to an old problem, namely a means to modify existing theories of leadership that have been vague and continue to be poorly understood despite considerable effort to explicate knowledge over several decades. Preliminary research suggests that interdisciplinary team leadership is a model of shared leadership that requires more development if it is to become the cornerstone of interdisciplinary team practice in a radically reforming health sector. Stewardship is proposed as a potential philosophy for interdisciplinary team leadership, and a new, shared leadership role of practice leader is suggested.


[Effect of the ingestion of dietary fiber on the digestibility of lipids in a sorghum-consuming African population].
Digestibility measurements were carried out on 12 men. Their habitual diet, deficient in animal products, is based on sorghum meals which supply between 2.4 and 4.2 g of crude fiber per 100 g of dry matter. Over three 11-day periods, the subjects received 3 successive diets (A, B and C) which supplied respectively 3.3, 4.8 and 5.4 g of crude fiber per 100 g of dry matter. Reduced lipids digestibility was noted, even for diet A which was the poorest in fiber content. No difference was observed between diet A and diet B (92.3 and 91.7% respectively). The apparent digestibility of lipids dropped to 86.1 with diet C. True digestibility of lipids is hidden by poorly digestible dietary lipids. Lipid losses increased more rapidly than nitrogen losses with increasing of fiber content in diets. On these regimens, there were no significant changes in concentrations of fecal fat. Concentration of fecal nitrogen decreases for diets B and C.


[Clinico-urodynamic correlation in the hereditary ataxias].
To evaluate lower urinary tract functional symptoms in a series of patients with ataxia and to determine by urodynamic studies the kind of bladder-urethra neurological dysfunction in each case. We posed the question if the clinical picture could be enough to establish the diagnosis and therapeutic management of these patients with hereditary ataxia, or on the contrary it would be necessary to perform urodynamic studies in all cases. Due to the low incidence of hereditary ataxias and patients' mobility it was necessary to recruit patients from various hospitals. The urodynamic study protocol employed in this study included 1) Evaluation of urinary symptoms; 2) Neurological physical examination; 3) Flowmetry with post void residual; 4) Cystomanometry; and 5) Perineal electromyography. We analyzed the relationship between urinary symptoms and urodynamic diagnosis, considering variables such as age, gender, type of ataxia, and time of evolution of the disease. The series includes 34 patients with ataxia and urinary symptoms, 14 cases of Friedreich's ataxia (FA) (41.2%) and other 20 cases of other various forms of ataxia we name non-Friedreich's (NF) (58.8%). Mean age was 37.2 years in FA and 50 years in NF (p < 0.05). Mean time of disease evolution was 20.5 yr. for FA, and 14.9 yr. for NF ataxia (p < 0.1). A mixed urinary syndrome was predominant in 53% of the patients, and 41.1% presented pure irritative symptoms in relation to voiding urgency (85.2%). The most frequent urodynamic diagnosis was detrusor hyperreflexia (61.7%) (37.5% with dyssynergia), followed by areflexia (or hyporeflexia) (23.5%), and normal studies (14.7%). Detrusor hyperreflexia presented with irritative urinary symptoms in 85.7% of the patients, and areflexia or hyporeflexia presented with obstructive symptoms in 75% of the cases. Although there is a good clinical-urodynamic correlation in cases of ataxia, we consider it is necessary to perform a complete urodynamic study in males with hereditary ataxia in order to rule out bladder outlet obstruction due to BPH. On the other hand, due to the fact that progression of the lesions can modify the clinical picture of the patient (including urinary tract symptoms), we consider essential to re-evaluate ataxic patients periodically to adapt their treatment to the urodynamic diagnosis.


Chinese sign language recognition based on surface electromyography and motion information.
Sign language (SL) has strong structural features. Various gestures and the complex trajectories of hand movements bring challenges to sign language recognition (SLR). Based on the inherent correlation between gesture and trajectory of SL action, SLR is organically divided into gesture-based recognition and gesture-related movement trajectory recognition. One hundred and twenty commonly used Chinese SL words involving 9 gestures and 8 movement trajectories, are selected as research and test objects. The method based on the amplitude state of surface electromyography (sEMG) signal and acceleration signal is used for vocabulary segmentation. The multi-sensor decision fusion method of coupled hidden Markov model is used to complete the recognition of SL vocabulary, and the average recognition rate is 90.41%. Experiments show that the method of sEMG signal and motion information fusion has good practicability in SLR.


Women's early warning symptoms of acute myocardial infarction.
Data remain sparse on women's prodromal symptoms before acute myocardial infarction (AMI). This study describes prodromal and AMI symptoms in women. Participants were 515 women diagnosed with AMI from 5 sites. Using the McSweeney Acute and Prodromal Myocardial Infarction Symptom Survey, we surveyed them 4 to 6 months after discharge, asking about symptoms, comorbidities, and demographic characteristics. Women were predominantly white (93%), high school educated (54.8%), and older (mean age, 66+/-12), with 95% (n=489) reporting prodromal symptoms. The most frequent prodromal symptoms experienced more than 1 month before AMI were unusual fatigue (70.7%), sleep disturbance (47.8%), and shortness of breath (42.1%). Only 29.7% reported chest discomfort, a hallmark symptom in men. The most frequent acute symptoms were shortness of breath (57.9%), weakness (54.8%), and fatigue (42.9%). Acute chest pain was absent in 43%. Women had more acute (mean, 7.3+/-4.8; range, 0 to 29) than prodromal (mean, 5.71+/-4.36; range, 0 to 25) symptoms. The average prodromal score, symptom weighted by frequency and intensity, was 58.5+/-52.7, whereas the average acute score, symptom weighted by intensity, was 16.5+/-12.1. These 2 scores were correlated (r=0.61, P<0.001). Women with more prodromal symptoms experienced more acute symptoms. After controlling for risk factors, prodromal scores accounted for 33.2% of acute symptomatology. Most women have prodromal symptoms before AMI. It remains unknown whether prodromal symptoms are predictive of future events.


Hematological alterations in the Otsuka Long-Evans Tokushima fatty (OLETF) rats--a model of type 2 diabetes mellitus.
The OLETF rat develops microangiopathic complications similar to human diabetes and is considered a useful model of Type 2 DM. Erythrocyte, platelet and leucocyte abnormalities described in diabetic patients are thought to play a role in the development of diabetic microangiopathy. This study was designed to investigate whether OLETF rats show hematological alterations and the effect of sucrose treatment on metabolic and blood parameters. Hematological parameters, body weight, food and water intake, fasting and non-fasting blood glucose (BG) and HbA1c were measured in OLETF rats treated for two months with 30% sucrose added to drinking water. Non-treated OLETF rats and non-diabetic Long-Evans Tokushima Otsuka (LETO) rats were used as controls. In the control OLETF rats the number of platelets (Plt) and red blood cells (RBC) was higher, while the mean cell volume (MCV) and the mean cell hemoglobin content (MCH) were lower compared with LETO. Mean cell hemoglobin concentration (MCHC) was significantly higher in the diabetic rats. Sucrose administration decreased food intake and body weight and increased fasting blood glucose and HbA1c. It resulted in a decrease of RBC, Hb, Hct, MCV and MCH compared with control OLETF, while Plt count increased significantly. Our results point to significant alterations in erythrocyte count and morphology and Plt count in diabetic OLETF rats compared with non-diabetic LETO. Sucrose administration accelerated the development of diabetes, affected blood cells inducing the suppression of RBC and an increase in Plt count and some of its effects persisted after sucrose withdrawal.


Comparison of the spectral biologically effective solar ultraviolet in adjacent tree shade and sun.
The solar spectral UVR irradiances in tree shade and sunlight have been measured in a sub-tropical southern hemisphere summer. The spectral data allowed the UVB and UVA irradiances and the biologically effective irradiances to be calculated for different harmful biological processes to human skin and eyes. The average of the ratio of the UVA to UVB irradiances was lower by 26% in the shade compared with the same ratio in the sun. The spectral shade ratio calculated as the ratio of the spectral biologically effective irradiances in the shade to those in the adjacent sun decreased with increasing wavelength for all of the trees. The decrease in the shade ratio was approximately 42% at 400 nm compared with the shade ratio at 300 nm. Despite the UVR protection provided by tree shade, the erythemal UVR exposure received in 1 h in the tree shade exceeded the occupational limit for UVR exposure.


Half-filled lowest Landau level on a thin torus.
We solve a model that describes an interacting electron gas in the half-filled lowest Landau level on a thin torus, with radius of the order of the magnetic length. The low-energy sector consists of noninteracting, one-dimensional, neutral fermions. The ground state, which is homogeneous, is the Fermi sea obtained by filling the negative energy states, and the excited states are gapless neutral excitations out of this one-dimensional sea. Although the limit considered is extreme, the solution has a striking resemblance to the composite fermion description of the bulk nu=1/2 state-the ground state is homogeneous and the excitations are neutral and gapless. This suggests a one-dimensional Luttinger liquid description, with possible observable effects in transport experiments, of the bulk state where it develops continuously from the state on a thin torus as the radius increases.


Conversation starters: Understanding the facilitators and barriers to physician-initiated secure firearm storage conversations.
This paper aims to understand what general practice physicians (GPs) perceive as facilitators and barriers to initiating anticipatory guidance around firearm safety. We employ qualitative interviewing to have in-depth conversations with 18 GPs. Participants were randomly selected from a national panel of physicians and screened for specialty (general practice or internist), practice setting (not hospital-based), and time spent on direct patient care (80% +). The sample was stratified at the state level by the presence of safe storage or child access protection laws, with half of the participants selected from each stratum. We identify five physician-perceived barriers to providing secure firearm storage counseling, including inadequate screening mechanisms to trigger conversations, physician perceptions of who is at risk for firearm injury, time pressures, concerns about patient receptivity, and a need for training. Prior to focusing on how to have conversations about firearm safety, interventions designed to increase the incidence of physician-initiated guidance need to address the structural issues of why those conversations typically do not occur. Findings indicate the need for revised screening tools and improved physician education as to who is at risk for gun injury and how to best approach firearm safety conversations.


Effects of recombinant human growth hormone on the development of burn scarring.
Anabolic agents, such as recombinant human growth hormone (rhGH), have been used effectively to ameliorate the catabolic response to burn injury and to improve wound-healing. However, in experimental animal models, growth hormone has also been associated with increased renal scarring. The effect of rhGH on the development of human scarring is unknown. Therefore, the purpose of this study was to assess the effect of rhGH on the scarring of human skin after burn injury. A series of 94 patients was studied in a prospective randomized double-blind clinical trial. Patients receiving 0.2 mg/kg/day subcutaneous rhGH during their acute hospital stays presented with the same quality and intensity of scarring as patients receiving a placebo. Similar reconstructive needs also resulted. The treatment of severely burned children with recombinant human growth hormone during the acute-phase hospital course did not increase scarring of the burn wound.


Carotid disease is a risk factor for stroke in coronary bypass operations.
The purpose of this study was to investigate the risk of perioperative major cerebrovascular events (MCVEs) in patients undergoing coronary artery bypass grafting (CABG) and to develop preventive therapy. After excluding the patients with marked ascending aortic atheromas and those with combined intracardiac procedures such as valve replacement and aneurysmectomy, 722 consecutive patients who had carotid artery duplex scanning (CADS) and CABG were studied. The results of the study showed the correlation of advanced age, smoking, previous major cerebrovascular event (MCVE), and severe coronary artery disease with high grade carotid artery stenosis of 80-99% (p < 0.05). A total of 13 patients had perioperative MCVE and an analysis of risk factors showed that the MCVE correlated with carotid stenosis of > 60% and reduced cardiac output requiring inotropic support (p < 0.01). Prophylactic carotid endarterectomy (CEA) in patients with 80% to 99% carotid stenosis notably decreased the incidence of MCVE (p < 0.01), and the use of the "pump off" technique instead of standard cardiopulmonary bypass decreased MCVE (p = 0.056). On the basis of these data, prophylactic carotid endarterectomy is effective in averting perioperative MCVE in subjects with carotid stenosis of 80% to 99%, and for those with 60% to 79% carotid stenosis, the pump off technique decreases MCVE.


Lack of association between mannose-binding lectin, acute otitis media and early Epstein-Barr virus infection among children in Greenland.
Low serum levels of mannose-binding lectin (MBL) have been associated with recurrent infections in early childhood. Otitis media (OM) is frequent in Greenlandic children and the first episode of acute OM (AOM) occurs early, as is the case also with Epstein-Barr virus (EBV) infection. We have therefore investigated the association between MBL genotypes, episodes of AOM, and early EBV infection in 82 community-based, unselected children in Greenland. Nasopharyngeal aspirations for EBV and MBL genotype examination, nasopharyngeal bacterial cultures, and history of AOM episodes were obtained. MBL genotypes were established in 73 specimens: 68% of these were homozygous for normal wildtype (AA), and 32% were homozygous or heterozygous for variant alleles that are associated with absence or low MBL serum level. The allele frequencies were: A = 0.88, B = 0.08 (codon 54) and D = 0.04 (codon 52). EBV was found in 41 specimens, more often with increasing age, and significantly related to ethnicity. Presence of variant MBL alleles or EBV infection was not associated with AOM, recurrent AOM (rAOM) or age at first AOM episode and EBV positive children with homozygosity for the normal MBL genotype did not have significantly more episodes of AOM, rAOM or earlier age at the first AOM episode. MBL genotypes and EBV infection alone or in interplay are not associated with the high prevalence of OM in Greenlandic children. The study suggests that low MBL level does not by itself predispose to AOM in community-based, unselected children.


[Effects of the Computer-Based Grapho-Phonological Training Lautarium in Children with Developmental Dyslexia].
Effects of the Computer-Based Grapho-Phonological Training Lautarium in Children with Developmental Dyslexia The effects of the computer-based training program Lautarium on phonological awareness and literacy skills were investigated in 41 third-grade children with developmental dyslexia who attended special dyslexia classes in a primary school in Saxony, Germany. Based on the proven efficacy of phonics-based instruction, Lautarium combines training of phoneme perception and phonological awareness with training of grapheme-phoneme-relationships and reading and spelling of transparent words. In addition, rapid access from written words to meaning is included. The children of the training group (N = 27) worked through the program during school lessons, 5 times per week for 30 minutes, for a period of 7 weeks. During the training period, the controls (N = 14) received traditional remedial reading instruction, 2-3 times per week, in small groups. Children's performance in phonological awareness, reading, and spelling was assessed at three time points (pretest, immediate posttest, and follow-up after 9 weeks). Pretest scores did not differ between groups. For spelling and subtests of phonological awareness, group comparisons of raw scores at posttest and follow-up including the respective pretest score as covariate confirmed stronger improvements in the training group when compared to the controls. Effect sizes were medium to strong. For reading, improvements did not differ between groups. In both groups, standard scores (T-scores) for reading and spelling increased significantly and substantially across the study period (from pretest to follow-up). The results confirm the efficacy of computer-based training with Lautarium in children with dyslexia, and the efficacy of school-based remedial instruction provided in the dyslexia classes.


BK channel openers inhibit ROS production of isolated rat brain mitochondria.
To delineate the potential mechanism of neuroprotective effects of potassium channel openers we have investigated, how Ca(2+)-activated large conductance potassium channel (BK(Ca) channel) openers influence the production of reactive oxygen species (ROS) by rat brain mitochondria, since mitochondrial generation of ROS is known to have a crucial influence on neuronal survival. We studied the effects of BK(Ca) channel openers CGS 7184 and NS 1619 on hydrogen peroxide production rate of isolated rat brain mitochondria. In K(+)-containing media 3 microM of both channel openers reduced the hydrogen peroxide production rates by approximately 20%. This effect was not observed in Na(+)-containing media. This potassium-dependent partial inhibition of hydrogen peroxide production was found to be sensitive to the selective blockers of BK(Ca) channel iberiotoxin and charybdotoxin applied in nanomolar concentrations. Taken together, our data are compatible with the viewpoint that the opening of a Ca(2+)-activated large conductance potassium channel being localised in the inner membrane of brain mitochondria inhibits ROS production by respiratory chain complex I. This finding is suggested to explain the beneficial effects of BK potassium channel openers on neuronal survival.


Hemoadsorption treatment of patients with acute infective endocarditis during surgery with cardiopulmonary bypass - a case series.
Infective endocarditis is a serious disease condition. Depending on the causative microorganism and clinical symptoms, cardiac surgery and valve replacement may be needed, posing additional risks to patients who may simultaneously suffer from septic shock. The combination of surgery bacterial spreadout and artificial cardiopulmonary bypass (CPB) surfaces results in a release of key inflammatory mediators leading to an overshooting systemic hyperinflammatory state frequently associated with compromised hemodynamic and organ function. Hemoadsorption might represent a potential approach to control the hyperinflammatory systemic reaction associated with the procedure itself and subsequent clinical conditions by reducing a broad range of immuno-regulatory mediators. We describe 39 cardiac surgery patients with proven acute infective endocarditis obtaining valve replacement during CPB surgery in combination with intraoperative CytoSorb hemoadsorption. In comparison, we evaluated a historical group of 28 patients with infective endocarditis undergoing CPB surgery without intraoperative hemoadsorption. CytoSorb treatment was associated with a mitigated postoperative response of key cytokines and clinical metabolic parameters. Moreover, patients showed hemodynamic stability during and after the operation while the need for vasopressors was less pronounced within hours after completion of the procedure, which possibly could be attributed to the additional CytoSorb treatment. Intraoperative hemoperfusion treatment was well tolerated and safe without the occurrence of any CytoSorb device-related adverse event. Thus, this interventional approach may open up potentially promising therapeutic options for critically-ill patients with acute infective endocarditis during and after cardiac surgery, with cytokine reduction, improved hemodynamic stability and organ function as seen in our patients.


Germline survival and apoptosis.
Germline apoptosis shares with somatic apoptosis a reliance on key components of the core apoptotic machinery, including CED-3 and CED-4. However, germline apoptosis differs from somatic apoptosis in its regulation. Whereas somatic apoptosis is developmentally programmed by cell lineage, germline apoptosis occurs as part of an oogenesis program. One category of germline apoptosis, dubbed "physiological" germline apoptosis, reduces the number of cells that complete oogenesis, and is independent of the BH3-only apoptosis effecter EGL-1. A second category, termed "stress-induced" germline apoptosis, is triggered by a genomic integrity checkpoint. Some mechanisms that are monitored by this DNA-damage checkpoint are also involved in germ cell "immortality," or preservation of a continuous germ cell lineage over successive generations. In addition, exposure to certain environmental insults or pathogens induces germ cell apoptosis. Here we will review the mechanisms that control each of the pathways leading to germ cell apoptosis and discuss their functional significance. Germline apoptosis is an integral part of oogenesis in many animals, including humans. Because many of the regulators of C. elegans germline apoptosis are conserved, we suggest that this nematode provides a valuable model for understanding controls of germline apoptosis more broadly.