Reducing antibiotic prescribing and addressing the global problem of antibiotic resistance by targeted hygiene in the home and everyday life settings: A position paper.
Antimicrobial resistance (AMR) continues to threaten global health. Although global and national AMR action plans are in place, infection prevention and control is primarily discussed in the context of health care facilities with home and everyday life settings barely addressed. As seen with the recent global SARS-CoV-2 pandemic, everyday hygiene measures can play an important role in containing the threat from infectious microorganisms. This position paper has been developed following a meeting of global experts in London, 2019. It presents evidence that home and community settings are important for infection transmission and also the acquisition and spread of AMR. It also demonstrates that the targeted hygiene approach offers a framework for maximizing protection against colonization and infections, thereby reducing antibiotic prescribing and minimizing selection pressure for the development of antibiotic resistance. If combined with the provision of clean water and sanitation, targeted hygiene can reduce the circulation of resistant bacteria in homes and communities, regardless of a country's Human Development Index (overall social and economic development). Achieving a reduction of AMR strains in health care settings requires a mirrored reduction in the community. The authors call upon national and international policy makers, health agencies, and health care professionals to further recognize the importance of targeted hygiene in the home and everyday life settings for preventing and controlling infection, in a unified quest to tackle AMR.


Outcome of Agenesis of the Corpus Callosum Diagnosed by Fetal MRI.
Fetal magnetic resonance imaging (MRI) is increasingly utilized for prenatal diagnosis of agenesis of the corpus callosum (ACC). This study aimed to (1) describe cases of ACC diagnosed by fetal MRI, (2) determine the frequency of postnatal confirmation by MRI, and (3) understand postnatal outcomes of infants with ACC. Maternal records from Children's National Hospital between January 2012 and June 2019 with a prenatal neurological consultation, fetal MRI, and ACC on imaging were included. Maternal, prenatal, and postnatal infant data were collected. Each case was categorized as complete or partial ACC and isolated or complex ACC by fetal MRI and group comparisons of outcomes were analyzed. A total of 127 maternal-fetal dyads with ACC were categorized into 45 isolated-complete, 17 isolated-partial, 46 complex-complete, and 19 complex-partial ACC. Of 75 live births, 72 had postnatal evaluations. In 43 of 59 (73%) cases with postnatal neuroimaging, prenatal ACC subcategory was confirmed. Children with isolated or complex and with partial or complete ACC had similar rates of developmental delays and epilepsy. Complex ACC cases had worse outcomes than isolated ACC, with complex ACC having more postnatal dysmorphisms and abnormal feeding and vision compared with isolated ACC. Similar neurodevelopmental outcomes were seen for partial and complete ACC. Children with isolated or complex ACC and with partial or complete ACC have a range of neurodevelopmental outcomes. Fetal and postnatal brain MRI is a valuable tool to understand differences of the corpus callosum that can guide genetic testing, prenatal counseling, and postnatal care.


Robust total retina thickness segmentation in optical coherence tomography images using convolutional neural networks.
We developed a fully automated system using a convolutional neural network (CNN) for total retina segmentation in optical coherence tomography (OCT) that is robust to the presence of severe retinal pathology. A generalized U-net network architecture was introduced to include the large context needed to account for large retinal changes. The proposed algorithm outperformed qualitative and quantitatively two available algorithms. The algorithm accurately estimated macular thickness with an error of 14.0 ± 22.1 µm, substantially lower than the error obtained using the other algorithms (42.9 ± 116.0 µm and 27.1 ± 69.3 µm, respectively). These results highlighted the proposed algorithm's capability of modeling the wide variability in retinal appearance and obtained a robust and reliable retina segmentation even in severe pathological cases.


Kaposi's sarcoma-associated herpesvirus infection of endothelial cells inhibits neutrophil recruitment through an interleukin-6-dependent mechanism: a new paradigm for viral immune evasion.
Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiological agent of Kaposi's sarcoma (KS), an endothelial cell (EC) neoplasm characterized by dysregulated angiogenesis and inflammation. KSHV infection of EC causes production of proinflammatory mediators, regarded as possible initiators of the substantial mononuclear leukocyte recruitment seen in KS. Conversely, KSHV immune evasion strategies exist, such as degradation of EC leukocyte adhesion receptors by viral proteins. Here, we report the effects of KSHV infection of primary EC on recruitment of flowing leukocytes. Infection did not initiate adhesion of any leukocyte subset per se. However, on cytokine-stimulated EC, KSHV specifically inhibited neutrophil, but not PBL or monocyte, transmigration, an observation consistent with the inflammatory cell profile found in KS lesions in vivo. This inhibition could be recapitulated on uninfected EC using supernatant from infected cultures. These supernatants contained elevated levels of human interleukin 6 (hIL-6), and both the KSHV- and the supernatant-induced inhibitions of neutrophil transmigration were abrogated in the presence of a hIL-6 neutralizing antibody. Furthermore, preconditioning of EC with hIL-6 mimicked the effect of KSHV. Using RNA interference (RNAi), we show that upregulation of suppressor of cytokine signaling 3 (SOCS3) was necessary for this effect of hIL-6. These studies reveal a novel paracrine mode of KSHV immune evasion, resulting in reduced recruitment of neutrophils, a cell type whose antiviral and antitumor roles are becoming increasingly appreciated. Moreover, the findings have implications for our understanding of the contribution of hIL-6 to the pathogenesis of other inflammatory disorders and tumors in which this cytokine is abundant.


Use of birth defects monitoring programs for assessing the effects of maternal substance abuse on pregnancy outcomes.
We have attempted to demonstrate that birth defects surveillance systems are a unique adjunct to clinical research data on maternal exposures, including substances of abuse. Surveillance system data reflect the experiences of the populations from which they are drawn and the characteristics of the people in those populations. Sensitive systems may reveal trends in health status and changes in behavioral, cultural, social, or environmental exposures. They can be used to monitor changing trends, to identify clusters for investigation, to generate and test hypotheses, and to conduct epidemiological studies. For researchers to interpret data derived from surveillance systems appropriately and wisely, they need a thorough knowledge of the data sources, the data-collection procedures, and the intent of the surveillance systems. Researchers using surveillance data should have a thorough understanding of the quality of their data and the methodologic subtleties that bear on its interpretation; researchers reviewing scientific literature based on surveillance data should be aware of the strengths and limitations inherent in the data.


Adenine Synthesis in a Model Prebiotic Reaction: Connecting Origin of Life Chemistry with Biology.
Many high school laboratory experiments demonstrate concepts related to biological evolution, but few exist that allow students to investigate life's chemical origins. This series of laboratory experiments has been developed to allow students to explore and appreciate the deep connection that exists between prebiotic chemistry, chemical evolution, and contemporary biological systems. In the first experiment of the series, students synthesize adenine, one of the purine nucleobases of DNA and RNA, from plausibly prebiotic precursor molecules. Students compare their product to authentic standards using thin-layer chromatography. The second and third experiments of the series allow students to extract DNA from a familiar organism, the strawberry, and hydrolyze it, releasing adenine, which they can then compare to the previously chemically-synthesized adenine. A fourth, optional experiment is included where the technique of thin-layer chromatography is introduced and chromatographic skills are developed for use in the other three experiments that comprise this series. Concepts relating to organic and analytical chemistry, as well as biochemistry and DNA structure, are incorporated throughout, allowing this series of laboratory experiments to be easily inserted into existing laboratory courses and to reinforce concepts already included in any high school chemistry or biology curriculum.


Complement genes strongly predict recurrence and graft outcome in adult renal transplant recipients with atypical hemolytic and uremic syndrome.
Atypical hemolytic and uremic syndrome (aHUS) is a severe disease strongly associated with genetic abnormalities in the complement alternative pathway. In renal posttransplantation, few data are available on recurrence risk and graft outcome according to genetic background in aHUS patients. The aim of this study was to identify risk factors for recurrence and transplant outcome and, in particular, the role of complement gene abnormalities. We retrospectively studied 57 aHUS patients who had received 71 renal transplants. A mutation in complement gene was identified in 39 (68%), in factor H (CFH), factor I (CFI), membrane cofactor-protein (MCP), C3 and factor B (CFB). At 5 years, death-censored graft survival was 51%. Disease recurrence was associated with graft loss (p = 0.001). Mutations in complement genes were associated with higher risk of recurrence (p = 0.009). Patients with CFH or gain of function (C3, CFB) mutations had a highest risk of recurrence. M-TOR inhibitor was associated with significant risk of recurrence (p = 0.043) but not calcineurin inhibitor immunosuppressive treatment (p = 0.29). Preemptive plasmatherapy was associated with a trend to decrease recurrence (p = 0.07). Our study highlights that characterization of complement genetic abnormalities predicts the risk of recurrence-related graft loss and paves the way for future genetically based individualized prophylactic therapeutic strategies.


The minor envelope glycoproteins GP2a and GP4 of porcine reproductive and respiratory syndrome virus interact with the receptor CD163.
Porcine reproductive and respiratory syndrome virus (PRRSV) contains the major glycoprotein, GP5, as well as three other minor glycoproteins, namely, GP2a, GP3, and GP4, on the virion envelope, all of which are required for generation of infectious virions. To study their interactions with each other and with the cellular receptor for PRRSV, we have cloned each of the viral glycoproteins and CD163 receptor in expression vectors and examined their expression and interaction with each other in transfected cells by coimmunoprecipitation (co-IP) assay using monospecific antibodies. Our results show that a strong interaction exists between the GP4 and GP5 proteins, although weak interactions among the other minor envelope glycoproteins and GP5 have been detected. Both GP2a and GP4 proteins were found to interact with all the other GPs, resulting in the formation of multiprotein complex. Our results further show that the GP2a and GP4 proteins also specifically interact with the CD163 molecule. The carboxy-terminal 223 residues of the CD163 molecule are not required for interactions with either the GP2a or the GP4 protein, although these residues are required for conferring susceptibility to PRRSV infection in BHK-21 cells. Overall, we conclude that the GP4 protein is critical for mediating interglycoprotein interactions and, along with GP2a, serves as the viral attachment protein that is responsible for mediating interactions with CD163 for virus entry into susceptible host cell.


Acquired pigmentation simulating Peutz-Jeghers syndrome: initial manifestation of diffuse uveal melanocytic proliferation.
A 74-year-old man with an occult carcinoma of the colon developed pigmentation of the mouth and penis typical of the Peutz-Jeghers syndrome as the first manifestation of bilateral diffuse uveal melanocytic proliferation. The simultaneous appearance of extraocular pigmented lesion and those in the uveal tract of both eyes of this patient provides further evidence that bilateral diffuse uveal melanocytic proliferation may be caused by activation of occult melanocytic naevus cells in response to either a hormone-producing carcinoma or to some other common oncogenic stimulus.


Enhancement of anti-tumor effects of 5-fluorouracil on hepatocellular carcinoma by low-intensity ultrasound.
Hepatocellular carcinoma (HCC) accounts for 75% of liver cancers and is the second most lethal cancer, associated with its multiple etiologies, poor prognosis and resistance to chemotherapy drugs. Chemotherapy treatment on HCC suffers low efficacy of drug uptake and can produce a range of side effects. Here we report an investigation on the effect of a combined treatment on human hepatocellular carcinoma BEL-7402 cells using low-intensity ultrasound (US) and 5-fluorouracil (5-FU). The uptake of 5-FU was measured by the high-performance liquid chromatography (HPLC). DNA damage was detected by the comet assay. MTT assay was used to examine cell viability. Intracellular reactive oxygen species (ROS) and mitochondrial membrane potential (Δψm) were respectively detected by the fluorescent probes DCFH-DA or JC-1. Endogenous apoptosis-associated proteins were analyzed by the western blot and immunohistochemistry. Histopathological changes were evaluated by the hematoxylin and eosin (H&E) staining. Cell apoptosis was evaluated by the TUNEL and flow cytometry assays. Cell proliferation was measured using the immunohistochemical staining of PCNA. Our results showed that low-intensity US (1.1 MHz, 1.0 W/cm2, 10% duty cycle) significantly enhanced the uptake of 5-FU, 5-FU-mediated DNA damage and reactive oxygen species (ROS) generation. The increased ROS production up-regulated the p53 protein level, which led to the up-regulation of Bax and down-regulation of Bcl-2. The enhancement of ROS generation and the activation of the apoptosis-associated proteins further triggered the collapse of mitochondrial membrane potential, released cytochrome c from mitochondria into cytosol and activated the mitochondria-caspase pathway, and cell apoptosis. Such enhanced effects could be partially blocked by the ROS scavenger N-acetylcysteine (NAC). Overall, low-intensity US combined with 5-FU led to an effective inhibition of tumor growth and prolonged overall survival of BEL-7402 HCC-bearing nude mice by more than 15% compared with 5-FU treatment alone. Our results showed that low-intensity ultrasound combined with 5-FU produced much enhanced synergistic anti-tumor effects via enhanced ROS production in treating HCC.


Linkage disequilibrium fine mapping of quantitative trait loci: a simulation study.
Recently, the use of linkage disequilibrium (LD) to locate genes which affect quantitative traits (QTL) has received an increasing interest, but the plausibility of fine mapping using linkage disequilibrium techniques for QTL has not been well studied. The main objectives of this work were to (1) measure the extent and pattern of LD between a putative QTL and nearby markers in finite populations and (2) investigate the usefulness of LD in fine mapping QTL in simulated populations using a dense map of multiallelic or biallelic marker loci. The test of association between a marker and QTL and the power of the test were calculated based on single-marker regression analysis. The results show the presence of substantial linkage disequilibrium with closely linked marker loci after 100 to 200 generations of random mating. Although the power to test the association with a frequent QTL of large effect was satisfactory, the power was low for the QTL with a small effect and/or low frequency. More powerful, multi-locus methods may be required to map low frequent QTL with small genetic effects, as well as combining both linkage and linkage disequilibrium information. The results also showed that multiallelic markers are more useful than biallelic markers to detect linkage disequilibrium and association at an equal distance.


Total energy expenditure and physical activity level of lactating Mesoamerindians.
Energy-sparing mechanisms may be elicited to meet increased energy requirements imposed by lactation on women who reside in poor, rural communities in developing countries. The objectives of this study were to measure total energy expenditure and its components, basal and activity energy expenditure, and to investigate their relationships with lactation performance in a total of 40 rural Mesoamerindians stratified according to postpartum body mass index. Total energy expenditure and fat-free mass were measured by the doubly labeled water method, and basal metabolic rate was determined by indirect calorimetry at 3 and 6 mo postpartum. Physical activity level was taken as the ratio of total energy expenditure to basal metabolic rate. Milk energy output, which is not included in total energy expenditure, was computed from 24-h milk intake (test-weighing) and energy concentration of milk (bomb calorimetry). Anthropometric measurements revealed negligible mobilization of tissue stores. Mean (+/- SD) total energy expenditures were 8912 +/- 1296 kJ/d and 9253 +/- 1298 kJ/d for the lower and higher body mass index groups, respectively. Adjusted for fat-free mass, total energy expenditure was higher in the lower body mass index group (P = 0.05). Adjusted for fat-free mass, basal metabolic rate did not differ between groups. Physical activity level was significantly higher in the lower body mass index group (P = 0.03). Lactation performance did not differ between groups and was not associated with total energy expenditure or its components. Despite the maintenance of energy balance and heightened energy requirements of lactation, energy-sparing mechanisms were not evident in these lactating Mesoamerindians.


Uveitis causes according to immune status of patients.
The advances in medicine have led to an increased number of people living with some form of immunodeficiency. Most ocular infections in immunocompromised patients may lead to irreversible blindness. We identify the causes of uveitis in immunocompetent and immunocompromised patients. A retrospective cohort study of 1354 consecutive patients. All patients underwent a standard work-up for uveitis. An immunocompromised state was identified in 171/1354 patients (13%), of whom 40 had Human immunodeficiency virus (HIV) infection, 52 received immunosuppressive medications, 28 had concurrent malignant disorder and 20 had other causes for their immunosuppression. In addition, 93/1354 patients (7%) had diabetes mellitus (DM). The prevalence of intraocular infections was much higher in immunocompromised patients than in immunocompetent patients and DM (p < 0.001). Causes of uveitis differed between the diverse immunocompromised groups. The non-HIV immunocompromised patients showed primarily intraocular herpes simplex and varicella zoster virus infections, whilst HIV-positive patients exhibited frequently cytomegalovirus (CMV) retinitis and syphilis. Patients with generalized malignancies were characterized by a lower prevalence of infections and higher prevalence of sarcoidosis. Patients with DM typically showed sarcoidosis and bacterial intraocular infections. The percentage of undetermined uveitis diagnoses was markedly lower in immunosuppressed patients (p < 0.001). In immunocompromised patients with uveitis, infections were diagnosed in 46% of cases in contrast to 12% in the immunocompetent patients. The causes of uveitis differed among the various types of immunosuppression. Immunocompromised patients with uveitis require a rapid assessment for the most expected infections.


Cofilin1-dependent actin dynamics control DRP1-mediated mitochondrial fission.
Mitochondria form highly dynamic networks in which organelles constantly fuse and divide. The relevance of mitochondrial dynamics is evident from its implication in various human pathologies, including cancer or neurodegenerative, endocrine and cardiovascular diseases. Dynamin-related protein 1 (DRP1) is a key regulator of mitochondrial fission that oligomerizes at the mitochondrial outer membrane and hydrolyzes GTP to drive mitochondrial fragmentation. Previous studies demonstrated that DRP1 recruitment and mitochondrial fission is promoted by actin polymerization at the mitochondrial surface, controlled by the actin regulatory proteins inverted formin 2 (INF2) and Spire1C. These studies suggested the requirement of additional actin regulatory activities to control DRP1-mediated mitochondrial fission. Here we show that the actin-depolymerizing protein cofilin1, but not its close homolog actin-depolymerizing factor (ADF), is required to maintain mitochondrial morphology. Deletion of cofilin1 caused mitochondrial DRP1 accumulation and fragmentation, without altering mitochondrial function or other organelles' morphology. Mitochondrial morphology in cofilin1-deficient cells was restored upon (i) re-expression of wild-type cofilin1 or a constitutively active mutant, but not of an actin-binding-deficient mutant, (ii) pharmacological destabilization of actin filaments and (iii) genetic depletion of DRP1. Our work unraveled a novel function for cofilin1-dependent actin dynamics in mitochondrial fission, and identified cofilin1 as a negative regulator of mitochondrial DRP1 activity. We conclude that cofilin1 is required for local actin dynamics at mitochondria, where it may balance INF2/Spire1C-induced actin polymerization.


Associations between white matter integrity of the cingulum bundle, surrounding gray matter regions, and cognition across the dementia continuum.
Previous Alzheimer's disease and related dementias (AD/ADRD) research studies have illustrated the significance of studying alterations in white matter (WM). Fewer studies have examined how WM integrity, measured with diffusion tensor imaging (DTI), is associated with volume of gray matter (GM) regions and measures of cognitive function in aged participants spanning the dementia continuum. Magnetic resonance imaging and cognitive data were collected from 241 Boston University Alzheimer's Disease Research Center participants who spanned from cognitively normal controls to amnestic mild cognitive impairment to having dementia. Primary DTI tracts of interest were the cingulum ventral (CV) and cingulum dorsal (CD) pathways. GM regions of interest (ROIs) were in the medial temporal lobe (MTL), prefrontal cortex, and retrosplenial cortex. Analyses of covariance models were used to assess differences in WM integrity across groups (control, amnestic mild cognitive impairment, and dementia). Multiple linear regression models were used to assess associations between WM integrity and GM volume, and with measures of memory and executive function. Differences in WM integrity were shown in both cingulum pathways in participants across the dementia continuum. Associations between WM integrity of both cingulum pathways and volume of selected GM ROIs were widespread. Functionally significant associations were found between WM of the CV pathway and memory, independent of MTL GM volume. Differences in WM integrity of the cingulum bundle and surrounding GM ROI are likely related to the progression of AD/ADRD. Such differences should continue to be studied, particularly in association with memory performance.


Neuronal defects in a human cellular model of 22q11.2 deletion syndrome.
22q11.2 deletion syndrome (22q11DS) is a highly penetrant and common genetic cause of neuropsychiatric disease. Here we generated induced pluripotent stem cells from 15 individuals with 22q11DS and 15 control individuals and differentiated them into three-dimensional (3D) cerebral cortical organoids. Transcriptional profiling across 100 days showed high reliability of differentiation and revealed changes in neuronal excitability-related genes. Using electrophysiology and live imaging, we identified defects in spontaneous neuronal activity and calcium signaling in both organoid- and 2D-derived cortical neurons. The calcium deficit was related to resting membrane potential changes that led to abnormal inactivation of voltage-gated calcium channels. Heterozygous loss of DGCR8 recapitulated the excitability and calcium phenotypes and its overexpression rescued these defects. Moreover, the 22q11DS calcium abnormality could also be restored by application of antipsychotics. Taken together, our study illustrates how stem cell derived models can be used to uncover and rescue cellular phenotypes associated with genetic forms of neuropsychiatric disease.


Can training trunk musculature influence musculoskeletal pain and physical performance in military police officers?
To investigate the effect of a Trunk Training (TT) program on the general musculoskeletal pain (GMP) and physical performance of Military Police Officers. Twenty officers were divided into either control group (CG) or TT group (TTG). Both groups performed nine weeks of traditional physical training. However, the TTG had 25-minutes allocated to TT during each scheduled physical training period. Anthropometric, trunk endurance, and physical fitness tests were completed pre- and post-training for both groups. Both groups also answered a weekly questionnaire about their GMP. Post-training, trunk endurance performance was significantly higher (p < 0.05) and the GMP significantly lower (p < 0.05) in the TTG when compared to the CG. Improvement in side plank test scores was associated with a decreased in GMP (r = -0.495, p < 0.05). TT can reduce the perception of GMP in addition to increasing the endurance of the trunk muscles. The side plank was the only physical test associated with GMP. Practitioner summary: Trunk Training can reduce general musculoskeletal pain and increase the endurance of the trunk muscles without a concomitant loss in general fitness in elite Military Police Officers. This research lasted 11 weeks and presents real-world and pragmatic findings.


Lymphatic vessel density and VEGF-C expression as independent predictors of melanoma metastases.
In many patients, the clinical behaviour of cutaneous melanoma is very difficult to predict by traditional histologic and clinical parameters. This study aimed to examine the role of quantitative parameters of tumour lymphangiogenesis and vascular endothelial growth factor (VEGF)-C in predicting metastatic risk in patients with cutaneous melanoma. One hundred melanoma specimens were stained with lymphatic-specific antibody D2-40 and with anti-VEGF-C antibody. Quantitative parameters of lymphangiogenesis-lymphatic vessel density (LVD) and lymphatic vessel area (LVA)-were determined by computer-assisted morphometric analysis. Moderate or strong staining was assessed as a positive expression of VEGF-C in tumour cells. Univariate analysis revealed that intratumoural LVD, peritumoural LVD, VEGF-C expression in tumour cells, melanoma thickness, Clark level, ulceration, gender and histologic type were significant predictors of lymph node metastasis (p = 0.000, p = 0.000, p = 0.000, p = 0.000, p = 0.005, p = 0.005, p = 0.011 and p = 0.027, respectively). No significant association of intratumoural and peritumoural LVA with metastases was found. In multivariate analysis, independent predictors of metastatic risks were melanoma thickness [odds ratio OR = 1.655, 95% confidence interval (CI) 1.102-2.484, p = 0.015], intratumoural LVD (OR = 1.086, 95% CI 1.027-1.148, p = 0.004), peritumoural LVD (OR = 1.050, 95% CI 1.008-1.094, p = 0.020) and a positive VEGF-C expression in tumour cells (OR = 20.337, 95% CI 2.579-160.350, p = 0.004). This study identified intratumoural and peritumoural LVD and the VEGF-C expression in tumour cells as more significant predictors of metastatic risk than melanoma thickness, ulceration and other clinical-pathological parameters.


Interstitial myocardial fibrosis in a captive chimpanzee (Pan troglodytes) population.
The clinical and necropsy records of 36 (25 male and 11 female) chimpanzees age 10 to 40 y old that died over a 6-y period (2001 to 2006) were reviewed. All animals had annual physical exams that included electrocardiograms and serial blood pressures. Nine of the 36 animals had a complete cardiac evaluation by a board certified veterinary cardiologist, and 7 of the 36 animals (19%) were diagnosed with some form of cardiomyopathy. Systemic hypertension was noted in 3 cases. Cardiac arrhythmias (ventricular ectopy) were seen in 15 (12 male and 3 female) of the 36 animals (42%). Sudden cardiac death (SCD) occurred in 13 (11 male and 2 female) chimps (36%) and was the leading cause of death (n = 13), followed by renal failure (n = 9) and septicemia (n = 3). Histologic examination of the hearts revealed interstitial myocardial fibrosis (IMF) in 29 chimpanzees (81%), and all of the animals that died suddenly due to cardiac causes had IMF to varying degrees. More data will be needed to identify the possible causes of IMF in captive chimpanzees, and IMF may be associated with arrhythmias and SCD in these animals.


Comparison of texture features based on Gabor filters.
Texture features that are based on the local power spectrum obtained by a bank of Gabor filters are compared. The features differ in the type of nonlinear post-processing which is applied to the local power spectrum. The following features are considered: Gabor energy, complex moments, and grating cell operator features. The capability of the corresponding operators to produce distinct feature vector clusters for different textures is compared using two methods: the Fisher (1923) criterion and the classification result comparison. Both methods give consistent results. The grating cell operator gives the best discrimination and segmentation results. The texture detection capabilities of the operators and their robustness to nontexture features are also compared. The grating cell operator is the only one that selectively responds only to texture and does not give false response to nontexture features such as object contours.


Covert sexual signaling: human flirtation and implications for other social species.
According to signaling theory and a large body of supporting evidence, males across many taxa produce courtship signals that honestly advertise their quality. The cost of producing or performing these signals maintains signal honesty, such that females are typically able to choose the best males by selecting those that produce the loudest, brightest, longest, or otherwise highest-intensity signals, using signal strength as a measure of quality. Set against this background, human flirting behavior, characterized by its frequent subtlety or covertness, is mysterious. Here we propose that the explanation for subtle and ambiguous signals in human courtship lies in socially imposed costs that (a) vary with social context and (b) are amplified by the unusual ways in which language makes all interactions potentially public. Flirting is a class of courtship signaling that conveys the signaler's intentions and desirability to the intended receiver while minimizing the costs that would accompany an overt courtship attempt. This proposal explains humans' taxonomically unusual courtship displays and generates a number of novel predictions for both humans and non-human social animals. Individuals who are courting should vary the intensity of their signals to suit the level of risk attached to the particular social configuration, and receivers may assess this flexible matching of signal to context as an indicator of the signaler's broader behavioral flexibility and social intelligence.


Oxyntic endocrine cells of hypergastrinaemic patients. Differential response to antrectomy or octreotide.
To evaluate the response of endocrine cells of the gastric oxyntic mucosa in hypergastrinaemic patients to either antrectomy or treatment with the somatostatin analogue octreotide. (a) Two patients with enterochromaffin-like (ECL) cell carcinoid and chronic atrophic gastritis, treated with antrectomy; (b) four patients with Zollinger-Ellison syndrome, treated with octreotide. Oxyntic endocrine cells were examined by ultrastructural morphometry on full thickness biopsy specimens taken: (a) before and four months after antrectomy, (b) before and after three months' treatment with octreotide 200 micrograms daily. Both treatments induced prompt, significant reduction of gastrinaemia and a significant decrease of the volume density of the whole endocrine cell mass and of the cross sectional area of all nucleated endocrine cell profiles (antrectomy: -38%, p < 0.04 and -31%, p < 0.04, respectively; octreotide: -59%, < 0.007 and -26%, < 0.04, respectively). Assessment of the relative proportion of individual endocrine cell types showed a different response to antrectomy or octreotide. After antrectomy, in fact, only the volume fraction of ECL cells was significantly reduced, from 56.5% to 22.5% (-60%, p < 0.04). After octreotide treatment, in contrast, the proportion of all endocrine cell types remained remarkably constant, showing that all cell types took part in the observed overall decrease. Postantrectomy reduction of oxyntic endocrine cells mostly reflects the withdrawal of the specific trophic stimulus of hypergastrinaemia on ECL cells. In contrast, the inhibitory response to octreotide seems to be exerted on virtually all types of oxyntic endocrine cells, probably reflecting a universal occurrence of somatostatin receptors.


Sense of community affects community satisfaction: Mediating role of community participation.
Community satisfaction is a central component of community development because it indicates the overall contentment of residents with their community. As such, it can indicate the directions for community development. This study is aimed at examining a sense of community and community participation as factors influencing community satisfaction in the Yirgachefe district of Ethiopia. We collected data from 360 randomly selected household heads (male = 80.2%, female = 19.2%) residing in 12 rural communities. We used structural equation modeling to analyze the data. Results revealed that residents with a higher sense of community were more likely to have participated in their community and to be satisfied with their community. However, sense of community only indirectly influenced community satisfaction and had an insignificant direct effect on community satisfaction. There is a fully mediating effect of community participation between sense of community and community satisfaction. We propose policy implications based on the study.


ECG-based machine-learning algorithms for heartbeat classification.
Electrocardiogram (ECG) signals represent the electrical activity of the human hearts and consist of several waveforms (P, QRS, and T). The duration and shape of each waveform and the distances between different peaks are used to diagnose heart diseases. In this work, to better analyze ECG signals, a new algorithm that exploits two-event related moving-averages (TERMA) and fractional-Fourier-transform (FrFT) algorithms is proposed. The TERMA algorithm specifies certain areas of interest to locate desired peak, while the FrFT rotates ECG signals in the time-frequency plane to manifest the locations of various peaks. The proposed algorithm's performance outperforms state-of-the-art algorithms. Moreover, to automatically classify heart disease, estimated peaks, durations between different peaks, and other ECG signal features were used to train a machine-learning model. Most of the available studies uses the MIT-BIH database (only 48 patients). However, in this work, the recently reported Shaoxing People's Hospital (SPH) database, which consists of more than 10,000 patients, was used to train the proposed machine-learning model, which is more realistic for classification. The cross-database training and testing with promising results is the uniqueness of our proposed machine-learning model.


P1 interneurons promote a persistent internal state that enhances inter-male aggression in Drosophila.
How brains are hardwired to produce aggressive behavior, and how aggression circuits are related to those that mediate courtship, is not well understood. A large-scale screen for aggression-promoting neurons in Drosophila identified several independent hits that enhanced both inter-male aggression and courtship. Genetic intersections revealed that 8-10 P1 interneurons, previously thought to exclusively control male courtship, were sufficient to promote fighting. Optogenetic experiments indicated that P1 activation could promote aggression at a threshold below that required for wing extension. P1 activation in the absence of wing extension triggered persistent aggression via an internal state that could endure for minutes. High-frequency P1 activation promoted wing extension and suppressed aggression during photostimulation, whereas aggression resumed and wing extension was inhibited following photostimulation offset. Thus, P1 neuron activation promotes a latent, internal state that facilitates aggression and courtship, and controls the overt expression of these social behaviors in a threshold-dependent, inverse manner.


How Do Noninvasive Imaging Facilities Perceive the Accreditation Process? Results of an Intersocietal Accreditation Commission Survey.
The Intersocietal Accreditation Commission (IAC) accredits vascular, echocardiography, nuclear medicine, computed tomography, and magnetic resonance imaging laboratories. How facilities involved in the accreditation process view accreditation is unknown. The objective of this study was to examine the perception of laboratory accreditation from those who had undergone the process. An electronic survey request was sent to all facilities that had received IAC accreditation at least once. Demographic information, as well as opinions on the perceived value of accreditation as it relates to 15 quality metrics was acquired. Responses were obtained from 2782 facilities. Of the 15 quality metrics examined, the process was perceived as leading to improvements by a majority of respondents for 10 (67%) metrics including: report standardization, adherence to guidelines, test standardization, report completeness, identification of deficiencies, improved staff knowledge, report timeliness, distinguished facility, correction of deficiencies, and image quality. Overall, the perceived improvement was greater for hospital-based facilities (global 66% vs 59%; P < 0.001). Survey data demonstrate that the accreditation process has a positive perceived impact on the majority of examined metrics. These findings suggest that those undergoing the process find value in accreditation.


Molecular surveillance of malaria in the Central Highlands, Vietnam.
Vietnam achieved outstanding success against malaria in the last few decades. The mortality and morbidity of malaria in Vietnam have decreased remarkably in recent years, but malaria is still a major public health concern in the country, particularly in the Central Highlands region. In this study, molecular analyses of malaria parasites in the Central Highlands were performed to understand the population structure and genetic diversity of the parasites circulating in the region. Plasmodium falciparum (68.7%) and P. vivax (27.4%) along with mixed infections with P. falciparum/P. vivax (3.9%) were detected in 230 blood samples from patients with malaria. Allele-specific nested-polymerase chain reaction (PCR) or PCR-restriction fragment length polymorphism (PCR-RFLP) analyses of pfmsp-1, pfama-1, pvcsp, and pvmsp-1 revealed complex genetic makeup in P. falciparum and P. vivax populations of Vietnam. Substantial multiplicity of infection (MOI) was also identified, suggesting significant genetic diversity and polymorphism of P. falciparum and P. vivax populations in the Central Highlands of Vietnam. These results provide fundamental insight into the current patterns of dispersion and genetic nature of malaria parasites as well as for the development of malaria elimination strategies in the endemic region.


The Myrosinases TGG1 and TGG2 Function Redundantly in Reactive Carbonyl Species Signaling in Arabidopsis Guard Cells.
Myrosinase (β-thioglucoside glucohydrolase, enzyme nomenclature, EC 18.104.22.168, TGG) is a highly abundant protein in Arabidopsis guard cells, of which TGG1 and TGG2 function redundantly in abscisic acid (ABA)- and methyl jasmonate-induced stomatal closure. Reactive carbonyl species (RCS) are α,β-unsaturated aldehydes and ketones, which function downstream of reactive oxygen species (ROS) production in the ABA signalling pathway in guard cells. Among the RCS, acrolein is the most highly reactive, which is significantly produced in ABA-treated guard cells. To clarify the ABA signal pathway downstream of ROS production, we investigated the responses of tgg mutants (tgg1-3, tgg2-1 and tgg1-3 tgg2-1) to acrolein. Acrolein induced stomatal closure and triggered cytosolic alkalization in wild type (WT), tgg1-3 single mutants and in tgg2-1 single mutants, but not in tgg1-3 tgg2-1 double mutants. Exogenous Ca2+ induced stomatal closure and cytosolic alkalization not only in WT but also in all of the mutants. Acrolein- and Ca2+-induced stomatal closures were inhibited by an intracellular acidifying agent, butyrate, a Ca2+ chelator, ethylene glycol tetraacetic acid (EGTA) and a Ca2+ channel blocker, LaCl3. Acrolein induced cytosolic free calcium concentration ([Ca2+]cyt) elevation in guard cells of WT plants but not in the tgg1-3 tgg2-1 double mutants. Exogenous Ca2+ elicited [Ca2+]cyt elevation in guard cells of WT and tgg1-3 tgg2-1. Our results suggest that TGG1 and TGG2 function redundantly, not between ROS production and RCS production, but downstream of RCS production in the ABA signal pathway in Arabidopsis guard cells.


Functional neuroimaging of attention-deficit/hyperactivity disorder: a review and suggested future directions.
Over the past few decades, functional neuroimaging techniques have begun to provide unprecedented windows on the neurobiology of attention-deficit/hyperactivity disorder (ADHD) and the neural effects of medications used to treat the disorder. Convergent data from neuroimaging, neuropsychological, genetics, and neurochemical studies have implicated dysfunction of fronto-striatal structures (lateral prefrontal cortex, dorsal anterior cingulate cortex, caudate, and putamen) as likely contributing to the pathophysiology of ADHD. This review 1) provides an overview of the main imaging techniques being used to study ADHD; 2) discusses their relative strengths and weaknesses, highlighting how they can complement one another; 3) shows how the functional imaging literature, which has built on the structural imaging data, is now being used to test focused hypotheses regarding the neurobiological substrate of ADHD; and 4) suggests guidelines for improving future functional imaging studies. Although at present there are no accepted uses for functional imaging in diagnosing ADHD, this article mentions possible future clinical uses of imaging in ADHD.


Vitrification of the human embryo: a more efficient and safer in vitro fertilization treatment.
Cryopreservation has become a central pillar in assisted reproduction, reflected in the exponential increase of "freeze all" cycles in the past few years. Vitrification makes it possible to cool and warm human eggs and embryos with far less cryo-damage than 'slow-freeze' and allows nearly intact survival of embryos with very high survival rates for eggs as well. This has resulted in a complete transformation how we manage treatment for in vitro fertilization patients. Fresh transfers can be avoided without compromising outcomes, and in fact, cumulative pregnancy/delivery rates may be improved by performing sequential elective "frozen" single embryo transfers. Some recent evidence suggests that previously vitrified embryos give better perinatal outcomes than fresh embryo transfers. Frozen embryo transfer, especially when coupled with preimplantation genetic testing allows for highly efficient single embryo transfers that translate to more singleton and therefore safer pregnancies, as well as healthier babies. Additionally, vitrification has also opened new options for patients, most notably fertility preservation (through oocyte cryopreservation), and donor egg banking.


Translation, but not transfection limits clinically relevant, exogenous mRNA based induction of alpha-4 integrin expression on human mesenchymal stem cells.
Mesenchymal stem cells (MSCs) represent promising resource of cells for regenerative medicine in neurological disorders. However, efficient and minimally invasive methods of MSCs delivery to the brain still have to be developed. Intra-arterial route is very promising, but MSCs are missing machinery for diapedesis through blood-brain barrier. Thus, here we have tested a mRNA-based method to induce transient expression of ITGA4, an adhesion molecule actively involved in cell extravasation. We observed that transfection with an ITGA4-mRNA construct bearing a conventional cap analogue (7-methylguanosine) failed to produce ITGA4 protein, but exogenous ITGA4-mRNA was detected in transfected MSCs. This indicates that not transfection, but rather translation being the major roadblock. Stabilization of ITGA4-mRNA with SSB proteins resulted in ITGA4 protein synthesis in HEK293 cells only, whereas in MSCs, satisfactory results were obtained only after using an anti-reverse-cap-analogue (ARCA). The presence of ITGA4 protein in MSCs was transient and lasted for up to 24 h after transfection. Membranous location was confirmed by flow cytometry of viable non-permeabilized cells using anti-ITGA4 antibody. The mRNA-based expression of itga4 transgene is potentially sufficient for diapedesis after intra-arterial delivery. To conclude, mRNA-based engineering of stem cells is a rapid and integration-free method and attractive from the perspective of potential future clinical application.


PC3-secreted microprotein is a novel chemoattractant protein and functions as a high-affinity ligand for CC chemokine receptor 2.
PC3-secreted microprotein (PSMP) or microseminoprotein is a newly discovered secreted protein whose function is currently unknown. In this study, PSMP was found to possess chemotactic ability toward monocytes and lymphocytes, and its functional receptor was identified as CCR2B. PSMP was identified as a chemoattractant protein from a PBMC chemoattractant platform screen that we established. The mature secreted PSMP was able to chemoattract human peripheral blood monocytes, PBLs, and CCR2B-expressing THP-1 cells, but not peripheral blood neutrophils, even though it does not contain the classical structure of chemokines. CCR2B was identified as one receptor for PSMP-mediated chemotaxis by screening HEK293 cells that transiently expressed classical chemokine receptors; results obtained from the chemotaxis, calcium flux, receptor internalization, and radioligand-binding assays all confirmed this finding. To further identify the major function of PSMP, we analyzed its expression profile in tissues. PSMP is highly expressed in benign prostatic hyperplasia and in some prostate cancers, and can also be detected in breast tumor tissue. In response to PSMP stimulation, phosphorylated ERK levels downstream of CCR2B signaling were upregulated in the PC3 cell line. Taken together, our data collectively suggest that PSMP is a chemoattractant protein acting as a novel CCR2 ligand that may influence inflammation and cancer development.


Neurochemistry of Hypomyelination Investigated with MR Spectroscopy.
Proton magnetic resonance spectroscopy (MRS) allows the noninvasive exploration of tissue metabolism in vivo, providing neurophysiological and neurochemical information. N-acetylaspartate (NAA) is generally considered to be a marker of neurons and axons, and many neurodegenerative disorders, including demyelinating disorders, exhibit a decrease in total NAA (tNAA). MRS in human hypomyelination disorders, such as Pelizaeus-Merzbacher disease (PMD), is characterized by normal to elevated tNAA, elevated myo-inositol and creatine (Cr), and normal to decreased choline (Cho). MRS in the thalamus of a hypomyelinating mouse model, a myelin synthesis-deficient (msd) mouse, a model of connatal PMD with mutation of the Plp1 gene, revealed increased tNAA and Cr and decreased Cho. That of a shiverer mouse with an autosomal recessive mutation of the Mbp gene showed decreased Cho with normal tNAA and Cr. Accordingly, the reduction of Cho on MRS might be a common marker for hypomyelinating disorders. tNAA concentrations range from normal to increased, probably depending upon the underlying pathology of oligodendrocytes. tNAA may be increased in hypomyelination with a reduced number of mature oligodendrocytes, such as PMD.


Disruption of intracellular processing of epidermal growth factor by methylamine inhibits epidermal growth factor-induced DNA synthesis but not early morphological or transcriptional events.
Upon internalization, epidermal growth factor (EGF) is proteolytically processed from its COOH terminus as it traverses intracellular vesicles and lysosomes. This report describes experiments which were conducted to determine whether lysosomotropic amines such as methylamine, which are known to inhibit degradation of EGF, are able to significantly inhibit the COOH-terminal processing of EGF, and whether disruption of EGF processing would negatively affect EGF-stimulated events such as DNA synthesis and induction of specific mRNA species. The results of these experiments indicated that, whereas methylamine treatment had no effect on EGF binding or internalization, vesicular translocation from endocytic vesicles to lysosomes was halted and processing of EGF was severely inhibited. The stimulation of DNA synthesis beginning 12 h after EGF exposure was also markedly inhibited by methylamine treatment. However, addition of methylamine alone produced a non-specific inhibition of DNA synthesis. The ability of EGF to induce specific transcription of the rat transin gene within 6 h of treatment was also not inhibited by methylamine treatment, but was actually increased in the presence of methylamine. These results suggest that at least some early transcriptionally regulated events induced by EGF do not require vesicular processing of EGF (or its receptor) and that the signal transduced by the binding of EGF to its receptor occurs in, or proximal to, the endocytic vesicles.


Optimizing near Infrared Reflectance Spectroscopy to Predict Nutritional Quality of Chickpea Straw for Livestock Feeding.
Multidimensional improvement programs of chickpea require screening of a large number of genotypes for straw nutritive value. The ability of near infrared reflectance spectroscopy (NIRS) to determine the nutritive value of chickpea straw was identified in the current study. A total of 480 samples of chickpea straw representing a nation-wide range of environments and genotypic diversity (40 genotypes) were scanned at a spectral range of 1108 to 2492 nm. The samples were reduced to 190 representative samples based on the spectral data then divided into a calibration set (160 samples) and a cross-validation set (30 samples). All 190 samples were analysed for dry matter, ash, crude protein, neutral detergent fibre, acid detergent fibre, acid detergent lignin, Zn, Mn, Ca, Mg, Fe, P, and in vitro gas production metabolizable energy using conventional methods. Multiple regression analysis was used to build the prediction equations. The prediction equation generated by the study accurately predicted the nutritive value of chickpea straw (R2 of cross validation > 0.68; standard error of prediction < 1%). Breeding programs targeting improving food-feed traits of chickpea could use NIRS as a fast, cheap, and reliable tool to screen genotypes for straw nutritional quality.


Rare Benign Entities of the Breast - Myoid Hamartoma and Capillary Hemangioma.
Hamartomas can occur in different areas of the breast, but they are rarely found in the breast. Myoid hamartomas with smooth muscle cells of the type described here are particularly unusual. The pathogenesis of this benign entity with its tendency to growth and recurrence is not clear. Excision is the therapy of choice. Capillary hemangiomas are rare vascular malformations of the breast which, in contrast to cavernous hemangiomas, usually remain clinically occult. It is important to differentiate these benign findings from malignant angiosarcoma. The possible heterogeneities between myoid hamartoma and capillary hemangioma using current breast imaging methods for the differential diagnosis (high-resolution ultrasound, duplex sonography, shear wave elastography, digital mammography, minimally invasive intervention) are discussed together with an overview of the literature.


Antioxidant activities and major anthocyanins of Myrobalan plum (Prunus cerasifera Ehrh.).
Total phenolic content, total antioxidant activity of Myrobalan plum (Prunus cerasifera Ehrh.) and anthocyanin content in peel were analyzed in this article. In addition, ultra-performance liquid chromatography with photodiode array detection and electrospray ionization tandem mass spectrometry were used to determine anthocyanin composition of this fruit. The range of total phenolic content of the tested samples was 1.34 to 6.11 g/kg fresh weight (FW), and anthocyanin content in fruit peel of Myrobalan plum was from 1.93 to 19.86 g/kg peel. Ferric reducing antioxidant power values varied from 11.20 to 44.83 μmol Trolox equivalent/g FW. Four main kinds of anthocyanins in purple Myrobalan plum were detected while 6 kinds in red ones. The article showed the anthocyanin composition, phenolic content, and antioxidant activities of wild Myrobalan plum. The purple Myrobalan plum could be developed as a resource of fruit drinks because of its high antioxidant activity and the peel could be used as the resource to extract natural pigments.


Cross-linking analysis of the ryanodine receptor and alpha1-dihydropyridine receptor in rabbit skeletal muscle triads.
In mature skeletal muscle, excitation-contraction (EC) coupling is thought to be mediated by direct physical interactions between the transverse tubular, voltage-sensing dihydropyridine receptor (DHPR) and the ryanodine receptor (RyR) Ca2+ release channel of the sarcoplasmic reticulum (SR). Although previous attempts at demonstrating interactions between purified RyR and alpha1-DHPR have failed, the cross-linking analysis shown here indicates low-level complex formation between the SR RyR and the junctional alpha1-DHPR. After cross-linking of membranes highly enriched in triads with dithiobis-succinimidyl propionate, distinct complexes of more than 3000 kDa were detected. This agrees with numerous physiological and electron-microscopic findings, as well as co-immunoprecipitation experiments with triad receptors and receptor domain-binding studies. However, a distinct overlap of immunoreactivity between receptors was not observed in crude microsomal preparations, indicating that the triad complex is probably of low abundance. Disulphide-bonded, high-molecular-mass clusters of triadin, the junctional protein proposed to mediate interactions in triads, were confirmed to be linked to the RyR. Calsequestrin and the SR Ca2+-ATPase were not found in cross-linked complexes of the RyR and alpha1-DHPR. Thus, whereas recent studies indicate that the two receptors exhibit temporal differences in their developmental inductions and that receptor interactions are not essential for the formation and maintenance of triads, this study supports the signal transduction hypothesis of direct physical interactions between triad receptors in adult skeletal muscle.


Glossopharyngeal (vagoglossopharyngeal) neuralgia: a study of 217 cases.
In 217 cases of glossopharyngeal neuralgia seen at the Mayo Clinic between 1922 and 1977, the disease was more common in patients older than 50 years (57%), but also occurred in 43% who were between 18 and 50. Spontaneous remissions were noted by 161 patients, but 37 had no periods of pain relief. Syncope was rarely a problem. Involvement was bilateral in 12%. The combination of glossopharyngeal and trigeminal neuralgia was found in 25 patients. Positive results on the cocaine test in 112 of 125 patients aided in diagnosis. Carbamazepine is the favored medication. Early surgical experience consisted of extracranial avulsion of the glossopharyngeal nerve or intracranial section at the jugular foramen; since 1948, surgical treatment has included section of the glossopharyngeal nerve and usually the upper rootlets of the vagus nerve and additional section of the fifth cranial nerve when trigeminal neuralgia was associated. Good relief of pain was obtained surgically in 110 patients.


Survived but feeling vulnerable and insecure: a qualitative study of the mental preparation for RTW after breast cancer treatment.
Improvements in treatment have resulted in an increasing number of cancer survivors potentially being able to return to work after medical treatment. In this paper we focus on the considerations regarding return to work (RTW) of breast cancer absentees in the Belgian context and how these considerations are related to reactions from their social environment. A qualitative study was performed to understand the RTW considerations of Belgian breast cancer absentees who had undergone breast cancer surgery in 2006. Twenty-two participants (mean age 46) were included and interviewed between May 2008 and August 2009 in their personal environment. An in-depth analysis (Grounded Theory) took place using the Qualitative Analysis Guide of Leuven (Quagol). Before the actual RTW, breast cancer employees try to build an image of the future resumption of work based on medical grounds and their knowledge of the workplace. Four matters are considered prior to RTW: (i) women want to leave the sick role and wish to keep their job; (ii) they consider whether working is worth the effort; (iii) they reflect on their capability; and (iv) they have doubts about being accepted in the workplace after returning. These inner thoughts are both product and input for the interaction with the social environment. The whole process is coloured by uncertainty and vulnerability. Our study demonstrated that mental preparation for RTW is not a linear process of improvement. It shows a detailed picture of four types of considerations made by breast cancer survivors before they actually resume work. Vulnerability appears to be an overarching theme during mental preparation. As the social environment plays an important role, people from that environment must become more aware of their influence on decreasing or increasing a woman's vulnerability while preparing for RTW.


The complexity of aging: cancer risk among elderly people and infectious risk among those with cancer.
Aging is associated with a reduced capability of the immune system to adequately respond to pathogens and to prevent tumor formation. As a consequence of immunosenescence, older people have a higher risk to develop infections as well as cancer. In addition, cancer itself may expose old patients to infections, including opportunistic infections, i.e. Pseudomonas aeruginosa, Aspergillus fumigatus and Cytomegalovirus infection. Patients with hematologic malignancies have a higher risk than patients with solid tumors, because of more prolonged disease-related and treatment-related neutropenia and intensive immunosuppressive regimens. Co-existing medical conditions, e.g. chronic renal failure, diabetes mellitus, emphysema, which are quite common in the elderly, may also contribute to rising the infectious risk, as well as the use of long term vascular catheters, which is required in a large number of cancer patients to administrate chemotherapy. Neutropenic infections do not only represent a major cause of morbidity and mortality, but may be responsible for a reduction of the antineoplastic treatment dose and dose intensity, thus compromising the overall treatment effectiveness. The use of antibiotic prophylaxis to reduce neutropenia-related infectious complications in patients with cancer is still object to debate. Quinolones represent the most attractive option, since these drugs have a broad antimicrobial spectrum, systemic bactericidal activity, good tolerability and lack of myelosuppression. However, fluoroquinolone prophylaxis has already been associated with the emergence and spread of resistant bacteria and strictly precludes the subsequent use of fluoroquinolones for initial empirical therapy; in addition, fluoroquinolones should be administered with caution among elderly patients, especially those with more pronounced vascular or degenerative impairment of the central nervous system, cardiac disease or electrolyte disturbances.


[Stress fractures in athletes].
Stress fractures are one of the most common overuse injuries seen in athletes, accounting for up to 20% of all injuries presented to sports medicine clinics. Runners are particularly prone to these injuries, however, it is difficult to predict injury as there is usually a critical interplay between the athlete's biomechanical predisposition, training methods, and other factors such as diet, and muscle strength and flexibility. This article will discuss the key clinical findings for the majority of stress fractures encountered in a sports medicine practice. A classification scheme will also be described that will allow the clinician to make appropriate treatment decisions based on the degree of risk for each injury.


Changes in adrenocorticotropin and cortisol responsiveness after repeated partial umbilical cord occlusions in the late gestation ovine fetus.
Despite many studies reporting fetal ACTH and cortisol (F) responses to acute fetal hypoxemia induced by several methods, effects of repeated short-term fetal hypoxia produced by umbilical cord occlusion (UCO) on ACTH and F are unknown. We examined fetal ACTH and F responses to repeated, controlled, 50% reductions in common umbilical arterial blood flow (CUBF) produced by an inflatable cord occluder. Ten sheep fetuses were instrumented at 123-128 days gestation (dGA) with arterial, venous, and amniotic catheters. A common umbilical artery transit-time ultrasound flow probe was implanted to measure CUBF. An inflatable occluder was placed around the proximal portion of the umbilicus. In five fetuses (group I) at 131 +/- 1 dGA (mean +/- SEM), 12 UCOs (CUBF reduced by 50%), each lasting 5 min separated by 15 min recovery, were performed. Changes in fetal arterial blood gases, pH and plasma ACTH, and F concentrations were determined before, during, and after the 1st, 6th, and 12th UCOs. Sham experiments were conducted on the other five fetuses at 130 +/- 1 dGA (group II). In group I, CUBF decreased to 49 +/- 1% (mean +/- SEM of 12 UCOs). After each UCO, CUBF returned to baseline within 5 min. A modest fall in fetal arterial PO2 and arterial pH (21.2 +/- 0.2 to 16.8 +/- 0.2 mmHg and 7.33 +/- 0 to 7.29 +/- 0, respectively) and a mild increase in fetal PaCO2 (49.9 +/- 0.5 to 54.9 +/- 0.4 mmHg; mean +/- SEM of 12 UCOs) occurred with each UCO. Whereas preocclusion fetal ACTH concentrations increased by the 12th UCO, F remained unchanged. Fetal ACTH increased after the 1st, 6th, and 12th UCOs. Fetal F increased after the 1st and 6th UCOs but not after the 12th UCO. Fetal plasma ACTH and F remained unchanged throughout the experiments in group II fetuses. We conclude that: 1) partial reductions in CUBF induce significant activation of the fetal anterior pituitary-adrenocortical axis in late-gestation fetal sheep; 2) after repeated UCOs, fetal ACTH responsiveness is maintained, but fetal F responses become attenuated.


The "Eyeballing" technique: an emerging and alerting trend of alcohol misuse.
Alternative methods of alcohol consumption have recently emerged among adolescents and young adults, including the alcohol "eyeballing", which consist in the direct pouring of alcoholic substances on the ocular surface epithelium. In a context of drug and behavioural addictions change, "eyeballing" can be seen as one of the latest and potentially highly risky new trends. We aimed to analyze the existing medical literature as well as online material on this emerging trend of alcohol misuse. Literature on alcohol eyeballing was searched in PsychInfo and Pubmed databases. Results were integrated with a multilingual qualitative assessment of the database provided by The Global Public Health Intelligence Network (GPHIN) and of a range of websites, drug fora and other online resources between March 2013 and July 2013. Alcohol eyeballing is common among adolescents and young adults; substances with high alcohol content, typically vodka, are used for this practice across the EU and internationally. The need for a rapid/intense effect of alcohol, competitiveness, novelty seeking and avoidance of "alcoholic fetor" are the most frequently reported motivations of "eyeballers". Local effects of alcohol eyeballing include pain, burning, blurred vision, conjunctive injection, corneal ulcers or scarring, permanent vision damage and eventually blindness. Alcohol eyeballing represents a phenomenon with potential permanent adverse consequences, deserving the attention of families and healthcare providers. Health and other professionals should be informed about this alerting trend of misuse. Larger observational studies are warranted to estimate the prevalence, characterize the effects, and identify adequate forms of interventions for this emerging phenomenon.


Late hypertension in renal transplant recipients: possible role of the donor in late primary hypertension.
Late onset (3-7 yrs) post-transplant renal hypertension is usually an indication of chronic, irreversible renal damage, and is a poor prognostic sign. In a small percent of patients (10%) however, hypertension can persist for years in conjunction with excellent renal function, and the absence of any known causes of early or late hypertension. This primary hypertension does not seem related to the recipient's pre-transplant blood pressure nor to the original renal disease. Rather, the high incidence of essential hypertension in the respective living related donor suggests that either a hypertensive diathesis exists, common to donor and recipient, or a transplantable factor inherent to the graft, or both causes, predispose to late onset primary hypertension.


Ecology, serology, and enterotoxin production of Vibrio cholerae in Chesapeake Bay.
A total of 65 isolates of Vibrio cholerae, serotypes other than O--1, have been recovered from water, sediment, and shellfish samples from the Chesapeake Bay. Isolations were not random, but followed a distinct pattern in which salinity appeared to be a controlling factor in V. cholerae distribution. Water salinity at stations yielding V. cholerae (13 out of 21 stations) was 4 to 17 0/00, whereas the salinity of water at stations from which V. cholerae organisms were not isolated was less than 4 or greater than 17 0/00. From results of statistical analyses, no correlation between incidence of fecal coliforms and V. cholerae could be detected, whereas incidence of Salmonella species, measured concurrently, was clearly correlated with fecal coliforms, with Salmonella isolated only in areas of high fecal coliform levels. A seasonal cycle could not be determined since strains of V. cholerae were detectable at low levels (ca. 1 to 10 cells/liter) throughout the year. Although none of the Chesapeake Bay isolates was agglutinable in V. cholerae O group 1 antiserum, the majority for Y-1 adrenal cells. Furthermore, rabbit ileal loop and mouse lethality tests were also positive for the Chesapeake Bay isolates, with average fluid accumulation in positive ileal loops ranging from 0.21 to 2.11 ml/cm. Serotypes of the strains of V. cholerae recovered from Chesapeake Bay were those of wide geographic distribution. It is concluded from the data assembled to date, that V. cholerae is an autochthonous estuarine bacterial species resident in Chesapeake Bay.


The TeleTriageTeam, Offering Continuity of Personalized Care Through Telemedicine: Development and Evaluation.
The COVID-19 pandemic taught us how to rethink care delivery. It catalyzed creative solutions to amplify the potential of personnel and facilities. This paper presents and evaluates a promptly introduced triaging solution that evolved into a tool to tackle the ever-growing waiting lists at an academic ophthalmology department, the TeleTriageTeam (TTT). A team of undergraduate optometry students, tutor optometrists, and ophthalmologists collaborate to maintain continuity of eye care. In this ongoing project, we combine innovative interprofessional task allocation, teaching, and remote care delivery. In this paper, we described a novel approach, the TTT; reported its clinical effectiveness and impact on waiting lists; and discussed its transformation to a sustainable method for delivering remote eye care. Real-world clinical data of all patients assessed by the TTT between April 16, 2020, and December 31, 2021, are covered in this paper. Business data on waiting lists and patient portal access were collected from the capacity management team and IT department of our hospital. Interim analyses were performed at different time points during the project, and this study presents a synthesis of these analyses. A total of 3658 cases were assessed by the TTT. For approximately half (1789/3658, 48.91%) of the assessed cases, an alternative to a conventional face-to-face consultation was found. The waiting lists that had built up during the first months of the pandemic diminished and have been stable since the end of 2020, even during periods of imposed lockdown restrictions and reduced capacity. Patient portal access decreased with age, and patients who were invited to perform a remote, web-based eye test at home were on average younger than patients who were not invited. Our promptly introduced approach to remotely review cases and prioritize urgency has been successful in maintaining continuity of care and education throughout the pandemic and has evolved into a telemedicine service that is of great interest for future purposes, especially in the routine follow-up of patients with chronic diseases. TTT appears to be a potentially preferred practice in other clinics and medical specialties. The paradox is that judicious clinical decision-making based on remotely collected data is possible, only if we as caregivers are willing to change our routines and cognitions regarding face-to-face care delivery.


Silencing of CXCR4 blocks breast cancer metastasis.
RNA interference technology, silencing targeted genes in mammalian cells, has become a powerful tool for studying gene function. For the first time in cancer research, we show that direct injection of a pool of naked small interfering RNA (siRNA) duplexes can prevent tumorigenesis in an animal model, suggesting a novel preventive and therapeutic strategy for cancer management. As a model system, we used siRNA duplexes of CXCR4 to block breast cancer metastasis. Here, we show that blocking CXCR4 expression at the mRNA level by a combination of two siRNAs impairs invasion of breast cancer cells in Matrigel invasion assay and inhibits breast cancer metastasis in an animal model. Targeting more than one site of the target gene may be important to overcome the functional redundancy of other variants of a single gene, especially in in vivo experiments. Moreover, our studies confirm the necessity of CXCR4 in breast cancer metastasis.


Merosin-negative congenital muscular dystrophy: magnetic resonance spectroscopy findings.
Congenital muscular dystrophies (CMD) are heterogeneous group of muscle disorders with autosomal recessive inheritance. Merosin deficiency has been identified in some patients with CMD all of whom also had white matter abnormalities on MRI. In postmortem studies, the brain showed extensive myelin pallor with a spongy appearance of white matter and moderate astrocytosis or demyelination. Direct assessment of neuropathologic aspects of MN-CMD such as demyelination is possible with MR spectroscopy (MRS). Although previous reports have described several neuro-imaging findings of this disease, MRS findings have not been reported in literature. In this case, we report MRS features of a 4-year old girl with MN-CMD. MRS of brain demonstrated that N-acetylaspartate (NAA)/Creatine (Cr) ratio was normal. Increased Choline (Cho)/Cr and Myo-inositol (MI)/Cr ratios were obtained. These findings were interpreted as demyelination and gliosis of white matter.


Nursing care of families with parents who are lesbian, gay, bisexual, or transgender.
Families in which parents are lesbian, gay, bisexual, or transgender are more diverse than they are similar. The numbers of parents and children in these families appear to be increasing with implications for nurses and other clinicians. This paper reviews the current literature to determine the fundamental issues facing alternate families that include sexual minority parents and their children. It also explores the unique nursing needs of families with gay, lesbian, transgender, or bisexual parents in the field, which are critically examined for direct relevance to psychiatric nursing practice. Current theoretical and research literature in nursing, child development, family law, and healthcare professional journals. Despite a relative lack of pathology noted in the literature related to families with sexual minority parents, nurses, and other healthcare professionals can incorporate current knowledge of unique child developmental, parenting, and legal issues into their work with these families. Assessments and interventions that address the unique needs of these families may help parents and children to deal with social stress from being perceived as "different" by other children, or as "problematic and threatening" by other parents.


Generation and phenotypic characterization of Pde1a mutant mice.
It has been proposed that a reduction in intracellular calcium causes an increase in intracellular cAMP and PKA activity through stimulation of calcium inhibitable adenylyl cyclase 6 and inhibition of phosphodiesterase 1 (PDE1), the main enzymes generating and degrading cAMP in the distal nephron and collecting duct, thus contributing to the development and progression of autosomal dominant polycystic kidney disease (ADPKD). In zebrafish pde1a depletion aggravates and overexpression ameliorates the cystic phenotype. To study the role of PDE1A in a mammalian system, we used a TALEN pair to Pde1a exon 7, targeting the histidine-aspartic acid dipeptide involved in ligating the active site Zn++ ion to generate two Pde1a null mouse lines. Pde1a mutants had a mild renal cystic disease and a urine concentrating defect (associated with upregulation of PDE4 activity and decreased protein kinase A dependent phosphorylation of aquaporin-2) on a wild-type genetic background and aggravated renal cystic disease on a Pkd2WS25/- background. Pde1a mutants additionally had lower aortic blood pressure and increased left ventricular (LV) ejection fraction, without a change in LV mass index, consistent with the high aortic and low cardiac expression of Pde1a in wild-type mice. These results support an important role of PDE1A in the renal pathogenesis of ADPKD and in the regulation of blood pressure.


High early failure rate after cementless hip replacement in the octogenarian.
Use of cementless hip replacements is increasing in many countries, but the best method for fixation for octogenarian patients remains unknown. We studied how fixation method (cemented, cementless, hybrid) affects the survival of primary hip replacements and mortality in patients 80 years or older. Specifically, we asked if fixation method affects (1) the risk of revision; (2) the reasons for revision; and (3) the mortality after contemporary primary hip replacement in octogenarian patients. A total of 4777 primary total hip replacements were performed in 4509 octogenarian patients with primary osteoarthritis in Finland between 1998 and 2009 and were registered in the Finnish Arthroplasty Register. Comorbidity data were collected from a nationwide quality register. Survival of hip replacements, using any revision as the end point, and mortality were analyzed using competing risks survival analysis and Cox regression analysis. The average followup was 4 years (range, 1-13 years). Cementless hip replacements were associated with a higher rate of early (within 1 year) revision compared with cemented hip replacements (hazard ratio, 2.9; 95% CI, 1.7-5.1), particularly in women. The difference was not explained by comorbidity or provider-related factors. Periprosthetic fracture was the leading mode of failure of cementless hip replacements. After 1 year, there were no differences in the survival rates although 10-year survival was slightly lower for cementless than cemented and hybrid hip replacements (93.9% [95% CI, 91.1%-96.7%] versus 97.4% [95% CI, 96.9%-98.0%] and 98.1% [95% CI, 96.9%-99.4%], respectively). Fixation method was not associated with mortality. Cementless fixation was associated with an increased risk of revision and did not provide any benefit in terms of lower mortality in octogenarian patients. Level II, therapeutic study. See the Instructions for Authors for a complete description of levels of evidence.


Reducing Transdermal Uptake of Semivolatile Plasticizers from Indoor Environments: A Clothing Intervention.
Models and laboratory studies suggest that everyday clothing influences the transdermal uptake of semivolatile organic compounds, including phthalate plasticizers, from indoor environments. However, this effect has not been documented in environmental exposure settings. In this pilot study, we quantified daily excretion of 17 urinary metabolites (μg/day) for phthalates and phthalate alternatives in nine participants during 5 days. On Day 0, baseline daily excretion was determined in participants' urine. Starting on Day 1, participants refrained from eating phthalate-heavy foods and using personal care products. On Days 3 and 4, participants wore precleaned clothing as an exposure intervention. We observed a reduction in the daily excretion of phthalates during the intervention; mono-n-butyl phthalate, monoisobutyl phthalate (MiBP), and monobenzyl phthalate were significantly reduced by 35, 38, and 56%, respectively. Summed metabolites of di(2-ethylhexyl)phthalate (DEHP) were also reduced (27%; not statistically significant). A similar reduction among phthalate alternatives was not observed. The daily excretion of MiBP during the nonintervention period strongly correlated with indoor air concentrations of diisobutyl phthalate (DiBP), suggesting that inhalation and transdermal uptake of DiBP from the air in homes are dominant exposure pathways. The results indicate that precleaned clothing can significantly reduce environmental exposure to phthalates and phthalate alternatives.


Active management of the third stage of labour: prevention and treatment of postpartum hemorrhage.
To review the clinical aspects of postpartum hemorrhage (PPH) and provide guidelines to assist clinicians in the prevention and management of PPH. These guidelines are an update from the previous Society of Obstetricians and Gynaecologists of Canada (SOGC) clinical practice guideline on PPH, published in April 2000. Medline, PubMed, the Cochrane Database of Systematic Reviews, ACP Journal Club, and BMJ Clinical Evidence were searched for relevant articles, with concentration on randomized controlled trials (RCTs), systematic reviews, and clinical practice guidelines published between 1995 and 2007. Each article was screened for relevance and the full text acquired if determined to be relevant. Each full-text article was critically appraised with use of the Jadad Scale and the levels of evidence definitions of the Canadian Task Force on Preventive Health Care. The quality of evidence was rated with use of the criteria described by the Canadian Task Force on Preventive Health Care. The Society of Obstetricians and Gynaecologists of Canada. Prevention of Postpartum Hemorrhage 1. Active management of the third stage of labour (AMTSL) reduces the risk of PPH and should be offered and recommended to all women. (I-A) 2. Oxytocin (10 IU), administered intramuscularly, is the preferred medication and route for the prevention of PPH in low-risk vaginal deliveries. Care providers should administer this medication after delivery of the anterior shoulder. (I-A) 3. Intravenous infusion of oxytocin (20 to 40 IU in 1000 mL, 150 mL per hour) is an acceptable alternative for AMTSL. (I-B) 4. An IV bolus of oxytocin, 5 to 10 IU (given over 1 to 2 minutes), can be used for PPH prevention after vaginal birth but is not recommended at this time with elective Caesarean section. (II-B) 5. Ergonovine can be used for prevention of PPH but may be considered second choice to oxytocin owing to the greater risk of maternal adverse effects and of the need for manual removal of a retained placenta. Ergonovine is contraindicated in patients with hypertension. (I-A) 6. Carbetocin, 100 microg given as an IV bolus over 1 minute, should be used instead of continuous oxytocin infusion in elective Caesarean section for the prevention of PPH and to decrease the need for therapeutic uterotonics. (I-B) 7. For women delivering vaginally with 1 risk factor for PPH, carbetocin 100 microg IM decreases the need for uterine massage to prevent PPH when compared with continuous infusion of oxytocin. (I-B) 8. Ergonovine, 0.2 mg IM, and misoprostol, 600 to 800 microg given by the oral, sublingual, or rectal route, may be offered as alternatives in vaginal deliveries when oxytocin is not available. (II-1B) 9. Whenever possible, delaying cord clamping by at least 60 seconds is preferred to clamping earlier in premature newborns (< 37 weeks' gestation) since there is less intraventricular hemorrhage and less need for transfusion in those with late clamping. (I-A) 10. For term newborns, the possible increased risk of neonatal jaundice requiring phototherapy must be weighed against the physiological benefit of greater hemoglobin and iron levels up to 6 months of age conferred by delayed cord clamping. (I-C) 11. There is no evidence that, in an uncomplicated delivery without bleeding, interventions to accelerate delivery of the placenta before the traditional 30 to 45 minutes will reduce the risk of PPH. (II-2C) 12. Placental cord drainage cannot be recommended as a routine practice since the evidence for a reduction in the duration of the third stage of labour is limited to women who did not receive oxytocin as part of the management of the third stage. There is no evidence that this intervention prevents PPH. (II-1C) 13. Intraumbilical cord injection of misoprostol (800 microg) or oxytocin (10 to 30 IU) can be considered as an alternative intervention before manual removal of the placenta. (II-2C) TREATMENT OF PPH: 14. For blood loss estimation, clinicians should use clinical markers (signs and symptoms) rather than a visual estimation. (III-B) 15. Management of ongoing PPH requires a multidisciplinary approach that involves maintaining hemodynamic stability while simultaneously identifying and treating the cause of blood loss. (III-C) 16. All obstetric units should have a regularly checked PPH emergency equipment tray containing appropriate equipment. (II-2B) 17. Evidence for the benefit of recombinant activated factor VII has been gathered from very few cases of massive PPH. Therefore this agent cannot be recommended as part of routine practice. (II-3L) 18. Uterine tamponade can be an efficient and effective intervention to temporarily control active PPH due to uterine atony that has not responded to medical therapy. (III-L) 19. Surgical techniques such as ligation of the internal iliac artery, compression sutures, and hysterectomy should be used for the management of intractable PPH unresponsive to medical therapy. (III-B) Recommendations were quantified using the evaluation of evidence guidelines developed by the Canadian Task Force on Preventive Health Care (Table 1).


Nerve distribution in the metacarpus and front digit of the horse.
The nerve distribution to the digit of the horse was studied with the compound microscope in serial transverse sections of fetal limbs and plotted on life-size outlines of the horse's foot. It was learned that there is much variation in the topography of the branches of the principal nerves. There is no mirror-image nerve distribution on the 2 sides of the foot. The dorsal branch of the ulnar nerve does not extend below the fetlock. The communication between the palmar metacarpal nerves and branches of the dorsal branch of the digital nerves is only a crossing of nerves without exchange of fibers. The palmar metacarpal nerves usually do not innervate structures distal to the pastern joint. The innervation of the deep structures of the equine foot was tabulated.


Synthesis of a polymyxin derivative for photolabeling studies in the gram-negative bacterium Escherichia coli.
The antimicrobial activity of polymyxins against Gram-negative bacteria has been known for several decades, but the mechanism of action leading to cell death has not been fully explored. A key step after binding of the antibiotic to lipopolysaccharide (LPS) exposed at the cell surface is 'self-promoted uptake' across the outer membrane (OM), in which the antibiotic traverses the asymmetric LPS-phospholipid bilayer before reaching the periplasm and finally targeting and disrupting the bacterial phospholipid inner membrane. The work described here was prompted by the hypothesis that polymyxins might interact with proteins in the OM, as part of their self-promoted uptake and permeabilizing effects. One way to test this is through photolabeling experiments. We describe the design and synthesis of a photoprobe based upon polymyxin B, containing photoleucine and an N-acyl group with a terminal alkyne suitable for coupling to a biotin tag using click chemistry. The resulting photoprobe retains potent antimicrobial activity, and in initial photolabeling experiments with Escherichia coli ATCC25922 is shown to photolabel several OM proteins. This photoprobe might be a valuable tool in more detailed studies on the mechanism of action of this family of antibiotics.


Shoulder arthroscopy. Technique and indications.
The development of shoulder arthroscopy is reviewed since its beginnings in 1931. The technique of posterior introduction of the arthroscope and positioning of the patient is presented. An additional portal for arthroscopic surgery is also described. The main indications for the procedure are reviewed, based on a survey of the literature and the author's experience, and five cases are presented illustrating some of the situations for which the technique proved beneficial.


Benzodiazepine receptors in the post-mortem brain of suicide victims and schizophrenic subjects.
To examine the role of benzodiazepine (BZ) receptors in suicide and schizophrenia, we determined BZ receptors in post-mortem brain (Brodmann's area 10) obtained from suicide victims, schizophrenic patients, and control subjects using [3H]RO15-1788 as the radioligand. The maximum number of binding sites (Bmax) of BZ receptors in the cortex of suicide victims was significantly higher compared with controls, but this increase was mainly due to those suicide victims who died by violent means and whose Bmax was significantly higher than of those who died by non-violent means or control subjects. In schizophrenic patients, Bmax was not significantly different from that of control subjects. When the schizophrenic subjects were separated into two groups, those on neuroleptics and those off neuroleptics for at least 12 months, however, the mean Bmax of BZ receptors in the prefrontal cortex in post-mortem brain obtained from schizophrenic patients on neuroleptics was significantly lower than Bmax in drug-free schizophrenic patients or normal controls. There were no significant differences among groups in values of the apparent dissociation constant (KD) of [3H]RO15-1788 binding. These results suggest that BZ receptors are up-regulated in the cortex of suicide victims, specifically those who used violent means, and that neuroleptic treatment may result in decreased central BZ receptor binding in the cortex of schizophrenic patients. Thus, the method of suicide and previous exposure to neuroleptics should be considered in the interpretation of data on BZ receptors.


A lower dose regimen for cephradine capsules in the treatment of urinary tract infections.
In this double-blind, randomized, multicenter trial, an oral dosing regimen of 500 mg twice daily (BID) of cephradine was evaluated for the treatment of acute uncomplicated urinary tract infections due to susceptible pathogens. This dose was compared to the already established cephradine regimen of 1,000 mg BID. Of the 218 cases entered into the study, 130 were evaluable for efficacy, 64 in the 500-mg BID group and 66 in the 1,000-mg BID group. There was no statistically significant difference between the two dosage regimens regarding rapidity of clinical improvement, eradication of the pathogens, and overall therapeutic outcome. Successful responses were obtained in 89.1% of the 500-mg BID cases and in 87.9% of the 1,000-mg BID cases. These results demonstrate the safety and efficacy of a 500-mg BID dosing regimen of cephradine for this use. This regimen offers the advantages of convenience, potentially improved compliance, and cost economy.


Complete genome sequence of community-associated methicillin-resistant Staphylococcus aureus (strain USA400-0051), a prototype of the USA400 clone.
Staphylococcus aureus subsp. aureus, commonly referred as S. aureus, is an important bacterial pathogen frequently involved in hospital- and community-acquired infections in humans, ranging from skin infections to more severe diseases such as pneumonia, bacteraemia, endocarditis, osteomyelitis, and disseminated infections. Here, we report the complete closed genome sequence of a community-acquired methicillin-resistant S. aureus strain, USA400-0051, which is a prototype of the USA400 clone.


An anti-inflammatory dietary intervention to reduce breast cancer recurrence risk: Study design and baseline data.
U.S. breast cancer survivors (BCSs) are expected to increase to 4 million in the next 5-10years. Cancer recurrence risk is highest among obese survivors. Inflammatory (Pro-I) biomarkers including C-reactive protein (CRP), Interleukins -3, -6, and -8 (IL-3, IL-6, IL-8), and Tumor Necrosis Factor (TNF)-α have been associated with cancer recurrence risk. Nutritional interventions aimed at reducing inflammation (INF) may contribute to reduced cancer recurrence risk, but studies have been limited to animal models. The goals of this one-year, culinary-based, pilot intervention were to: 1) decrease Pro-I biomarkers and increase anti-inflammatory (AI) cytokine, IL-10, by promoting AI food incorporation into BCS diets; and 2) examine intervention effects on cancer risk factors including body mass index (BMI) and circulating adipose stromal cells (ASCs). A total of 153 BCSs were recruited. Overweight and obese women aged 18 or older were randomized into Intervention (IG; n=76) and Control (CG; n=77) groups. CG received monthly nutritional brochures from the American Institute for Cancer Research. IG attended 6 monthly workshops (lectures on AI topics and chef-prepared food demonstrations), and received monthly newsletters and telephone calls incorporating Motivational Interviewing. At baseline, 6- and 12-month assessments, fasting serum was assayed for Pro-I/AI marker and ASC levels. Using R and Stata version 14 (Stata Corp, 2015), no significant differences were found between groups on baseline demographic variables. Correlations between serum cytokine levels, BMI, % body fat, ASCs, and self-reported variables are discussed.


Evaluation of internet-based patient education materials from internal medicine subspecialty organizations: will patients understand them?
The majority of Americans use the Internet daily, if not more often, and many search online for health information to better understand a diagnosis they have been given or to research treatment options. The average American reads at an eighth-grade level. The purpose of this study is to evaluate the readability of online patient education materials on the websites of 14 professional organizations representing the major internal medicine subspecialties. We used ten well-established quantitative readability scales to assess written text from patient education materials published on the websites of the major professional organizations representing the following subspecialty groups: allergy and immunology, cardiology, endocrinology, gastroenterology, geriatrics, hematology, hospice and palliative care, infectious disease, nephrology, oncology, pulmonology and critical care, rheumatology, sleep medicine, and sports medicine. Collectively the 540 articles analyzed were written at an 11th-grade level (SD 1.4 grade levels). The sleep medicine and nephrology websites had the most readable materials, written at an academic grade level of 8.5 ± 1.5 and 9.0 ± 0.2, respectively. Material at the infectious disease site was written at the most difficult level, with average readability corresponding to grades 13.9 ± 0.3. None of the patient education materials we reviewed conformed to the American Medical Association (AMA) and the National Institutes of Health (NIH) guidelines requiring that patient education articles be written at a third- to seventh-grade reading level. If these online resources were rewritten, it is likely that more patients would derive benefit from reading them.


Introgression from domestic goat generated variation at the major histocompatibility complex of Alpine ibex.
The major histocompatibility complex (MHC) is a crucial component of the vertebrate immune system and shows extremely high levels of genetic polymorphism. The extraordinary genetic variation is thought to be ancient polymorphisms maintained by balancing selection. However, introgression from related species was recently proposed as an additional mechanism. Here we provide evidence for introgression at the MHC in Alpine ibex (Capra ibex ibex). At a usually very polymorphic MHC exon involved in pathogen recognition (DRB exon 2), Alpine ibex carried only two alleles. We found that one of these DRB alleles is identical to a DRB allele of domestic goats (Capra aegagrus hircus). We sequenced 2489 bp of the coding and non-coding regions of the DRB gene and found that Alpine ibex homozygous for the goat-type DRB exon 2 allele showed nearly identical sequences (99.8%) to a breed of domestic goats. Using Sanger and RAD sequencing, microsatellite and SNP chip data, we show that the chromosomal region containing the goat-type DRB allele has a signature of recent introgression in Alpine ibex. A region of approximately 750 kb including the DRB locus showed high rates of heterozygosity in individuals carrying one copy of the goat-type DRB allele. These individuals shared SNP alleles both with domestic goats and other Alpine ibex. In a survey of four Alpine ibex populations, we found that the region surrounding the DRB allele shows strong linkage disequilibria, strong sequence clustering and low diversity among haplotypes carrying the goat-type allele. Introgression at the MHC is likely adaptive and introgression critically increased MHC DRB diversity in the genetically impoverished Alpine ibex. Our finding contradicts the long-standing view that genetic variability at the MHC is solely a consequence of ancient trans-species polymorphism. Introgression is likely an underappreciated source of genetic diversity at the MHC and other loci under balancing selection.


Friendship interventions for children with neurodevelopmental needs: A systematic review and meta-analysis.
Children with neurodevelopmental disorders such as attention-deficit hyperactivity disorder (ADHD), autism, developmental language disorder (DLD), intellectual disability (ID), and social (pragmatic) communication disorder (SPCD) experience difficulties with social functioning due to differences in their social, emotional and cognitive skills. Previous systematic reviews have focussed on specific aspects of social functioning rather than broader peer functioning and friendships. To systematically review and methodologically appraise the quality and effectiveness of existing intervention studies that measured friendship outcomes for children with ADHD, autism, DLD, ID, and SPCD. Following PRISMA guidelines, we searched five electronic databases: CINAHL, Embase, Eric, PsycINFO, and PubMed. Two independent researchers screened all abstracts and disagreements were discussed with a third researcher to reach consensus. The methodological quality of studies was assessed using the Cochrane Risk of Bias Tool for Randomised Trials. Twelve studies involving 15 interventions were included. Studies included 683 children with a neurodevelopmental disorder and 190 typically-developing children and diagnosed with either autism or ADHD. Within-group meta-analysis showed that the pooled intervention effects for friendship across all interventions were small to moderate (z = 2.761, p = 0.006, g = 0.485). The pooled intervention effect between intervention and comparison groups was not significant (z = 1.206, p = 0.400, g = 0.215). Findings provide evidence that some individual interventions are effective in improving social functioning and fostering more meaningful friendships between children with neurodevelopmental disorders and their peers. Effective interventions involved educators, targeted child characteristics known to moderate peer functioning, actively involved peers, and incorporated techniques to facilitate positive peer perceptions and strategies to support peers. Future research should evaluate the effectiveness of friendship interventions for children with DLD, ID and SPCD, more comprehensively assess peer functioning, include child self-report measures of friendship, and longitudinally evaluate downstream effects on friendship.