Understanding inequalities in child health in Ethiopia: health achievements are improving in the period 2000-2011.
In Ethiopia, coverage of key health services is low, and community based services have been implemented to improve access to key services. This study aims to describe and assess the level and the distribution of health outcomes and coverage for key services in Ethiopia, and their association with socioeconomic and geographic determinants. Data were obtained from the 2000, 2005 and 2011 Ethiopian Demographic and Health Surveys. As indicators of access to health care, the following variables were included: Under-five and neonatal deaths, skilled birth attendance, coverage of vaccinations, oral rehydration therapy for diarrhoea, and antibiotics for suspected pneumonia. For each of the indicators in 2011, inequality was described by estimating their concentration index and a geographic Gini index. For further assessment of the inequalities, the concentration indices were decomposed. An index of health achievement, integrating mean coverage and the distribution of coverage, was estimated. Changes from 2000 to 2011 in coverage, inequality and health achievement were assessed. Significant pro-rich inequalities were found for all indicators except treatment for suspected pneumonia in 2011. The geographic Gini index showed significant regional inequality for most indicators. The decomposition of the 2011 concentration indices revealed that the factor contributing the most to the observed inequalities was different levels of wealth. The mean of all indicators improved from 2000 to 2011, and the health achievement index improved for most indicators. The socioeconomic inequalities seem to increase from 2000 to 2011 for under-five and neonatal deaths, whereas they are stable or decreasing for the other indicators. There is an unequal socioeconomic and geographic distribution of health and access to key services in Ethiopia. Although the health achievement indices improved for most indicators from 2000 to 2011, socioeconomic determinants need to be addressed in order to achieve better and more fairly distributed health.


Transitional B cells commit to marginal zone B cell fate by Taok3-mediated surface expression of ADAM10.
Notch2 and B cell antigen receptor (BCR) signaling determine whether transitional B cells become marginal zone B (MZB) or follicular B (FoB) cells in the spleen, but it is unknown how these pathways are related. We generated Taok3-/- mice, lacking the serine/threonine kinase Taok3, and found cell-intrinsic defects in the development of MZB but not FoB cells. Type 1 transitional (T1) B cells required Taok3 to rapidly respond to ligation by the Notch ligand Delta-like 1. BCR ligation by endogenous or exogenous ligands induced the surface expression of the metalloproteinase ADAM10 on T1 B cells in a Taok3-dependent manner. T1 B cells expressing surface ADAM10 were committed to becoming MZB cells in vivo, whereas T1 B cells lacking expression of ADAM10 were not. Thus, during positive selection in the spleen, BCR signaling causes immature T1 B cells to become receptive to Notch ligands via Taok3-mediated surface expression of ADAM10.


Delineating the roles of males and females in sperm competition.
Disentangling the relative roles of males, females and their interactive effects on competitive fertilization success remains a challenge in sperm competition. In this study, we apply a novel experimental framework to an ideally suited externally fertilizing model system in order to delineate these roles. We focus on the chinook salmon, Oncorhynchus tshawytscha, a species in which ovarian fluid (OF) has been implicated as a potential arbiter of cryptic female choice for genetically compatible mates. We evaluated this predicted sexually selected function of OF using a series of factorial competitive fertilization trials. Our design involved a series of 10 factorial crosses, each involving two 'focal' rival males whose sperm competed against those from a single 'standardized' (non-focal) rival for a genetically uniform set of eggs in the presence of OF from two focal females. This design enabled us to attribute variation in competitive fertilization success among focal males, females (OF) and their interacting effects, while controlling for variation attributable to differences in the sperm competitive ability of rival males, and male-by-female genotypic interactions. Using this experimental framework, we found that variation in sperm competitiveness could be attributed exclusively to differences in the sperm competitive ability of focal males, a conclusion supported by subsequent analyses revealing that variation in sperm swimming velocity predicts paternity success. Together, these findings provide evidence that variation in paternity success can be attributed to intrinsic differences in the sperm competitive ability of rival males, and reveal that sperm swimming velocity is a key target of sexual selection.


Meibomian Gland Dysfunction in Primary and Secondary Sjögren Syndrome.
We hypothesized that women with primary (pSS) and secondary Sjögren syndrome (sSS; with systemic lupus erythematosus [SLE] or rheumatoid arthritis [RA]) have meibomian gland dysfunction (MGD). We sought to test our hypothesis. Subjects with pSS, sSS + SLE, sSS + RA, and non-SS-related MGD were recruited from the Sjögren's Syndrome Foundation or outpatient clinics at Tufts University School of Dental Medicine or Brigham and Women's Hospital. The control population was recruited from the Greater Boston area. After providing written informed consent, the subjects underwent an eye examination and/or completed two questionnaires that assess symptoms of dry eye disease (DED). Our results demonstrate that pSS and sSS patients have MGD. These subjects had meibomian gland orifice metaplasia, an increased number of occluded meibomian gland orifices, and a reduced quality of meibomian gland secretions. Further, patients with pSS, sSS + SLE, sSS + RA, and MGD had significant alterations in their tear film, lid margin, cornea, and conjunctiva. Symptoms of DED were increased ∼10-fold in all pSS, sSS, and MGD groups relative to controls. Our findings support our hypothesis and show that individuals with pSS, sSS + SLE, and sSS + RA have MGD. In addition, our study indicates that patients with pSS and sSS have both aqueous-deficient and evaporative DED.


Combined T1-mapping and tissue tracking analysis predicts severity of ischemic injury following acute STEMI-an Oxford Acute Myocardial Infarction (OxAMI) study.
Early risk stratification after ST-segment-elevation myocardial infarction (STEMI) is of major clinical importance. Strain quantifies myocardial deformation and can demonstrate abnormal global and segmental myocardial function in acute ischaemia. Native T1-mapping allows assessment of the severity of acute ischemic injury, however its clinical applicability early post MI is limited by the complex dynamic changes happening in the myocardium post MI. We aimed to explore relationship between T1-mapping and feature tracking imaging, to establish whether combined analysis of these parameters could predict recovery after STEMI. 96 STEMI patients (aged 60 ± 11) prospectively recruited in the Oxford Acute Myocardial Infarction (OxAMI) study underwent 3T-CMR scans acutely (within 53 ± 32 h from primary percutaneous coronary intervention) and at 6 months (6M). The imaging protocol included: cine, ShMOLLI T1-mapping and late gadolinium enhancement (LGE). Segments were divided in the infarct, adjacent and remote zones based on the presence of LGE. Peak circumferential (Ecc) and radial (Err) strain was assessed using cvi42 software. Acute segmental strain correlated with segmental T1-mapping values (T1 vs. Err - 0.75 ± 0.25, p < 0.01; T1 vs. Ecc 0.72 ± 0.32, p < 0.01) and with LGE segmental injury (LGE vs. Err - 0.56 ± 0.29, p < 0.01; LGE vs. Ecc 0.54 ± 0.35, p < 0.01). Moreover, acute segmental T1 and strain predicted segmental LGE transmurality on 6M scans (p < 0.001, r = 0.5). Multiple regression analysis confirmed combined analysis of global Ecc and T1-mapping was significantly better than either method alone in predicting final infarct size at 6M (r = 0.556 vs r = 0.473 for global T1 only and r = 0.476 for global Ecc only, p < 0.001). This novel CMR method combining T1-mapping and feature tracking analysis of acute CMR scans predicts LGE transmurality and infarct size at 6M following STEMI.


Current State of In vitro Cell-Based Renal Models.
Renal proximal tubule (PT) epithelial cells, expressing uptake and efflux transporters at basolateral and apical membranes, are the location of active renal drug secretion and reabsorption. In addition to singly transfected cells, an in vitro renal cell-based model is a requirement to study the active renal secretion of drugs, drug-drug interactions (DDIs), drug-induced kidney injury, nephrotoxicity holistically and potentially renal replacement therapies. So far, two-dimensional (2D) cell culture of primary and immortalized PT cells has been the only tool to study drugs active secretion, interactions and nephrotoxicity, however a number of in vivo characteristics of cells such as drug transporter expression and function, along with morphological features are lost during in vitro cell culture. Cellular microenvironment, extracellular matrix, cell-cell interactions, microfluidic environment and tubular architecture are the factors lacking in 2D cell culture. Currently, there are a few 3D cell culture platforms mimicking the in vivo conditions of PT cells and thus potentially enabling the necessary factors for the full functional PT cells. In this review, we address in vivo physiological and morphological characteristics of PT cells, comparing their available sources and remaining in vivo features. In addition, 2D and 3D cell culture platforms and the influence of cell culture architecture on the physiological characteristics of cells are reviewed. Finally, future perspective of 3D models, kidney and multi organs on a chip, generation of kidney organoids, other ex vivo renal models and their capabilities to study drug disposition and in vitro-in vivo extrapolation are described.


Prognostic significance of CD20 expression in adults with de novo precursor B-lineage acute lymphoblastic leukemia.
Immunophenotypic classification of acute lymphoblastic leukemia (ALL) has well-recognized prognostic implications. The significance of CD20 expression has been evaluated in childhood precursor B-lineage ALL with conflicting results. We retrospectively analyzed the influence of CD20 expression on outcome in 253 adults with de novo precursor B-lineage ALL treated with either conventional (VAD/CVAD) or intensive (hyper-CVAD) frontline chemotherapy regimens in the pre-rituximab era. Overall, CD20 positivity of at least 20% was associated with lower 3-year rates of complete remission duration (CRD; 20% vs 55%, P < .001) and overall survival (OS; 27% vs 40%, p = .03). In the CD20 negative subset, the 3-year rates for CRD (58% vs 42%, p = .04) and OS (60% vs 28%, P < .001) were superior for hyper-CVAD compared with VAD/CVAD; rates were particularly favorable for the CD20 negative younger age group (68% and 85%, respectively). In contrast, 3-year CRD and OS rates were uniformly poor for the CD20-positive group regardless of therapy (27% or less). Multivariate analysis for event-free survival identified older age, leukocyte count higher than 30 x 10(9)/L, presence of Philadelphia chromosome, high systemic risk classification, and CD20 positivity as independent predictors of worse outcome. In conclusion, CD20 expression in de novo adult precursor B-lineage ALL appears to be associated with a poor prognosis. Incorporation of monoclonal antibodies directed against CD20 into frontline chemotherapy regimens warrants investigation.


Rebuilding biodiversity of Patagonian marine molluscs after the end-Cretaceous mass extinction.
We analysed field-collected quantitative data of benthic marine molluscs across the Cretaceous-Palaeogene boundary in Patagonia to identify patterns and processes of biodiversity reconstruction after the end-Cretaceous mass extinction. We contrast diversity dynamics from nearshore environments with those from offshore environments. In both settings, Early Palaeogene (Danian) assemblages are strongly dominated by surviving lineages, many of which changed their relative abundance from being rare before the extinction event to becoming the new dominant forms. Only a few of the species in the Danian assemblages were newly evolved. In offshore environments, however, two newly evolved Danian bivalve species attained ecological dominance by replacing two ecologically equivalent species that disappeared at the end of the Cretaceous. In both settings, the total number of Danian genera at a locality remained below the total number of late Cretaceous (Maastrichtian) genera at that locality. We suggest that biotic interactions, in particular incumbency effects, suppressed post-extinction diversity and prevented the compensation of diversity loss by originating and invading taxa. Contrary to the total number of genera at localities, diversity at the level of individual fossiliferous horizons before and after the boundary is indistinguishable in offshore environments. This indicates an evolutionary rapid rebound to pre-extinction values within less than ca 0.5 million years. In nearshore environments, by contrast, diversity of fossiliferous horizons was reduced in the Danian, and this lowered diversity lasted for the entire studied post-extinction interval. In this heterogeneous environment, low connectivity among populations may have retarded the recolonisation of nearshore habitats by survivors.


Toxicological and biochemical characterizations of AChE in phosalone-susceptible and resistant populations of the common pistachio psyllid, Agonoscena pistaciae.
The toxicological and biochemical characteristics of acetylcholinesterases (AChE) in nine populations of the common pistachio psyllid, Agonoscena pistaciae Burckhardt and Lauterer (Hemiptera: Psyllidae), were investigated in Kerman Province, Iran. Nine A. pistaciae populations were collected from pistachio orchards, Pistacia vera L. (Sapindales: Anacardiaceae), located in Rafsanjan, Anar, Bam, Kerman, Shahrbabak, Herat, Sirjan, Pariz, and Paghaleh regions of Kerman province. The previous bioassay results showed these populations were susceptible or resistant to phosalone, and the Rafsanjan population was most resistant, with a resistance ratio of 11.3. The specific activity of AChE in the Rafsanjan population was significantly higher than in the susceptible population (Bam). The affinity (K(M)) and hydrolyzing efficiency (Vmax) of AChE on acetylthiocholine iodide, butyrylthiocholine iodide, and propionylthiocholine odide as artificial substrates were clearly lower in the Bam population than that in the Rafsanjan population. These results indicated that the AChE of the Rafsanjan population had lower affinity to these substrates than that of the susceptible population. The higher Vmax value in the Rafsanjan population compared to the susceptible population suggests a possible over expression of AChE in the Rafsanjan population. The in vitro inhibitory effect of several organophosphates and carbamates on AChE of the Rafsanjan and Bam populations was determined. Based on I50, the results showed that the ratios of AChE insensitivity of the resistant to susceptible populations were 23 and 21.7-fold to monocrotophos and phosphamidon, respectively. Whereas, the insensitivity ratios for Rafsanjan population were 0.86, 0.8, 0.78, 0.46, and 0.43 for carbaryl, eserine, propoxur, m-tolyl methyl carbamate, and carbofuran, respectively, suggesting negatively correlated sensitivity to organophosphate-insensitive AChE. Therefore, AChE from the Rafsanjan population showed negatively correlated sensitivity, being insensitive to phosphamidon and monocrotophos and sensitive to N-methyl carbamates.


Association of complement 5 genetic polymorphism with renal allograft outcomes in Korea.
Complements play important roles in both rejection and ischemia-reperfusion injury after transplantation. Complement 5 (C5) is a pivotal complement, which initiates the assembly of the membrane attack complex, and mediates chemotaxis of various immune cells. We investigated the impacts of genetic variations in C5 and its receptor (C5aR) of both recipients and donors on renal allograft outcomes. Seven single-nucleotide polymorphisms (SNPs) in C5 (rs12237774, rs2159776, rs17611, rs25681, rs2241004, rs10985126 and rs10818500) and one SNP (rs10404456) in the C5aR gene were genotyped in 191 recipient-donor pairs. The association of the polymorphisms with allograft outcomes was determined. Three C5 SNPs (rs2159776, rs17611 and rs25681) in recipients had a tendency toward a reduced glomerular filtration rate at 1 year after transplantation. There were four haplotypes in the H2 linkage disequilibrium block, which was formed by four SNPs (rs2159776, rs17611, rs25681 and rs2241004). The GGCG haplotype in both recipients and donors was associated with lower glomerular filtration rate at 1 year (60.9 ± 15.9 versus 66.4 ± 15.5 mL/min/1.73 m(2), P = 0.020; 60.6 ± 15.3 versus 66.2 ± 15.8 mL/min/1.73 m(2), P = 0.017). The association was sustained over 7 years after transplantation (P = 0.015 in recipients; P = 0.039 in donors). The presence of the GGCG haplotype in recipients was associated with poorer graft survival (logrank test, P = 0.024). However, C5 polymorphisms were not correlated with serum C5 level. C5aR polymorphism had no significant impact on the allograft outcomes. The GGCG haplotype of C5 in both recipients and donors was associated with lower renal allograft function.


Characterization of poultry egg-white avidins and their potential as a tool in pretargeting cancer treatment.
Chicken avidin and bacterial streptavidin are proteins used in a wide variety of applications in the life sciences due to their strong affinity for biotin. A new and promising use for them is in medical pretargeting cancer treatments. However, their pharmacokinetics and immunological properties are not always optimal, thereby limiting their use in these applications. To search for potentially beneficial new candidates, we screened egg white from four different poultry species for avidin. Avidin proteins, isolated from the duck, goose, ostrich and turkey, showed a similar tetrameric structure, similar glycosylation and stability against both temperature and proteolytic activity of proteinase K as chicken avidin. Biotin-binding properties of these avidins, measured using IAsys optical biosensor, were similar to those found in avidin from the chicken. Three of these novel avidins, however, showed different immunological cross-reactivities when compared with chicken avidin. The patient sera responses to duck, goose and ostrich avidins were also lower than those observed for chicken and turkey avidins. Our findings suggest that the use of these proteins offers advantages over chicken avidin and bacterial streptavidin in pretargeting applications.


Satisfactory outcome after intensive chemotherapy with pragmatic use of minimal residual disease (MRD) monitoring in older patients with Philadelphia-negative B cell precursor acute lymphoblastic leukaemia: a Swedish registry-based study.
The introduction of minimal residual disease (MRD) monitoring, in the Swedish national guidelines for acute lymphoblastic leukaemia, was evaluated in 35 patients aged 46-79 years (median 61), who were diagnosed from 2007 to 2011 and treated with high-intensity, block-based chemotherapy (ABCDV/VABA induction). Both a high complete remission rate (91 %) and acceptable overall survival (OS) rate (47 %) at 5 years were achieved. MRD by flow cytometry was measured in 73 % of the patients reaching complete remission after the first course, but was omitted by the clinicians for eight patients who were either over 70 years of age or already met conventional high-risk criteria. Factors negatively influencing OS were age over 65 years and WHO status ≥2. MRD < 0.1 % after induction had positive impact on continuous complete remission but not on OS. Only five patients were allocated to allogeneic haematopoietic stem cell transplantation in first remission, mainly due to conventional high risk factors. Thus, use of intensive remission induction therapy is effective in a selection of older patients. In a population for whom the possibilities of treatment escalation are limited, the optimal role of MRD monitoring remains to be determined.


Taiwan's legal framework for marine pollution control and responses to marine oil spills and its implementation on T.S. Taipei cargo shipwreck salvage.
Many shipwreck events occur in the neighboring areas of Taiwan due to the volume of maritime traffic and geographical conditions around Taiwan. The oil spills from such events can be devastating for the surrounding sea and coastal areas. The government realized the importance of marine pollution prevention and enforced the Marine Pollution Control Act and the Major Marine Oil Pollution Emergency Response Plan to mitigate the impact of oil spill pollution. The T.S. Taipei shipwreck highlighted the effectiveness of the national marine pollution prevention system. Inter-departmental cooperation and collaboration with private sectors are the keys for effective response. This article is the first detailed documentation of an oil spill response for a maritime incident from the beginning to the final termination of shipwreck removal. It shows the people in Taiwan intend to collaborate with other states to make a significant contribution to marine environment conservation and sustainability.


Extension of research data repository system to support direct compute access to biomedical datasets: enhancing Dataverse to support large datasets.
Access to experimental X-ray diffraction image data is important for validation and reproduction of macromolecular models and indispensable for the development of structural biology processing methods. In response to the evolving needs of the structural biology community, we recently established a diffraction data publication system, the Structural Biology Data Grid (SBDG, data.sbgrid.org), to preserve primary experimental datasets supporting scientific publications. All datasets published through the SBDG are freely available to the research community under a public domain dedication license, with metadata compliant with the DataCite Schema (schema.datacite.org). A proof-of-concept study demonstrated community interest and utility. Publication of large datasets is a challenge shared by several fields, and the SBDG has begun collaborating with the Institute for Quantitative Social Science at Harvard University to extend the Dataverse (dataverse.org) open-source data repository system to structural biology datasets. Several extensions are necessary to support the size and metadata requirements for structural biology datasets. In this paper, we describe one such extension-functionality supporting preservation of file system structure within Dataverse-which is essential for both in-place computation and supporting non-HTTP data transfers.


Assessing patterns and determinants of latrine use in rural settings: A longitudinal study in Odisha, India.
Monitoring of sanitation programs is often limited to sanitation access and coverage, with little emphasis on use of the facilities despite increasing evidence of widespread non-use. We assessed patterns and determinants of individual latrine use over 12 months in a low- income rural study population that had recently received latrines as part of the Government of India's Total Sanitation Campaign (TSC) in coastal Puri district in Odisha, India. We surveyed 1938 individuals (>3years) in 310 rural households with latrines from 25 villages over 12 months. Data collection rounds were timed to correspond with the seasons. The primary outcome was reported use by each member of the household over the prior 48h. We classified use into three categories-"never", "sometimes" and "always/usually". We also assessed consistency of use over six days across the three seasons (dry cold, dry hot, rainy). We explored the association between individual and household-level variables and latrine use in any given season and longitudinally using multinomial logistic regression. We also inquired about reasons for non-use. Overall, latrine use was poor and inconsistent. The average response probability at any given round of never use was 43.5% (95% CI=37.9, 49.1), sometimes use was 4.6% (95% CI=3.8, 5.5), and always/usual use was 51.9% (95% CI=46.2, 57.5). Only two-thirds of those who reported always/usually using a latrine in round one reported the same for all three rounds. Across all three rounds, the study population was about equally divided among those who reported never using the latrine (30.1%, 95% CI=23.0, 37.2), sometimes using the latrine (33.2%, 95% CI=28.3, 38.1) and always/usually using the latrine (36.8%, 95% CI=31.8, 41.8). The reported likelihood of always/usually versus never using the latrine was significantly greater in the dry cold season (OR=1.50, 95% CI=1.18, 1.89, p=0.001) and in the rainy season (OR=1.34, 95% CI=1.07, 1.69, p=0.012), than in the dry hot season. Across all three seasons, there was increased likelihood of always/usually and sometimes using the latrine versus never using it among females and where latrines had a door and roof. Older age groups, including those aged 41-59 years and 60+ years, and increase in household size were associated with a decreased likelihood of always/usually using the latrine versus never using it. The leading reason for non-use was a preference for open defecation. Results highlight the low and inconsistent use of subsidized latrines built under the TSC in rural Odisha. This study identifies individual and household levels factors that may be used to target behavior change campaigns to drive consistent use of sanitation facilities by all.


Processing negative emotion in two languages of bilinguals: Accommodation and assimilation of the neural pathways based on a meta-analysis.
Numerous functional magnetic resonance imaging (fMRI) studies have examined the neural mechanisms of negative emotional words, but scarce evidence is available for the interactions among related brain regions from the functional brain connectivity perspective. Moreover, few studies have addressed the neural networks for negative word processing in bilinguals. To fill this gap, the current study examined the brain networks for processing negative words in the first language (L1) and the second language (L2) with Chinese-English bilinguals. To identify objective indicators associated with negative word processing, we first conducted a coordinate-based meta-analysis on contrasts between negative and neutral words (including 32 contrasts from 1589 participants) using the activation likelihood estimation method. Results showed that the left medial prefrontal cortex (mPFC), the left inferior frontal gyrus (IFG), the left posterior cingulate cortex (PCC), the left amygdala, the left inferior temporal gyrus (ITG), and the left thalamus were involved in processing negative words. Next, these six clusters were used as regions of interest in effective connectivity analyses using extended unified structural equation modeling to pinpoint the brain networks for bilingual negative word processing. Brain network results revealed two pathways for negative word processing in L1: a dorsal pathway consisting of the left IFG, the left mPFC, and the left PCC, and a ventral pathway involving the left amygdala, the left ITG, and the left thalamus. We further investigated the similarity and difference between brain networks for negative word processing in L1 and L2. The findings revealed similarities in the dorsal pathway, as well as differences primarily in the ventral pathway, indicating both neural assimilation and accommodation across processing negative emotion in two languages of bilinguals.


Barrier removal in increasing physical activity levels in obese African American women with disabilities.
This pilot study examined the effectiveness of a telephone-based intervention to increase physical activity in obese African American women with mobility disabilities by targeting the removal of barriers to participation. Severely obese (mean body mass index [BMI] = 49.1 kg.m²) African American women (n = 33) with mobility disabilities completed a 6-month telephone-based physical activity coaching intervention. The major environmental/facility barriers at preintervention were cost of the program (66.7%), lack of transportation (48.5%), not aware of fitness center in the area (45.5%), and lack of accessible facilities (45.5%). The major personal barriers were pain (63.6%), don't know how to exercise (45.5%), health concerns (39.4%), don't know where to exercise (39.4%), and lack of energy (36.4%). Despite only two personal barriers being significantly lower at posttest (don't know where to exercise and don't know how to exercise) (p < 0.01), total exercise time increased from < 6 minutes/day to 27 minutes/day at posttest (p < 0.001), and total physical activity time (structured exercise, leisure, indoor and outdoor household activity) increased from 26 minutes/day to 89 minutes/day at posttest (p < 0.001). Interventions aimed at increasing physical activity participation among obese African American women with mobility disabilities should start with increasing their awareness/knowledge on where and how to exercise. Other reported barriers (e.g., cost, transportation, finding an accessible facility, health concerns, pain) may not be as critical to alter/remove as identifying where participants can exercise (i.e., home, outdoors, gym) and providing them with a variety of routines that can be performed safely in their desired setting.


"A different kind of beauty": scientific and architectural style in I.M. Pei's Mesa Laboratory and Louis Kahn's Salk Institute.
I.M. Pei's Mesa Laboratory for the National Center for Atmospheric Research in Boulder, Colorado, and Louis Kahn's Salk Institute in La Jolla, California, are rare examples of laboratories as celebrated for their architecture as for their scientific contributions. Completed in the mid-1960s, these signature buildings still express the scientific style of their founding directors, Walter Roberts and Jonas Salk. yet in commissioning their laboratories, Roberts and Salk had to work with architects as strong-willed as themselves. A close reading of the two laboratories reveals the ongoing negotiations and tensions in collaborations between visionary scientist and visionary architect. Moreover, Roberts and Salk also had to become architects of atmospheric and biomedical sciences. For laboratory architecture, however flexible in theory, necessarily stabilizes scientific practice, since a philosophy of research is embedded in the very structure of the building and persists far longer than the initial vision and mission that gave it life. Roberts and Salk's experiences suggest that even the most carefully designed laboratories must successfully adapt to new disciplinary configurations, funding opportunities, and research priorities, or risk becoming mere architectural icons.


Why volunteers helped to promote a community breast self-exam program.
Involving volunteers in community health programs is common practice. However, there is little information about specific methods to motivate volunteers to become involved and stay involved. In a community breast self-exam (BSE) education project, volunteers played a major role in the recruitment of women for BSE training presentations given by nurse instructors. Working in a support group capacity, approximately 20 women volunteers in each of two communities completed recruitment tasks such as hosting presentations in their own homes, arranging for presentations for a club or organization, and endorsing the program in the media. At the end of a three-month period, the activities of these volunteers had increased participation of community women in presentations by 50% in one community and 115% in the second community, and the BSE education program had increased both the frequency and quality of BSE practice throughout both communities. Because of the success of the volunteer support group strategy, an interview was conducted with the eleven "super-star" volunteers to assess the motivational factors influencing their initial and continued involvement. Results include a description of common characteristics of these highly motivated volunteers and several recommendations for volunteer administrators or for anyone attempting to recruit and maintain motivated groups of volunteers.


Classification of Infectious and Noninfectious Diseases Using Artificial Neural Networks from 24-Hour Continuous Tympanic Temperature Data of Patients with Undifferentiated Fever.
Fever is one of the major clinical symptoms of undifferentiated fever cases. Early diagnosis of undifferentiated fever is a challenging task for the physician. The aim of this study was to classify infectious and noninfectious diseases from 24-hour continuous tympanic temperature recordings of patients with undifferentiated fever using a machine learning algorithm (artificial neural network). This was an observational study conducted in 103 patients who presented with undifferentiated fever. Twenty-four-hour continuous tympanic temperature was recorded from each patient. Features were extracted from temperature signals and classified into infectious and noninfectious diseases using an artificial neural network (ANN). The ANN classifier provided the highest accuracy at 91.3% for differentiating infectious and noninfectious diseases from undifferentiated fever cases. Significant kappa agreement (κ = 0.777) was found between the final diagnosis as determined by the physician and the classification obtained using an ANN classifier. Based on our results, we conclude that the continuous 24-hour temperature monitoring and application of an ANN classifier provides a simple noninvasive and inexpensive supplementary diagnostic method to differentiate infectious and noninfectious diseases.


Interpretation of bedside chest X-rays in the ICU: is the radiologist still needed?
To compare diagnostic accuracy of intensivists to radiologists in reading bedside chest X-rays. In a retrospective trial, 33 bedside chest X-rays were evaluated by five radiologists and five intensivists with different experience. Images were evaluated for devices and lung pathologies. Interobserver agreement and diagnostic accuracy were calculated. Computed tomography served as reference standard. Seniors had higher diagnostic accuracy than residents (mean-ExpB(Senior)=1.456; mean-ExpB(Resident)=1.635). Interobserver agreement for installations was more homogenously distributed between radiologists compared to intensivists (ExpB(Rad)=1.204-1.672; ExpB(Int)=1.005-2.368). Seniors had comparable diagnostic accuracy. No significant difference in diagnostic performance was seen between seniors of both disciplines, whereas the resident intensivists might still benefit from an interdisciplinary dialogue.


Core Outcome Set-STAndards for Reporting: The COS-STAR Statement.
Core outcome sets (COS) can enhance the relevance of research by ensuring that outcomes of importance to health service users and other people making choices about health care in a particular topic area are measured routinely. Over 200 COS to date have been developed, but the clarity of these reports is suboptimal. COS studies will not achieve their goal if reports of COS are not complete and transparent. In recognition of these issues, an international group that included experienced COS developers, methodologists, journal editors, potential users of COS (clinical trialists, systematic reviewers, and clinical guideline developers), and patient representatives developed the Core Outcome Set-STAndards for Reporting (COS-STAR) Statement as a reporting guideline for COS studies. The developmental process consisted of an initial reporting item generation stage and a two-round Delphi survey involving nearly 200 participants representing key stakeholder groups, followed by a consensus meeting. The COS-STAR Statement consists of a checklist of 18 items considered essential for transparent and complete reporting in all COS studies. The checklist items focus on the introduction, methods, results, and discussion section of a manuscript describing the development of a particular COS. A limitation of the COS-STAR Statement is that it was developed without representative views of low- and middle-income countries. COS have equal relevance to studies conducted in these areas, and, subsequently, this guideline may need to evolve over time to encompass any additional challenges from developing COS in these areas. With many ongoing COS studies underway, the COS-STAR Statement should be a helpful resource to improve the reporting of COS studies for the benefit of all COS users.


Effects of an intensive 12-wk training program by elite swimmers on neutrophil oxidative activity.
The effects of an intensive 12-wk training program by 12 national-level swimmers on neutrophil oxidative activity were studied. Eleven sedentary (untrained) subjects (6 males and 5 females) served as environmental controls. Blood samples (10 ml) were taken at rest from an antecubital vein and neutrophils isolated by standard separation techniques. The oxidative burst activity of isolated neutrophils was assessed with an in vitro flow cytometric assay that used the fluorescent probe dihydrorhodamine 123. Two-way ANOVA (repeated measures) showed that oxidative activity was lower (P < 0.05) in the elite swimmers compared with the sedentary control group across the 12-wk period. Analysis of cells from swimmers in training was made: repeated measures ANOVA provided evidence of a significant decline (P < 0.05) in the number of cells responding positively ito in vitro challenge. Despite this decline, there was no significant difference in self-reported upper respiratory tract infection rate between the swimmers and sedentary individuals. These data show that: (i) elite swimmers undertaking intensive training have a significantly lower neutrophil oxidative activity at rest than do age- and sex-matched sedentary individuals; (ii) aspects of oxidative activity in swimmers are further suppressed during periods of strenuous training, and (iii) the extent of the suppression does not appear to be of clinical significance.


The effects of maximal and submaximal arm crank ergometry and cycle ergometry on postural sway.
Abstract This study aimed to determine whether arm crank ergometry (ACE) disturbed postural sway to the same extent as cycle ergometry (CE). Nine healthy, none specifically trained adults undertook posturographic tests before and after five separate exercise trials consisting of: two incremental exercise tests to exhaustion for ACE and CE to examine postural sway responses to maximal exercise and to determine peak power output (W max); two subsequent tests of 30 min duration for ACE and CE at a relative workload corresponding to 50% of the ergometer-specific W max (ACErel; 53 ± 8 W and CErel; 109 ± 16 W). A final CE trial was performed at the same absolute power output (CEabs) as the submaximal ACE trial to match absolute exercise intensity (i.e., 53 ± 8 W). The centre of pressure (COP) displacement was recorded using a force platform before, immediately after exercise and during a 30-min recovery period. ACE had no effects on postural sway (P > 0.05). An increase in mediolateral COP displacement was observed following maximal CE only (P = 0.001), while anteroposterior COP displacement and COP path length increased following maximal and submaximal CE (P < 0.05). These differences in postural sway according to exercise mode likely stem from the activity of postural muscles when considering that CE recruits lower limb muscles involved in balance. This study provides evidence of an exercise mode which does not elicit post-exercise balance impairments, therefore possesses applications to those at an increased risk of falling.


Glutathione conjugate mediated toxicities.
Glutathione (gamma-glutamyl-L-cysteinylglycine: GSH) is present in high concentrations in most living cells and participates in a variety of vital cellular reactions. In particular, GSH protects cells from potentially toxic electrophiles formed via the metabolism of xenobiotics, and such reactions have long been associated with the process of detoxication (Baumann and Preusse, 1879; Jaffe, 1879). Compounds that form GSH conjugates are processed by gamma-glutamyl transpeptidase (gamma-GT) and dipeptidases to cysteine S-conjugates, which are usually excreted in urine as their corresponding mercapturic acids (S-substituted N-acetyl-L-cysteine conjugates). In addition, GSH peroxidase activity, whether catalyzed by the selenium-dependent GSH peroxidase or by the GSH S-transferases, serves to detoxify hydrogen peroxide and organic hydroperoxides. However, in recent years, evidence indicating that GSH conjugation plays an important role in the formation of toxic metabolites from a variety of chemicals has accumulated. Thus, several classes of compounds are converted, via conjugation with GSH, into either cytotoxic, genotoxic, or mutagenic metabolites. The purposes of the symposium on "Glutathione Conjugate Mediated Toxicities" presented at the 1990 Society of Toxicology Annual Meeting were to discuss recent findings in this rapidly moving field, to present ideas on the mechanisms and modulation of GSH conjugate-dependent toxicities, to present a consensus on the broader significance of this work, and to identify directions for future research. This paper summarizes these presentations. GSH conjugation reactions are involved in the bioactivation of several classes of xenobiotics, and four types of GSH-dependent bioactivation reactions can be identified: (1) directly toxic GSH conjugates may be formed from vicinal dihaloalkanes via formation of electrophilic sulfur mustards; (2) cysteine conjugate beta-lyase-dependent bioactivation is involved in the selective nephrotoxicity of haloalkenes; (3) GSH conjugates of hydroquinones and isothiocyanates may serve as transport and targeting metabolites; and (4) GSH-dependent reactions may be involved in the release of toxic agents from precursor organic thiocyanates and nitrosoguanidines (N-methyl-N'-nitro-N-nitroguanidine).


Regularized reconstruction of absorbing and phase objects from a single in-line hologram, application to fluid mechanics and micro-biology.
Reconstruction of phase objects is a central problem in digital holography, whose various applications include microscopy, biomedical imaging, and fluid mechanics. Starting from a single in-line hologram, there is no direct way to recover the phase of the diffracted wave in the hologram plane. The reconstruction of absorbing and phase objects therefore requires the inversion of the non-linear hologram formation model. We propose a regularized reconstruction method that includes several physically-grounded constraints such as bounds on transmittance values, maximum/minimum phase, spatial smoothness or the absence of any object in parts of the field of view. To solve the non-convex and non-smooth optimization problem induced by our modeling, a variable splitting strategy is applied and the closed-form solution of the sub-problem (the so-called proximal operator) is derived. The resulting algorithm is efficient and is shown to lead to quantitative phase estimation on reconstructions of accurate simulations of in-line holograms based on the Mie theory. As our approach is adaptable to several in-line digital holography configurations, we present and discuss the promising results of reconstructions from experimental in-line holograms obtained in two different applications: the tracking of an evaporating droplet (size ∼ 100μm) and the microscopic imaging of bacteria (size ∼ 1μm).


Amyloid-β induces synaptic dysfunction through G protein-gated inwardly rectifying potassium channels in the fimbria-CA3 hippocampal synapse.
Last evidences suggest that, in Alzheimer's disease (AD) early stage, Amyloid-β (Aβ) peptide induces an imbalance between excitatory and inhibitory neurotransmission systems resulting in the functional impairment of neural networks. Such alterations are particularly important in the septohippocampal system where learning and memory processes take place depending on accurate oscillatory activity tuned at fimbria-CA3 synapse. Here, the acute effects of Aβ on CA3 pyramidal neurons and their synaptic activation from septal part of the fimbria were studied in rats. A triphasic postsynaptic response defined by an excitatory potential (EPSP) followed by both early and late inhibitory potentials (IPSP) was evoked. The EPSP was glutamatergic acting on ionotropic receptors. The early IPSP was blocked by GABAA antagonists whereas the late IPSP was removed by GABAB antagonists. Aβ perfusion induced recorded cells to depolarize, increase their input resistance and decrease the late IPSP. Aβ action mechanism was localized at postsynaptic level and most likely linked to GABAB-related ion channels conductance decrease. In addition, it was found that the specific pharmacological modulation of the GABAB receptor effector, G-protein-coupled inward rectifier potassium (GirK) channels, mimicked all Aβ effects previously described. Thus, our findings suggest that Aβ altering GirK channels conductance in CA3 pyramidal neurons might have a key role in the septohippocampal activity dysfunction observed in AD.


Differential regulation of gene expression in mouse spermatogonial cells after blocking c-kit-SCF interaction with RNAi.
c-Kit, the gene product of the W locus is a receptor tyrosine kinase that regulates the survival, growth and differentiation of spermatogonial cells (SGCs). Stem cell factor (SCF), the gene product of the steel (Sl) locus is the ligand for c-kit. Normal function of SGCs requires cross-talk between c-kit and SCF through which the receptor-ligand pair regulates the functions of SGCs. The implications of cross-talk between c-kit and SCF in regulating SGC function remains unclear due to the molecular complexity of this interaction. In the present study, we analyzed the interactions between c-kit and SCF in mouse primary SGCs after blocking the c-kit expression by c-kit siRNA and its effect on cell fate were determined using cDNA Expression Array and Real-time PCR. Immunofluorescence (IF) and western blot studies revealed that c-kit protein was detected in SGCs and knocked down to undetectable levels at 24 hr post transfection with 10 nM concentration of c-kit siRNA. We further demonstrated that expression of various genes involved in cell signaling, cell differentiation, apoptosis and cell cycle pathways was altered. SGC functions are affected by SCF signaling through c-kit receptor and this signaling appears to be important to maintain balance between cell proliferation and apoptosis along with the modulation of inflammatory responses of SGCs. To the best of our knowledge, this is the first report that identifies the putative molecular pathways in murine SGCs in response to specific blocking of c-kit-SCF interactions by siRNA. In conclusion, the present study may provide useful insights into siRNA function and hopefully aid in understanding the involvement of c-kit in the early events of SGC activities and spermatogenesis in mice.


Prevalence of mental disorders, suicidal ideation and suicides in the general population before and during the COVID-19 pandemic in Norway: A population-based repeated cross-sectional analysis.
Self-report data on mental distress indicate a deterioration of population mental health in many countries during the COVID-19 pandemic. A Norwegian epidemiological diagnostic psychiatric interview survey was conducted from January to September 2020, allowing for comparison of mental disorder and suicidal ideation prevalence from before through different pandemic periods. Prevalence of suicide deaths were compared between 2020 and 2014-2018. Participants from the Trøndelag Health Study (HUNT) in Trondheim were recruited through repeated probability sampling. Using the Composite International Diagnostic Interview (CIDI 5.0) (n = 2154), current prevalence of mental disorders and suicidal ideation was examined in repeated cross-sectional analyzes. Data on suicide deaths was retrieved from the Norwegian Cause of Death Registry and compared for the months March to May in 2014-2018 and 2020. Prevalence of current mental disorders decreased significantly from the pre-pandemic period (January 28th to March 11th 2020; 15•3% (95% CI 12•4-18•8)) to the first pandemic period (March 12th - May 31st; 8•7% (6•8-11•0)). Prevalences were similar between the pre-pandemic period and the interim (June 1st July 31st; 14•2% (11•4-17•5)) and second periods (August 1st-September 18th; 11•9% (9•0-15•6)). No significant differences were observed in suicidal ideation or in suicide deaths. Except for a decrease in mental disorders in the first pandemic period, the findings suggest stable levels of mental disorders, suicidal ideation and suicide deaths during the first six months of the COVID-19 pandemic compared to pre-pandemic levels. Potential methodological and contextual explanations of these findings compared with findings from other studies are discussed. None.


Mixing and matching siderophore clusters: structure and biosynthesis of serratiochelins from Serratia sp. V4.
Interrogation of the evolutionary history underlying the remarkable structures and biological activities of natural products has been complicated by not knowing the functions they have evolved to fulfill. Siderophores-soluble, low molecular weight compounds-have an easily understood and measured function: acquiring iron from the environment. Bacteria engage in a fierce competition to acquire iron, which rewards the production of siderophores that bind iron tightly and cannot be used or pirated by competitors. The structures and biosyntheses of "odd" siderophores can reveal the evolutionary strategy that led to their creation. We report a new Serratia strain that produces serratiochelin and an analog of serratiochelin. A genetic approach located the serratiochelin gene cluster, and targeted mutations in several genes implicated in serratiochelin biosynthesis were generated. Bioinformatic analyses and mutagenesis results demonstrate that genes from two well-known siderophore clusters, the Escherichia coli enterobactin cluster and the Vibrio cholera vibriobactin cluster, were shuffled to produce a new siderophore biosynthetic pathway. These results highlight how modular siderophore gene clusters can be mixed and matched during evolution to generate structural diversity in siderophores.


Construction and properties of retrovirus packaging cells based on gibbon ape leukemia virus.
We have constructed hybrid retrovirus packaging cell lines that express the gibbon ape leukemia virus env and the Moloney murine leukemia virus gag-pol proteins. These cells were used to produce a retrovirus vector at over 10(6) CFU/ml, with a host range that included rat, hamster, bovine, cat, dog, monkey, and human cells. The gag-pol and env expression plasmids were separately transfected to reduce the potential for helper virus production, which was not observed. The NIH 3T3 mouse cells from which the packaging lines were made are not infectable by gibbon ape leukemia virus; thus, the generation and spread of possible recombinant viruses in the packaging cells is greatly reduced. These simian virus-based packaging cells extend the host range of currently available murine and avian packaging cells and should be useful for efficient gene transfer into higher mammals.


Interaction Support for Visual Comparison Inspired by Natural Behavior.
Visual comparison is an intrinsic part of interactive data exploration and analysis. The literature provides a large body of existing solutions that help users accomplish comparison tasks. These solutions are mostly of visual nature and custom-made for specific data. We ask the question if a more general support is possible by focusing on the interaction aspect of comparison tasks. As an answer to this question, we propose a novel interaction concept that is inspired by real-world behavior of people comparing information printed on paper. In line with real-world interaction, our approach supports users (1) in interactively specifying pieces of graphical information to be compared, (2) in flexibly arranging these pieces on the screen, and (3) in performing the actual comparison of side-by-side and overlapping arrangements of the graphical information. Complementary visual cues and add-ons further assist users in carrying out comparison tasks. Our concept and the integrated interaction techniques are generally applicable and can be coupled with different visualization techniques. We implemented an interactive prototype and conducted a qualitative user study to assess the concept's usefulness in the context of three different visualization techniques. The obtained feedback indicates that our interaction techniques mimic the natural behavior quite well, can be learned quickly, and are easy to apply to visual comparison tasks.


Regional distribution of neurotrophin receptors in the developing auditory brainstem.
Neuron survival and axonal regeneration become severely limited during early postnatal development. In conjunction with our recent organotypic analysis of regeneration in the auditory midbrain, we wished to determine whether neurotrophins could serve as a trophic substance during the postnatal period. Therefore, the current study examines the development of three neurotrophin receptor tyrosine kinases (TrkA, TrkB, and TrkC) in the gerbil auditory brainstem. Immunoreactivity to TrkA, the nerve growth-factor receptor, was observed in nonneuronal cells during the first two postnatal weeks. In the cochlear nucleus of mature animals, however, there was a TrkA-positive neuronal subpopulation. In contrast, immunoreactivity to TrkB and TrkC (the receptors for brain-derived neurotrophic factor and neurotrophin-3, respectively) displayed a widespread distribution in the auditory brainstem. At postnatal day 0, TrkB and TrkC staining was virtually absent from auditory nuclei, although immunopositive neurons were present in the mesencephalic trigeminal nucleus. By postnatal day 7, TrkB- and TrkC-positive neurons were present in most brainstem auditory nuclei. At postnatal day 15, TrkB immunoreactivity was observed throughout the inferior colliculus (IC), the cochlear nucleus, the medial and lateral nuclei of the trapezoid body, and the lateral superior olive, whereas TrkC labeled only a subpopulation of neurons within the central nucleus of the IC. The TrkB immunoreactivity was present on both neuronal somata and dendrites, whereas TrkC was generally restricted to cell bodies. At postnatal day 30, TrkB immunostaining was observed on most neurons of the IC. The medial and lateral nuclei of the trapezoid body displayed extremely strong TrkB staining, followed by the cochlear nucleus. In contrast, the TrkC immunostaining was decreased dramatically by postnatal day 21. Observations at the ultrastructural level confirmed a neuronal localization of TrkB and TrkC. Immunostaining for both receptors was restricted largely to the postsynaptic density of synaptic profiles in both dendrites and somata. In summary, this study illustrates a differential pattern of immunoreactivity between three neurotrophin receptors during development. The general increase of TrkB expression is well correlated with the onset of sound-evoked activity in this system, and its synaptic localization suggests that it may be involved in the modulation or maintenance of postsynaptic physiology.


Oxfendazole: a promising agent for the treatment and control of helminth infections in humans.
Oxfendazole (methyl [5-(phenylsulphinyl)-1H benzimidazole-2-yl] carbamate) has a particularly long metabolic half-life in ruminants, and its metabolite fenbendazole also has anthelminthic action. A very limited number of drugs are available for the treatment of some zoonotic helminth infections, such as neurocysticercosis and echinococcosis. More recent work has expanded oxfendazole's nonclinical safety profile and demonstrated its safety and bioavailability in healthy human volunteers, thus advancing the possibility of a new and greatly needed option for antiparasitic treatment of geohelminths and tissue parasites. Areas covered: The present article reviews evidence supporting the safety and efficacy of oxfendazole against both gut and tissue dwelling helminths in animals, as well as more recent safety and pharmacokinetic data supporting its potential for use in human parasitoses. Expert commentary: The pharmacokinetics, safety, and wide spectrum of efficacy of oxfendazole are consistently demonstrated in intestinal helminth infections of animals as well as in tissue dwelling larval cestode and trematode infections in diverse animal species. Now supported by first-in-human safety and pharmacokinetic data, oxfendazole becomes a promising alternative to the limited portfolio of antiparasitic drugs available to treat helminthic diseases of humans.


A methodology for centrifuge selection for the separation of high solids density cell broths by visualisation of performance using windows of operation.
Expression systems capable of growing to high cell densities are now readily available and are popular due to the benefits of increased product concentration. However, such high solids density cultures pose a major challenge for bioprocess engineers as choosing the right separation equipment and operating it at optimal conditions is crucial for efficient recovery. This study proposes a methodology for the rapid determination of suitable operating conditions for the centrifugal recovery of high cell density fermentation broths. An ultra scale-down (USD) approach for the prediction of clarification and dewatering levels achieved in a range of typical high-speed centrifuges is presented. Together with a visualisation tool, a Window of Operation, this provides for the rapid analysis of separation performance and evaluation of the available operating conditions, as an aid in the selection of the centrifuge equipment most appropriate for a given process duty. A case study examining centrifuge selection for the processing of a high cell density Pichia pastoris culture demonstrates the method. The study examines semi-continuous disc-stack centrifuges and batch-operated machines such as multi-chamber bowls and Carr Powerfuges. Performance is assessed based on the variables of clarification, dewatering and product yield. Inclusion of limits imposed by the centrifuge type and design, and operation itself, serve to constrain the process and to define the Windows of Operation. The insight gained from the case study provides a useful indication of the utility of the methodology presented and illustrates the challenges of centrifuge selection for the demanding case of high solids concentration feed streams.


Testing predictive models of positive and negative affect with psychosocial, acculturation, and coping variables in a multiethnic undergraduate sample.
Despite the prevalence and popularity of research on positive and negative affect within the field of psychology, there is currently little research on affect involving the examination of cultural variables and with participants of diverse cultural and ethnic backgrounds. To the authors' knowledge, currently no empirical studies have comprehensively examined predictive models of positive and negative affect based specifically on multiple psychosocial, acculturation, and coping variables as predictors with any sample populations. Therefore, the purpose of the present study was to test the predictive power of perceived stress, social support, bidirectional acculturation (i.e., Canadian acculturation and heritage acculturation), religious coping and cultural coping (i.e., collective, avoidance, and engagement coping) in explaining positive and negative affect in a multiethnic sample of 301 undergraduate students in Canada. Two hierarchal multiple regressions were conducted, one for each affect as the dependent variable, with the above described predictors. The results supported the hypotheses and showed the two overall models to be significant in predicting affect of both kinds. Specifically, a higher level of positive affect was predicted by a lower level of perceived stress, less use of religious coping, and more use of engagement coping in dealing with stress by the participants. Higher level of negative affect, however, was predicted by a higher level of perceived stress and more use of avoidance coping in responding to stress. The current findings highlight the value and relevance of empirically examining the stress-coping-adaptation experiences of diverse populations from an affective conceptual framework, particularly with the inclusion of positive affect. Implications and recommendations for advancing future research and theoretical works in this area are considered and presented.


Multiple functions of the EGF receptor in Drosophila eye development.
During animal development, cells need to make spatially and temporally regulated fate decisions. These decisions are largely controlled by intercellular signalling, often through receptor tyrosine kinases. One of these, the epidermal growth factor receptor (EGFR), regulates multiple cell fate decisions. Its importance in the recruitment of photoreceptors in the developing fly eye, a useful model for neural development, has already been reported. Other EGFR functions in the eye have not been characterised. We have examined the consequences of removing or activating the EGFR at different stages of eye development. The earliest stages of assembly occurred normally within EGFR- clones--the morphogenetic furrow was unimpeded and the R8 photoreceptor was specified. All subsequent photoreceptor recruitment was blocked. EGFR- clones had a characteristic shape indicating that they had undergone substantial cell death posterior to the furrow, where the differentiation program is normally activated; consistent with this, excess apoptosis was detected. We found that the receptor also regulates cell proliferation in the disc, has an early function at the disc margin (where the morphogenetic furrow initiates) and contributes to the regulation of spacing of the R8 precursors. Finally, we found that activation of the receptor is sufficient to trigger non-R8 photoreceptor development, even in cells in front of the furrow or in the absence of the proneural gene atonal. At least five distinct functions of EGFR signalling need to be integrated during fly eye development. These include roles in cell proliferation, survival and differentiation.


Improvement in posttraumatic stress disorder in postconflict Rwandan women.
Depression and posttraumatic stress disorder (PTSD) are common in developing and postconflict countries. The purpose of this study is to examine longitudinal changes in PTSD in HIV-infected and uninfected Rwandan women who experienced the 1994 genocide. Five hundred thirty-five HIV-positive and 163 HIV-negative Rwandan women in an observational cohort study were followed for 18 months. Data on PTSD symptoms were collected longitudinally by the Harvard Trauma Questionnaire (HTQ) and analyzed in relationship to demographics, HIV status, antiretroviral treatment (ART), and depression. PTSD was defined as a score on the HTQ of ≥2. There was a continuing reduction in HTQ scores at each follow-up visit. The prevalence of PTSD symptoms changed significantly, with 61% of the cohort having PTSD at baseline vs. 24% after 18 months. Women with higher HTQ score were most likely to have improvement in PTSD symptoms (p<0.0001). Higher rate of baseline depressive symptoms (p<0.0001) was associated with less improvement in PTSD symptoms. HIV infection and ART were not found to be consistently related to PTSD improvement. HIV care settings can become an important venue for the identification and treatment of psychiatric problems affecting women with HIV in postconflict and developing countries. Providing opportunities for women with PTSD symptoms to share their history of trauma to trained counselors and addressing depression, poverty, and ongoing violence may contribute to reducing symptoms.


Psychosocial Work Conditions and Mental Health: Examining Differences Across Mental Illness and Well-Being Outcomes.
Psychosocial work conditions are determinants of mental illness among worker populations. However, while the focus on negative aspects of mental health has generated important contributions to the development of workplace interventions, there is less evidence on the factors that support the positive aspects of mental well-being. This study aimed to examine the association between psychosocial work conditions and mental health outcomes among a representative sample of Canadian workers; and to assess whether the relationships are consistent across measures of mental illness versus mental well-being. Population-based data were obtained from the cross-sectional 2012 Canadian Community Health Survey. Psychosocial work conditions were measured using an abbreviated version of the Job Content Questionnaire. For mental illness, we focused on major depressive episodes, generalized anxiety disorders, and bipolar disorders in the past 12 months, as measured using Composite International Diagnostic Interview criteria. Mental well-being was defined as having flourishing mental health, based on items from the Mental Health Continuum-Short Form. Regression models provided odds ratios (ORs) and fitted probabilities for the relationship between work conditions and mental health, adjusting for covariates. Higher levels of job control, social support, and job security were associated with being free of disorders (ORs ranging from 1.08 to 1.15) as well as having flourishing mental health (ORs ranging from 1.10 to 1.14). Lower physical effort was associated with decreased odds of having flourishing mental health (OR 0.89). Psychological demands were not associated with any of the mental health outcomes in the fully-adjusted models. The overall pattern of these relationships was consistent across the two outcome models, although there was evidence of heterogeneity on the absolute probability scale. Specifically, there was a relatively stronger relationship between job control/social support/physical demands and well-being outcomes, compared with disorder outcomes. Psychosocial work conditions were associated with both negative and positive measures of mental health. However, mental illness and mental well-being may represent complementary, yet distinct, aspects in relation to psychosocial work conditions. Interventions targeting the psychosocial work environment may serve to improve both of these dimensions, although the measurement and examination of specific dimensions may be required to obtain an integrated and comprehensive understanding of mental health in the workplace.


Oseltamivir and influenza-related complications in children: a retrospective cohort in primary care.
Influenza and influenza-like illness (ILI) place considerable burden on healthcare systems, especially during influenza epidemics and pandemics. During the 2009/10 H1N1 influenza pandemic, UK national guidelines recommended antiviral medications for patients presenting within 72 h of ILI onset. However, it is not clear whether antiviral treatment was associated with reductions in influenza-related complications. Our study population consisted of a retrospective cohort of children aged ≤17 years who presented with influenza/ILI at UK primary care practices contributing to the Clinical Practice Research Datalink during the 2009/10 pandemic. We used doubly robust inverse-probability weighted propensity scores and physician prior prescribing instrumental variable methods to estimate the causal effect of oseltamivir prescribing on influenza-related complications. Secondary outcomes were complications requiring intervention, pneumonia, pneumonia or hospitalisation, influenza-related hospitalisation and all-cause hospitalisation. We included 16 162 children, of whom 4028 (24.9%) were prescribed oseltamivir, and 753 (4.7%) had recorded complications. Under propensity score analyses oseltamivir prescriptions were associated with reduced influenza-related complications (risk difference (RD) -0.015, 95% CI -0.022--0.008), complications requiring further intervention, pneumonia, pneumonia or hospitalisation and influenza-related hospitalisation, but not all-cause hospitalisation. Adjusted instrumental variable analyses estimated reduced influenza-related complications (RD -0.032, 95% CI -0.051--0.013), pneumonia or hospitalisation, all-cause and influenza-related hospitalisations. Based on causal inference analyses of observational data, oseltamivir treatment in children with influenza/ILI was associated with a small but statistically significant reduction in influenza-related complications during an influenza pandemic.


Noncompliance with Public Health Service (PHS) policy on humane care and use of laboratory animals: an exploratory analysis.
The National Institutes of Health (NIH) is a major biomedical research-funding body in the United States. Approximately 40% of NIH-funded research involves experimentation on nonhuman animals (Monastersky, 2008). Institutions that conduct animal research with NIH funds must adhere to the Public Health Service (PHS) care and use standards of the Office of Laboratory Animal Welfare (OLAW, 2002a). Institutions deviating significantly from the PHS's animal care and use standards must report these incidents to the NIH's OLAW. This study is an exploratory analysis of all the significant deviations reported by animal-research facilities to OLAW during a 3-month period. The study identifies the most common issues reported and species involved. The study found that the majority of the incidents resulted in animal pain and distress and that 75% ended in animal death. This study offers preliminary recommendations to address the most common problems identified in this analysis. This study urges OLAW and other stakeholders to analyze larger, more recent samples of reported deviations to compare with these results and ultimately improve adherence to animal welfare standards.


A multidisciplinary primary care team consultation in a socio-economically deprived community: an exploratory randomised controlled trial.
Psychosocial problems in socioeconomically deprived communities are not always amenable to traditional medical approaches. Mothers living in these areas are a particularly vulnerable group. The objective of this study was to evaluate the effectiveness of a lengthened multi-disciplinary team consultation in primary care in reducing anxiety and depression in mothers. This was a prospective randomised controlled trial of a multidisciplinary team consultation against normal care. 94 mothers were recruited from three general practices from an area of extreme socio-economic deprivation. Mothers randomised into the intervention group attended a multidisciplinary consultation with up to four case-specific health care professionals. Consultations addressed medical, psychological and social problems and lasted up to one hour. Conventional primary care continued to be available to the intervention families. Control group families received normal primary care services. The outcomes measured were anxiety and depression as using the Hospital Anxiety and Depression Scale (HADS), health status using SF36v2, and quality of life using the abbreviated Schedule for the Evaluation of Individual Quality of Life (SEIQoL-DW) at baseline, 6 months and 12 months. Ordered logistic regression was used to analyse the data. There was no significant difference found between intervention and control groups after 6 months and 12 months in all of the measured outcomes. The new lengthened multi-disciplinary team consultation did not have any impact on the mental health, general health, and quality of life of mothers after 6 and 12 months. Other methods of primary health care delivery in socio-economically deprived communities need to be evaluated.


Characteristics of arterial myosin in experimental renal hypertension in the dog.
We compared myosin samples isolated from iliac-femoral arteries of control and renal (stenosis) hypertensive dogs to determine the effects of increased blood pressure on the characteristics of the myosin. The ratio of 204-kd (SM-1) to 200-kd (SM-2) myosin heavy chains was approximately 1:0.75 for myosin from the iliac-femoral artery of normotensive dogs. This was not altered significantly in response to hypertension. Both SM-1 and SM-2 myosin heavy chains cross-reacted with antibody against smooth muscle myosin on Western blot analysis. In addition to these heavy chains, purified myosin from both groups showed a very faint protein band slightly below the 200-kd myosin heavy chain on electrophoresis on a highly porous sodium dodecyl sulfate-polyacrylamide gel. This protein band cross-reacted with antibody against nonmuscle myosin but not with smooth muscle myosin antibody. The 20- and 17-kd light chains of myosin isolated from normotensive and hypertensive dogs gave similar results on isoelectric focusing. Peptide maps of tryptic digests of heavy chains revealed both quantitative and qualitative differences. The Ca(2+)-activated myosin ATPase activity measured in high salt (0.5 mol/L KCl) was similar for myosin from both groups, whereas the potassium (ethylenedinitrilo)tetraacetic acid-stimulated ATPase of myosin from hypertensive animals was higher than that from normotensive animals.(ABSTRACT TRUNCATED AT 250 WORDS)


Long term outcomes from the IMPACT randomised trial for depressed elderly patients in primary care.
To determine the long term effectiveness of collaborative care management for depression in late life. Two arm, randomised, clinical trial; intervention one year and follow-up two years. 18 primary care clinics in eight US healthcare organisations. Patients 1801 primary care patients aged 60 and older with major depression, dysthymia, or both. Patients were randomly assigned to a 12 month collaborative care intervention (IMPACT) or usual care for depression. Teams including a depression care manager, primary care doctor, and psychiatrist offered education, behavioural activation, antidepressants, a brief, behaviour based psychotherapy (problem solving treatment), and relapse prevention geared to each patient's needs and preferences. Interviewers, blinded to treatment assignment, conducted interviews in person at baseline and by telephone at each subsequent follow up. They measured depression (SCL-20), overall functional impairment and quality of life (SF-12), physical functioning (PCS-12), depression treatment, and satisfaction with care. IMPACT patients fared significantly (P < 0.05) better than controls regarding continuation of antidepressant treatment, depressive symptoms, remission of depression, physical functioning, quality of life, self efficacy, and satisfaction with care at 18 and 24 months. One year after IMPACT resources were withdrawn, a significant difference in SCL-20 scores (0.23, P < 0.0001) favouring IMPACT patients remained. Tailored collaborative care actively engages older adults in treatment for depression and delivers substantial and persistent long term benefits. Benefits include less depression, better physical functioning, and an enhanced quality of life. The IMPACT model may show the way to less depression and healthier lives for older adults.


Robust subspace discovery via relaxed rank minimization.
This letter examines the problem of robust subspace discovery from input data samples (instances) in the presence of overwhelming outliers and corruptions. A typical example is the case where we are given a set of images; each image contains, for example, a face at an unknown location of an unknown size; our goal is to identify or detect the face in the image and simultaneously learn its model. We employ a simple generative subspace model and propose a new formulation to simultaneously infer the label information and learn the model using low-rank optimization. Solving this problem enables us to simultaneously identify the ownership of instances to the subspace and learn the corresponding subspace model. We give an efficient and effective algorithm based on the alternating direction method of multipliers and provide extensive simulations and experiments to verify the effectiveness of our method. The proposed scheme can also be used to tackle many related high-dimensional combinatorial selection problems.


The cost-effectiveness of hypertonic saline inhalations for infant bronchiolitis.
Pharmacological treatment for bronchiolitis is primarily supportive because bronchodilators, steroids, and antibiotics, show little benefit. Clinical studies have suggested that nebulized 3% hypertonic solution is useful for infants with bronchiolitis. This study aims to evaluate the cost-effectiveness of the HS inhalations in infant bronchiolitis in a tropical country. Decision tree analysis was used to calculate the expected costs and QALYs. All cost and use of resources were collected directly from medical invoices of 193 patient hospitalized with diagnosis of bronchiolitis in tertiary centers, of Rionegro, Colombia. The utility values applied to QALYs calculations were collected from the literature. The economic analysis was carried out from a societal perspective. The model showed that nebulized 3% hypertonic solution, was associated with lower total cost than controls (US $200vs US $240 average cost per patient), and higher QALYs (0.92 vs 0.91 average per patient); showing dominance. A position of dominance negates the need to calculate an incremental cost-effectiveness ratio. The nebulized 3% hypertonic solution was cost-effective in the inpatient treatment of infant bronchiolitis. Our study provides evidence that should be used by decision-makers to improve clinical practice guidelines and should be replicated to validate their results in other tropical countries.


Capturing the Fantastic Voyage of Monocytes Through Time and Space.
Monocytes are a subset of cells that are categorized together with dendritic cells (DCs) and macrophages in the mononuclear phagocyte system (MPS). Despite sharing several phenotypic and functional characteristics with MPS cells, monocytes are unique cells with the ability to function as both precursor and effector cells in their own right. Before the development of hematopoietic stem cells (HSCs) in utero, monocytes are derived from erythro-myeloid precursors (EMPs) in the fetal liver that are important for populating the majority of tissue resident macrophages. After birth, monocytes arise from bone marrow (BM)-derived HSCs and are released into the circulation upon their maturation, where they survey peripheral tissues and maintain endothelial integrity. Upon sensing of microbial breaches or inflammatory stimuli, monocytes migrate into tissues where their plasticity allows them to differentiate into cells that resemble macrophages or DCs according to the environmental niche. Alternatively, they may also migrate into tissues in the absence of inflammation and remain in an undifferentiated state where they perform homeostatic roles. As monocytes are typically on the move, the availability of intravital imaging approaches has provided further insights into their trafficking patterns in distinct tissue compartments. In this review, we outline the importance of understanding their functional behavior in the context of tissue compartments, and how these studies may contribute towards improved vaccine and future therapeutic strategies.


Nutrient supply and intervertebral disc metabolism.
The metabolic environment of disc cells is governed by the avascular nature of the tissue. Because cellular energy metabolism occurs mainly through glycolysis, the disc cells require glucose for survival and produce lactic acid at high rates. Oxygen is also necessary for cellular activity, although not for survival; its pathway of utilization is unclear. Because the tissues are avascular, disc cells depend on the blood supply at the margins of the discs for their nutrients. The nucleus and inner anulus of the disc are supplied by capillaries that arise in the vertebral bodies, penetrate the subchondral bone, and terminate at the bone-disc junction. Small molecules such as glucose and oxygen then reach the cells by diffusion under gradients established by the balance between the rate of transport through the tissue to the cells and the rate of cellular demand. Metabolites such as lactic acid are removed by the reverse pathway. The concentrations of nutrients farthest from the source of supply can thus be low; oxygen concentrations as low as 1% have been measured in the discs of healthy animals. Although gradients cannot be measured easily in humans, they can be calculated. Measured concentrations in surgical patients are in agreement with calculated values.


Economic evaluations of onchocerciasis interventions: a systematic review and research needs.
To provide a systematic review of economic evaluations that has been conducted for onchocerciasis interventions, to summarise current key knowledge and to identify research gaps. A systematic review of the literature was conducted on the 8th of August 2018 using the PubMed (MEDLINE) and ISI Web of Science electronic databases. No date or language stipulations were applied to the searches. We identified 14 primary studies reporting the results of economic evaluations of onchocerciasis interventions, seven of which were cost-effectiveness analyses. The studies identified used a variety of different approaches to estimate the costs of the investigated interventions/programmes. Originally, the studies only quantified the benefits associated with preventing blindness. Gradually, methods improved and also captured onchocerciasis-associated skin disease. Studies found that eliminating onchocerciasis would generate billions in economic benefits. The majority of the cost-effectiveness analyses evaluated annual mass drug administration (MDA). The estimated cost per disability-adjusted life year (DALY) averted of annual MDA varies between US$3 and US$30 (cost year variable). The cost benefit and cost effectiveness of onchocerciasis interventions have consistently been found to be very favourable. This finding provides strong evidential support for the ongoing efforts to eliminate onchocerciasis from endemic areas. Although these results are very promising, there are several important research gaps that need to be addressed as we move towards the 2020 milestones and beyond.


Progesterone metabolism in hepatic microsomes. Effect of the cytochrome P-450 inhibitor, ketoconazole, and the NADPH 5 alpha-reductase inhibitor, 4-MA, upon the metabolic profile in human, monkey, dog, and rat.
Progesterone was incubated in the presence of NADPH with hepatic microsomes isolated from male and female human, monkey, dog, and rat and the effect of 17 beta-NN-diethylcarbamoyl-4-methyl-4-aza-5 alpha- androstan-3-one (4-MA), an NADPH 5 alpha-reductase inhibitor, and ketoconazole, a cytochrome P-450 inhibitor, upon oxidative metabolism was evaluated. 4-MA caused an increase in detectable oxidative products only with microsomes isolated from rat. An increase in 2 alpha- and 16 alpha-hydroxylation was observed in male rat, and an increase in the formation rate of nine products was observed in female rat. delta 6-Progesterone, 6 beta-, 15 alpha-, 16 alpha-, and 21-hydroxyprogesterone (6 beta-, 15 alpha-, 16 alpha-, and 21-OHP) were common products in both sexes of all species studied. Differences were observed in the formation rate of 2 alpha-, 2 beta-, 6 alpha-, 7 alpha-, and 17 alpha-OHPs. At the 2-carbon, microsomes isolated from both sexes of primates hydroxylated progesterone exclusively at the 2 beta-position. Microsomes from both dog sexes and female rat formed 2 alpha- and 2 beta-OHP, while microsomes isolated from male rat formed exclusively 2 alpha-OHP. 7 alpha-Hydroxylation was detected exclusively in rat, and 6 alpha-hydroxylation was detected in both dog and rat. 17 alpha-Hydroxylase activity in primates was detected only in microsomes from male human. IC50 values associated with ketoconazole inhibition of progesterone metabolism differed among species.(ABSTRACT TRUNCATED AT 250 WORDS)


Heterozygous neuregulin 1 mice are more sensitive to the behavioural effects of Delta9-tetrahydrocannabinol.
Cannabis use may precipitate schizophrenia especially if the individual has a genetic vulnerability to this mental disorder. Human and animal research indicates that neuregulin 1 (Nrg1) is a susceptibility gene for schizophrenia. The aim of this study was to investigate whether dysfunction in the Nrg1 gene modulates the behavioural effects of Delta(9)-tetrahydrocannabinol (THC), the major psychotropic component of cannabis. Heterozygous Nrg1 transmembrane-domain knockout mice (Nrg1 HET) were treated with acute THC (0, 5 or 10 mg/kg i.p.) 30 min before being tested using open field (OF), hole board (HB), light-dark (LD), elevated plus maze (EPM), social interaction (SI) and prepulse inhibition (PPI) tests. Nrg1 HET mice showed differences in baseline behaviour with regard to locomotor activity, exploration and anxiety. More importantly, they were more sensitive to the locomotor suppressant actions of THC compared to wild type-like (WT) mice. In addition, Nrg1 HET mice expressed a greater THC-induced enhancement in % PPI than WT mice. The effects of THC on anxiety-related behaviour were task-dependent, with Nrg1 HET mice being more susceptible than WT mice to the anxiogenic effects of THC in LD, but not in the EPM, SI and OF tests. Nrg1 HET mice were more sensitive to the acute effects of THC in an array of different behaviours including those that model symptoms of schizophrenia. It appears that variation in the schizophrenia-related neuregulin 1 gene alters the sensitivity to the behavioural effects of cannabinoids.


The effect of music amplitude on the reaction to unexpected visual events.
The effects of music amplitude on participants' response time to randomly presented, unexpected, visual events were investigated. Ninety participants completed a motor-reaction task without music and with music played at 60, 70, or 80 dBA. Males preferred more intense music than females did, with males selecting a comfort level of 72 dBA and females, 66 dBA. However, participants' reaction time and the total time to respond to a randomly activated red light were independent of gender. All participants responded more quickly when the music was played at 70 dBA (close to their comfort level) than when it played at lower (60 dBA) or higher (80 dBA) amplitudes. It is proposed that people may react more quickly to visual events (e.g., the sudden appearance of a plane on the screen of an air traffic controller, or the unpredictable activation of a car's rear brake lights when driving) with music playing at a volume preset to maintain individual comfort levels against other situational background noise.


Cloning, characterization, and functional expression in Escherichia coli of chaperonin (groESL) genes from the phototrophic sulfur bacterium Chromatium vinosum.
A recombinant lambda phage which was able to propagate in groE mutants of Escherichia coli was isolated from a Chromatium vinosum genomic DNA library. A 4-kbp SalI DNA fragment, isolated from this phage and subcloned in plasmid vectors, carried the C. vinosum genes that allowed lambda growth in these mutants. Sequencing of this fragment indicated the presence of two open reading frames encoding polypeptides of 97 and 544 amino acids, respectively, which showed high similarity to the molecular chaperones GroES and GroEL, respectively, from several eubacteria and eukaryotic organelles. Expression of the cloned C. vinosum groESL genes in E. coli was greatly enhanced when the cells were transferred to growth temperatures that induce the heat shock response in this host. Coexpression in E. coli of C. vinosum groESL genes and the cloned ribulose bisphosphate carboxylase/oxygenase genes from different phototrophic bacteria resulted in an enhanced assembly of the latter enzymes. These results indicate that the cloned DNA fragment encodes C. vinosum chaperonins, which serve in the assembly process of oligomeric proteins. Phylogenic analysis indicates a close relationship between C. vinosum chaperonins and their homologs present in pathogenic species of the gamma subdivision of the eubacterial division Proteobacteria.


Curcumin enhances the effect of cisplatin in suppression of head and neck squamous cell carcinoma via inhibition of IKKβ protein of the NFκB pathway.
Previous experiments have shown that curcumin or cisplatin treatment suppresses growth of head and neck squamous cell carcinoma (HNSCC). To study the potential cooperative effect of both agents, two HNSCC cell lines were treated with curcumin or cisplatin alone or in combination. In vivo studies consisted of intravenous tail vein injection of liposomal curcumin, with intraperitoneal cisplatin, into nude mice growing xenograft HNSCC tumors. Introduction of curcumin and suboptimal concentrations of cisplatin showed a significant suppressive effect compared with treatment with either agent alone. Reduced expression of cyclin D1, IκBα, phospho-IκBα, and IKKβ occurred in cisplatin- and curcumin-treated cell lines. Confocal microscopy showed expression of IKKβ in the nucleus of the cell lines. Chromatin immunoprecipitation assay on DNA isolated from IKKβ immunoprecipitated samples showed PCR amplification of interleukin-8 promoter sequences, a binding site of NFκB, indicating an interaction between IKKβ and NFκB. Curcumin inhibited IKKβ in the cytoplasm and nucleus, leading to reduced NFκB activity, with no effect on phospho-AKT. In vivo studies showed significant growth inhibition of xenograft tumors treated with a combination of liposomal curcumin and cisplatin. The suppressive effect of curcumin was mediated through inhibition of cytoplasmic and nuclear IKKβ, resulting in inhibition of NFκB activity. Cisplatin treatment led to cellular senescence, indicating an effect mediated by p53 activation. The mechanisms of the two agents through different growth signaling pathways suggest potential for the clinical use of subtherapeutic doses of cisplatin in combination with curcumin, which will allow effective suppression of tumor growth while minimizing the toxic side effects of cisplatin.


High incidence of profound biotinidase deficiency detected in newborn screening blood spots in the Somalian population in Minnesota.
Newborns identified with profound biotinidase deficiency (BTD) by the Minnesota Newborn Screening Program (MN NBS) between 1 October 2004 and 30 May 2008 were all from new immigrant groups. Thirty-three positive cases of BTD were identified out of 264 727 infants screened by the Wolf colorimetric system during the period of this study by MN NBS. Five cases of profound BTD (0.1 to <0.6 nmol/min per ml) and 26 cases of partial BTD (0.9 to 2.3 nmol/min per ml) were later confirmed through measurement of serum biotinidase activity. The incidence of combined partial and profound BTD of 1/8540 and that of profound BTD of 1/52 945 in Minnesota are unusually high in comparison with the reported worldwide numbers of 1/61 067 for combined BTD and 1/137 401 for profound BTD. Four out of the 5 cases of profound BTD ascertained in the MN NBS cohort were of Somali ethnic background, and the remaining case was of Asian (Pakistani/Indian) ethnic background. All four Somali patients have the P497S mutation, with one of the four being homozygous for the mutation. The three compound heterozygotes all have a novel mutation (P142T) and two of them have another change (Y428Y) that has never been described. Within the last two decades, Minnesota has become home to an estimated 40 000 Somali immigrants and their children (<1% of the total Minnesota population). New population demographics prompt careful analysis of case cohorts to identify specific groups at risk for rare inborn errors of metabolism.


Clinical evaluation of hybrid ionomer restoratives in Class V abrasion lesions: two-year results.
Eighty Class V abrasion cavities were selected, and 20 cavities were restored with one of three resin-modified glass-ionomer materials (Fuji II LC, Photac-Fil, and Vitremer) or a polyacid-modified resin composite (Dyract). The restorations were clinically evaluated after 1 and 2 years with the US Public Health Service criteria. The results revealed a statistically significant difference in the percentage of restorations rated Alfa for color match at 2 years. No statistically significant difference was found in the percentage of alfa rating for anatomic form. Restorations of all materials showed some marginal discrepancies that were not statistically significant.


Pyridine nucleotides and calcium signalling in arterial smooth muscle: from cell physiology to pharmacology.
It is generally accepted that the mobilisation of intracellular Ca2+ stores plays a pivotal role in the regulation of arterial smooth muscle function, paradoxically during both contraction and relaxation. However, the spatiotemporal pattern of different Ca2+ signals that elicit such responses may also contribute to the regulation of, for example, differential gene expression. These findings, among others, demonstrate the importance of discrete spatiotemporal Ca2+ signalling patterns and the mechanisms that underpin them. Of fundamental importance in this respect is the realisation that different Ca2+ storing organelles may be selected by the discrete or coordinated actions of multiple Ca2+ mobilising messengers. When considering such messengers, it is generally accepted that sarcoplasmic reticulum (SR) stores may be mobilised by the ubiquitous messenger inositol 1,4,5 trisphosphate. However, relatively little attention has been paid to the role of Ca2+ mobilising pyridine nucleotides in arterial smooth muscle, namely, cyclic adenosine diphosphate-ribose (cADPR) and nicotinic acid adenine dinucleotide phosphate (NAADP). This review will therefore focus on these novel mechanisms of calcium signalling and their likely therapeutic potential.


Axonal gap junctions between principal neurons: a novel source of network oscillations, and perhaps epileptogenesis.
We hypothesized in 1998 that gap junctions might be located between the axons of principal hippocampal neurons, based on the shape of spikelets (fast prepotentials), occurring during gap junction-mediated very fast (to approximately 200 Hz) network oscillations in vitro. More recent electrophysiological, pharmacological and dye-coupling data indicate that axonal gap junctions exist; so far, they appear to be located about 100 microm from the soma, in CA1 pyramidal neurons. Computer modeling and theory predict that axonal gap junctions can lead to very fast network oscillations under three conditions: a) there are spontaneous axonal action potentials; b) the number of gap junctions in the network is neither too low (not less than to approximately 1.5 per cell on average), nor too high (not more than to approximately 3 per cell on average); c) action potentials can cross from axon to axon via gap junctions. Simulated oscillations resemble biological ones, but condition (c) remains to be demonstrated directly. Axonal network oscillations can, in turn, induce oscillatory activity in larger neuronal networks, by a variety of mechanisms. Axonal networks appear to underlie in vivo ripples (to approximately 200 Hz field potential oscillations superimposed on physiological sharp waves), to drive gamma (30-70 Hz) oscillations that appear in the presence of carbachol, and to initiate certain types of ictal discharge. If axonal gap junctions are important for seizure initiation in humans, there could be practical consequences for antiepileptic therapy: at least one gap junction-blocking compound, carbenoxolone, is already in clinical use (for treatment of ulcer disease), and it crosses the blood-brain barrier.


An in vitro bioassay for a mulluscan gonadotropin.
1. Protein synthesis occurs at a high rate in the ovaries of maturing Octopus vulgaris and can be measured from the incorporation of [14C]leucine in vivo and in isolated groups of eggs in vitro. 2. Removal of the optic glands in vivo 1--3 days prior to testing markedly reduces amino acid incorporation in vivo or in vitro. After 5 days in vivo incorporation stops. 3. The rate of incorporation in vitro is increased by the addition of optic gland extract. 4. Analysis of the kinetics of leucine uptake and incorporation in vitro indicates that the hormone has an effect on the inward transport of leucine which is independent of its action on protein synthesis. 5. Electron-microscope studies of the follicle cells and ova show that the former are the site of protein synthesis. 6. Changes in either uptake or incorporation into protein by the follicle cells can be used as a qualitative biolobical assay for the optic gland hormone. Uptake is very easy to measure but incorporation is the more sensitive parameter. Either is potentially suitable as a quantitative assay for this and perhaps also for other molluscan gonadotropins.


Caffeine and menopausal symptoms: what is the association?
We assessed the association between caffeine intake and menopausal symptom bother, particularly vasomotor symptoms. A cross-sectional survey was conducted using the Menopause Health Questionnaire, which is a comprehensive survey of menopause-related health information. Questionnaires were completed by 2,507 consecutive women who presented with menopausal concerns at the Women's Health Clinic at Mayo Clinic (Rochester, MN) between July 25, 2005 and July 25, 2011. Data from 1,806 women who met all inclusion criteria were analyzed. Menopausal symptom ratings were compared between women who used caffeine and women who did not use caffeine using two-sample t test and analysis of covariance, with smoking and menopause status included as covariates. In all cases, two-tailed P < 0.05 was considered statistically significant. Caffeine use was positively associated with mean (SD) vasomotor symptom scores (2.30 [0.91] vs 2.15 [0.94], P = 0.011). This finding remained significant after adjustment for menopause status and cigarette smoking (P = 0.027). Caffeine use is associated with greater vasomotor symptom bother in postmenopausal women.