DISC1, PDE4B, and NDE1 at the centrosome and synapse.
Disrupted-In-Schizophrenia 1 (DISC1) is a risk factor for schizophrenia and other major mental illnesses. Its protein binding partners include the Nuclear Distribution Factor E Homologs (NDE1 and NDEL1), LIS1, and phosphodiesterases 4B and 4D (PDE4B and PDE4D). We demonstrate that NDE1, NDEL1 and LIS1, together with their binding partner dynein, associate with DISC1, PDE4B and PDE4D within the cell, and provide evidence that this complex is present at the centrosome. LIS1 and NDEL1 have been previously suggested to be synaptic, and we now demonstrate localisation of DISC1, NDE1, and PDE4B at synapses in cultured neurons. NDE1 is phosphorylated by cAMP-dependant Protein Kinase A (PKA), whose activity is, in turn, regulated by the cAMP hydrolysis activity of phosphodiesterases, including PDE4. We propose that DISC1 acts as an assembly scaffold for all of these proteins and that the NDE1/NDEL1/LIS1/dynein complex is modulated by cAMP levels via PKA and PDE4.


A brain-machine interface enables bimanual arm movements in monkeys.
Brain-machine interfaces (BMIs) are artificial systems that aim to restore sensation and movement to paralyzed patients. So far, BMIs have enabled only one arm to be moved at a time. Control of bimanual arm movements remains a major challenge. We have developed and tested a bimanual BMI that enables rhesus monkeys to control two avatar arms simultaneously. The bimanual BMI was based on the extracellular activity of 374 to 497 neurons recorded from several frontal and parietal cortical areas of both cerebral hemispheres. Cortical activity was transformed into movements of the two arms with a decoding algorithm called a fifth-order unscented Kalman filter (UKF). The UKF was trained either during a manual task performed with two joysticks or by having the monkeys passively observe the movements of avatar arms. Most cortical neurons changed their modulation patterns when both arms were engaged simultaneously. Representing the two arms jointly in a single UKF decoder resulted in improved decoding performance compared with using separate decoders for each arm. As the animals' performance in bimanual BMI control improved over time, we observed widespread plasticity in frontal and parietal cortical areas. Neuronal representation of the avatar and reach targets was enhanced with learning, whereas pairwise correlations between neurons initially increased and then decreased. These results suggest that cortical networks may assimilate the two avatar arms through BMI control. These findings should help in the design of more sophisticated BMIs capable of enabling bimanual motor control in human patients.


Methods to create a stringent selection system for mammalian cell lines.
The efficient establishment of high protein producing recombinant mammalian cell lines is facilitated by the use of a stringent selection system. Here, we describe two methods to create a stringent selection system based on the Zeocin resistance marker. First, we cloned increasingly longer stretches of DNA, encoding a range of 8-131 amino acids immediately upstream of the Zeocin selection marker gene. The DNA stretches were separated from the open reading frame of the selection marker gene by a stopcodon. The idea behind this was that the translation machinery will first translate the small peptide, stop and then restart at the AUG of the Zeocin marker. This process, however, will become less efficient with increasingly longer stretches of DNA upstream of the Zeocin marker that has to be translated first. This would result in lower levels of the Zeocin selection marker protein and thus a higher selection stringency of the system. Secondly, we performed a genetic screen to identify PCR induced mutations in the Zeocin selection protein that functionally impair the selection marker protein. Both the insertion of increasingly longer peptides and several Zeocin selection protein mutants resulted in a decreasing number of stably transfected colonies that concomitantly displayed higher protein expression levels. When the Zeocin mutants were combined with very short small peptides (8-14 amino acids long), this created a flexible, high stringency selection system. The system allows the rapid establishment of few, but high protein producing mammalian cell lines.


Mississippi Communities for Healthy Living: Implementing a nutrition intervention effectiveness study in a rural health disparate region.
Intervention research in rural, health disparate communities presents unique challenges for study design, implementation, and evaluation. Challenges include 1) culturally appropriate intervention components, 2) participant recruitment and retention, 3) treatment cross-contamination, 4) intervention delivery and data collection, and 5) potential measurement reactivity. The purposes of this paper are to 1) detail the methods of the MCHL study and 2) report baseline demographic characteristics of study participants. The secondary aim is to determine if study participants were engaging in behavior changes after enrollment and prior to intervention initiation. MCHL was developed using the RE-AIM planning and evaluation framework (reach, effectiveness, adoption, implementation, maintenance). Intervention components were based on Roger's diffusion of innovation attributes that promote adoption of a new innovation as well as on the psychosocial constructs of social support, self-efficacy and decisional balance. Rolling enrollment data collection was used to acquire sufficient sample size and a second data collection just prior to intervention implementation assessed measurement reactivity effects. Participant outcomes included diet quality, blood pressure, weight status, and quality of life. Cluster stratified assignment to one of two treatment arms was utilized to minimize cross contamination. Generalized linear models were used to compare enrollment measures between the two treatment arms while mixed model linear regression was used to test for changes in diet quality outcomes from enrollment to pre-intervention baseline. There were no significant differences in participant demographic, anthropometric or clinical measures between the two treatment arms at enrollment. With the exception of total vegetables, none of the diet quality indicators were significantly different between enrollment and baseline timepoints. Conducting nutrition intervention research in a rural health disparate region requires flexibility in adapting the recruitment, retention, and data collection procedures while maintaining a high level of scientific rigor. Negligible research participation effects, such as measurement reactivity, were noted in this population. However, further research is needed to identify methods to successfully recruit and retain Caucasian females to participate in community-based nutrition interventions in this region.


Pinus Roxburghii essential oil anticancer activity and chemical composition evaluation.
The present study was conducted to appraise the anticancer activity of Pinus roxburghii essential oil along with chemical composition evaluation. MTT assay revealed cytotoxicity induction in colon, leukemia, multiple myeloma, pancreatic, head and neck and lung cancer cells exposed to essential oil. Cancer cell death was also observed through live/dead cell viability assay and FACS analysis. Apoptosis induced by essential oil was confirmed by cleavage of PARP and caspase-3 that suppressed the colony-forming ability of tumor cells and 50 % inhibition occurred at a dose of 25 μg/mL. Moreover, essential oil inhibited the activation of inflammatory transcription factor NF-κB and inhibited expression of NF-κB regulated gene products linked to cell survival (survivin, c-FLIP, Bcl-2, Bcl-xL, c-Myc, c-IAP2), proliferation (Cyclin D1) and metastasis (MMP-9). P. roxburghii essential oil has considerable anticancer activity and could be used as anticancer agent, which needs further investigation to identify and purify the bioactive compounds followed by in vivo studies.


Potential Mechanisms Influencing the Inverse Relationship Between Cannabis and Nonalcoholic Fatty Liver Disease: A Commentary.
Nonalcoholic fatty liver disease (NAFLD) develops when the liver is unable to oxidize or export excess free fatty acids generated by adipose tissue lipolysis, de novo lipogenesis, or dietary intake. Although treatment has generally been centered on reversing metabolic risk factors that increase the likelihood of NAFLD by influencing lifestyle modifications, therapeutic modalities are being studied at the cellular and molecular level. The endocannabinoid system has been of recent focus. The agonism and antagonism of cannabinoid receptors play roles in biochemical mechanisms involved in the development or regression of NAFLD. Exocannabinoids and endocannabinoids, the ligands which bind cannabinoid receptors, have been studied in this regard. Exocannabinoids found in cannabis (marijuana) may have a therapeutic benefit. Our recent study demonstrated an inverse association between marijuana use and NAFLD among adults in the United States. This commentary combines knowledge on the role of the endocannabinoid system in the setting of NAFLD with the findings in our article to hypothesize different potential mechanisms that may influence the inverse relationship between cannabis and NAFLD.


The role of energy in economic growth.
This paper reviews the mainstream, resource economics, and ecological economics models of growth. A possible synthesis of energy-based and mainstream models is presented. This shows that when energy is scarce it imposes a strong constraint on the growth of the economy; however, when energy is abundant, its effect on economic growth is much reduced. The industrial revolution released the constraints on economic growth by the development of new methods of using coal and the discovery of new fossil fuel resources. Time-series analysis shows that energy and GDP cointegrate, and energy use Granger causes GDP when capital and other production inputs are included in the vector autoregression model. However, various mechanisms can weaken the links between energy and growth. Energy used per unit of economic output has declined in developed and some developing countries, owing to both technological change and a shift from poorer quality fuels, such as coal, to the use of higher quality fuels, especially electricity. Substitution of other inputs for energy and sectoral shifts in economic activity play smaller roles.


Long-term Outcomes of MRI Stage IIB Cervical Cancer.
Magnetic resonance imaging (MRI) can be used to assess parametrial invasion (PMI) in cervical cancer. Discordance between MRI findings and International Federation of Gynecology and Obstetrics (FIGO) staging is not uncommon because FIGO staging depends on physical examination. The purpose of this study was to retrospectively evaluate the long-term outcomes of MRI stage IIB cervical cancer. A total of 312 patients with MRI stage IIB cervical cancer were retrospectively found between 2002 and 2011. Of these patients, 171 (group 1) were FIGO stage IIB cervical cancers and 141 (group 2) were MRI stage IIB cervical cancers that were negative PMI on physical examination. Group 1 was treated with chemotherapy and/or radiation therapy, and group 2 was treated with radical hysterectomy and lymph node dissection. The FIGO stages and pathologic findings of group 2 were recorded. Groups 1 and 2 were compared regarding 5-year overall survival rate. The FIGO stages of group 2 were IB1 in 51 (36.2%), IB2 in 28 (19.9%), and IIA in 62 (44%), whereas those of group 1 were all IIB. Group 2 showed lymphovascular space invasion in 71 (50.4%), lymph node metastasis in 48 (34.0%), PMI in 46 (32.6%), and vagina invasion in 9 (6.4%). Five-year overall survival rates of groups 1 and 2 were 73.7% and 84.5%, respectively (P = 0.013). Magnetic resonance imaging stage IIB cervical cancers with negative PMI on physical examination should be surgically treated because of better survival rate than FIGO stage IIB cervical cancers.


Complex health care interventions: Characteristics relevant for ethical analysis in health technology assessment.
Complexity entails methodological challenges in assessing health care interventions. In order to address these challenges, a series of characteristics of complexity have been identified in the Health Technology Assessment (HTA) literature. These characteristics are primarily identified and developed to facilitate effectiveness, safety, and cost-effectiveness analysis. However, ethics is also a constitutive part of HTA, and it is not given that the conceptions of complexity that appears relevant for effectiveness, safety, and cost-effectiveness analysis are also relevant and directly applicable for ethical analysis in HTA. The objective of this article is therefore to identify and elaborate a set of key characteristics of complex health care interventions relevant for addressing ethical aspects in HTA. We start by investigating the relevance of the characteristics of complex interventions, as defined in the HTA literature. Most aspects of complexity found to be important when assessing effectiveness, safety, and efficiency turn out also to be relevant when assessing ethical issues of a given health technology. However, the importance and relevance of the complexity characteristics may differ when addressing ethical issues rather than effectiveness. Moreover, the moral challenges of a health care intervention may themselves contribute to the complexity. After identifying and analysing existing conceptions of complexity, we synthesise a set of five key characteristics of complexity for addressing ethical aspects in HTA: 1) multiple and changing perspectives, 2) indeterminate phenomena, 3) uncertain causality, 4) unpredictable outcome, and 5) ethical complexity. This may serve as an analytic tool in addressing ethical issues in HTA of complex interventions.


Vibrational spectroscopy and imaging: applications for tissue engineering.
Tissue engineering (TE) approaches strive to regenerate or replace an organ or tissue. The successful development and subsequent integration of a TE construct is contingent on a series of in vitro and in vivo events that result in an optimal construct for implantation. Current widely used methods for evaluation of constructs are incapable of providing an accurate compositional assessment without destruction of the construct. In this review, we discuss the contributions of vibrational spectroscopic assessment for evaluation of tissue engineered construct composition, both during development and post-implantation. Fourier transform infrared (FTIR) spectroscopy in the mid and near-infrared range, as well as Raman spectroscopy, are intrinsically label free, can be non-destructive, and provide specific information on the chemical composition of tissues. Overall, we examine the contribution that vibrational spectroscopy via fiber optics and imaging have to tissue engineering approaches.


Shutting Down Shigella Secretion: Characterizing Small Molecule Type Three Secretion System ATPase Inhibitors.
Many important human pathogens rely on one or more type three secretion systems (T3SSs) to inject bacterial effector proteins directly into the host cell cytoplasm. Secretion of protein through the needlelike type three secretion apparatus (T3SA) is essential for pathogen virulence and relies on a highly conserved ATPase at the base of the apparatus, making it an attractive target for anti-infective therapeutics. Here, we leveraged the ability to purify an active oligomeric Shigella T3SS ATPase to provide kinetic analyses of three T3SS ATPase inhibitors of Spa47. In agreement with in silico docking simulations, the inhibitors displayed noncompetitive inhibition profiles and efficiently reduced Spa47 ATPase activity with IC50s as low as 52 ± 3 μM. Two of the inhibitors functioned well in vivo, nearly abolishing effector protein secretion without significantly affecting the Shigella growth phenotype or HeLa cell viability. Furthermore, characterization of Spa47 complexes in vitro and Shigella T3SA formation in vivo showed that the inhibitors do not function through disruption of Spa47 oligomers or by preventing T3SA formation. Together, these findings suggest that inhibitors targeting Spa47 may be an effective means of combating Shigella infection by shutting down type three secretion without preventing presentation of the highly antigenic T3SA tip proteins that aid in clearing the infection and developing pan- Shigella immunological memory. In summary, this is the first report of Shigella T3SS ATPase inhibitors and one of only a small number of studies characterizing T3SS ATPase inhibition in general. The work presented here provides much-needed insight into T3SS ATPase inhibition mechanisms and provides a strong platform for developing and evaluating non-antibiotic therapeutics targeting Spa47 and other T3SS ATPases.


A brief motivational interviewing as an adjunct to periodontal therapy-A potential tool to reduce relapse in oral hygiene behaviours. A three-year study.
To evaluate (ii) whether inclusion of a single motivational interviewing (MI) session, as an adjunct to periodontal therapy, might be beneficial for preventing relapse in oral hygiene behaviours among patients treated for chronic periodontitis and (ii) whether individual and clinical characteristics can be of predictive value for retention of sufficient oral hygiene behaviours. This 3-year follow-up of a previously reported randomized controlled trial (RCT) study of 6-month duration included 26 patients. Patients in the test group had received one MI session by a clinical psychologist before initiation of the periodontal treatment. Otherwise, all patients followed the same treatment protocol for conventional educational intervention and non-surgical periodontal therapy. Efficacy variables assessed for evaluation of the standard of self-performed periodontal infection control were marginal bleeding index (MBI; primary efficacy variable) and plaque score (PI). The patterns of change in MBI and PI scores were similar for test and control groups over the observation period. At 3 years, both groups showed a desirable mean full-mouth MBI of 15%, a figure that was comparable to that at the short-term evaluation after active periodontal treatment. The post-treatment MBI was the only variable identified as a predictor of retained adequate oral hygiene behaviours. A single MI session as an adjunct to conventional periodontal therapy could not be proven to be of long-term beneficial additive effect with regard to prevention of relapse in oral hygiene behaviour. Desirable standard of self-performed infection control after active periodontal treatment predicted the retention of sufficient oral hygiene behaviour over time.


Use of Menopausal Hormone Therapy and Bioidentical Hormone Therapy in Australian Women 50 to 69 Years of Age: Results from a National, Cross-Sectional Study.
Menopausal Hormone Therapy (MHT) use in Australia fell by 55% from 2001 to 2005, following the release of large-scale findings on its risks and benefits. Comprehensive national data, including information on overall prevalence of MHT use as well as information on duration of use in Australia have not been reported since the 2004-5 National Health Survey, when 11% of women aged 45+ years were estimated to be current MHT users. No national data are available on prevalence of use of "bioidentical" hormone therapy (BHT). The objective of this study was to determine recent prevalence of MHT and BHT use. A cross-sectional, national, age-stratified, population survey was conducted in 2013. Eligible women, aged 50-69 years, resident in Australia were randomly sampled in 5-year age groups from the Medicare enrolment database (Australia's universal health scheme). The response rate was 22% based on return of completed questionnaires, and analyses were restricted to 4,389 women within the specified age range. The estimated population-weighted prevalence of current use of MHT was 13% (95%CI 12-14), which was broadly similar to the previously reported national figures in 2004-5, suggesting that the use of MHT in Australia has largely stabilised over the past decade. A total of 39% and 20% of current-users with an intact uterus reported use of oestrogen-progestagen MHT and oestrogen-only MHT, respectively, whereas 77% of hysterectomised current-users used oestrogen-only MHT. Almost three-quarters of current-users [population-weighted prevalence 9% (95%CI 8-10)] had used MHT for ≥5 years. In regard to BHT, estimated population-weighted prevalence of ever use was 6% (95%CI 6-7) and 2% (95%CI 2-3) for current use. The population-weighted prevalence of MHT and BHT combined, in current users in their fifties and sixties was 15% (95%CI 14-16). These data provide a recent national "snapshot" of Australian women's use of both conventional MHT and of BHT.


Recent progress towards transition metal-catalyzed synthesis of γ-lactams.
The occurrence of the γ-lactam unit in the framework of various biologically active compounds has greatly contributed to the design and development of new synthetic transformations to access this important structural motif. Among the numerous methods developed so far, those based on transition metal catalysis are of high value as they generally allow efficient and selective access to functionalized γ-lactams under rather mild reaction conditions. An overview of the recent advances in this field is presented herein. Metal-catalyzed processes are reviewed by highlighting their specificity and applicability, and the mechanistic rationale is presented where possible.


Chronic Q fever endocarditis.
Eight patients with chronic Q fever endocarditis were treated with tetracycline for up to 40 months. In addition, five of these patients received co-trimoxazole. Six patients had prosthetic valves. Two patients who had Q fever endocarditis on their native valves required valve replacement because of haemodynamic difficulties: in only one did the Q fever endocarditis contribute to the haemodynamic difficulty. One patient died. It is suggested that medical treatment is continued until clinically and haematologically there is no evidence of endocarditis and the Q fever phase 1 antibody titre is less than 200. No recurrence of Q fever endocarditis has been detected in three of our patients who have now stopped treatment.


Interpretation of Serological Complement Biomarkers in Disease.
Complement system aberrations have been identified as pathophysiological mechanisms in a number of diseases and pathological conditions either directly or indirectly. Examples of such conditions include infections, inflammation, autoimmune disease, as well as allogeneic and xenogenic transplantation. Both prospective and retrospective studies have demonstrated significant complement-related differences between patient groups and controls. However, due to the low degree of specificity and sensitivity of some of the assays used, it is not always possible to make predictions regarding the complement status of individual patients. Today, there are three main indications for determination of a patient's complement status: (1) complement deficiencies (acquired or inherited); (2) disorders with aberrant complement activation; and (3) C1 inhibitor deficiencies (acquired or inherited). An additional indication is to monitor patients on complement-regulating drugs, an indication which may be expected to increase in the near future since there is now a number of such drugs either under development, already in clinical trials or in clinical use. Available techniques to study complement include quantification of: (1) individual components; (2) activation products, (3) function, and (4) autoantibodies to complement proteins. In this review, we summarize the appropriate indications, techniques, and interpretations of basic serological complement analyses, exemplified by a number of clinical disorders.


A tunable digital ishihara plate for pre-school aged children.
Colors play a fundamental role for children, both in the everyday life and in education. They recognize the surrounding world, and play games making a large use of colors. They learn letters and numbers by means of colors. As a consequence, early diagnosis of color blindness is an crucial to support an individual affected by this visual perception alteration at the initial phase of his/her life. The diagnosis of red-green color deficiencies (protanopia or deuteranopia) is commonly accomplished by means of the Ishihara test, which consists of plates showing dots with different sizes where some of them compose numbers within a gamut of colors while the ones composing the background have different colors. In this paper, a web application written in javascript is presented, that implements a digital Ishihara-like test for pre-school aged children. Instead numbers or letters, It can transform any binary image representing animal shapes, or any other child-friendly shape, into an Ishihara-like image. This digital plate is not static. The operator can increment the dot density to improve the quality of the shape contour and the entire plate can be redrawn with different dot sizes/colors chosen randomly according to the color pattern of the test. Separate controls for brightness and saturation are implemented to calibrate the chromatic aspect of the background and foreground dots.


A Developmental Functional MRI Study of Prefrontal Activation during Performance of a Go-No-Go Task.
This study examines important developmental differences in patterns of activation in the prefrontal cortex during performance of a Go-No-Go paradigm using functional magnetic resonance imaging (fMRI). Eighteen subjects (9 children and 9 adults) were scanned using gradient echo, echo planar imaging during performance of a response inhibition task. The results suggest four general findings. First, the location of activation in the prefrontal cortex was not different between children and adults, which is similar to our earlier pediatric fMRI results of prefrontal activation during a working memory task (Casey et al., 1995). Second, the volume of activation was significantly greater for children relative to adults. These differences in volume of activation were observed predominantly in the dorsal and lateral prefrontal cortices. Third, although inhibitory processes have typically been associated with more ventral or orbital frontal regions, the current study revealed activation that was distributed across both dorsolateral and orbitofrontal cortices. Finally, consistent with animal and human lesion studies, activity in orbital frontal and anterior cingulate cortices correlated with behavioral performance (i.e., number of false alarms). These results further demonstrate the utility of this methodology in studying pediatric populations.


Echocardiographic findings in infants with presumed congenital Zika syndrome: Retrospective case series study.
To report the echocardiographic evaluation of 103 infants with presumed congenital Zika syndrome. An observational retrospective study was performed at Instituto de Medicina Integral Prof. Fernando Figueira (IMIP), Recife, Brazil. 103 infants with presumed congenital Zika syndrome. All infants had microcephaly and head computed tomography findings compatible with congenital Zika syndrome. Zika IgM antibody was detected in cerebrospinal fluid samples of 23 infants. In 80 infants, the test was not performed because it was not available at that time. All infants had negative serology for HIV, syphilis, rubella, cytomegalovirus and toxoplasmosis. A complete transthoracic two-dimensional, M-mode, continuous wave and pulsed wave Doppler and color Doppler echocardiographic (PHILIPS HD11XE or HD15) examination was performed on all infants. 14/103 (13.5%) echocardiograms were compatible with congenital heart disease: 5 with an ostium secundum atrial septal defect, 8 had a hemodynamically insignificant small apical muscular ventricular septal defect and one infant with dyspnea had a large membranous ventricular septal defect. The echocardiograms considered normal included 45 infants with a persistent foramen ovale and 16 with a minimum patent ductus arteriosus. Preliminarily this study suggests that congenital Zika syndrome may be associated with an increase prevalence of congenital heart disease. However the types of defects noted were septal defects, a proportion of which would not be hemodynamically significant.


Psychological alternatives to long-term benzodiazepine use.
The aim of the study was to evaluate the effectiveness of psychological management of anxiety as an alternative to long-term benzodiazepine medication. Fifty patients were identified who had been taking benzodiazepines continuously for at least one year. No significant differences were found between patients who joined a treatment group and patients who were simply advised by letter to cut down their pills. Patients gave a variety of reasons for initially requiring medication and somewhat different reasons for needing to maintain chemotherapy, which suggested that pill-taking might be self-maintaining through withdrawal symptoms.


Ascertaining gene flow patterns in livestock populations of developing countries: a case study in Burkina Faso goat.
Introgression of Sahel livestock genes southwards in West Africa may be favoured by human activity and the increase of the duration of the dry seasons since the 1970's. The aim of this study is to assess the gene flow patterns in Burkina Faso goat and to ascertain the most likely factors influencing geographic patterns of genetic variation in the Burkina Faso goat population. A total of 520 goat were sampled in 23 different locations of Burkina Faso and genotyped for a set of 19 microsatellites. Data deposited in the Dryad repository: http://dx.doi.org/10.5061/dryad.41h46j37. Although overall differentiation is poor (FST = 0.067 ± 0.003), the goat population of Burkina Faso is far from being homogeneous. Barrier analysis pointed out the existence of: a) genetic discontinuities in the Central and Southeast Burkina Faso; and b) genetic differences within the goat sampled in the Sahel or the Sudan areas of Burkina Faso. Principal component analysis and admixture proportion scores were computed for each population sampled and used to construct interpolation maps. Furthermore, Population Graph analysis revealed that the Sahel and the Sudan environmental areas of Burkina Faso were connected through a significant number of extended edges, which would be consistent with the hypothesis of long-distance dispersal. Genetic variation of Burkina Faso goat followed a geographic-related pattern. This pattern of variation is likely to be related to the presence of vectors of African animal trypanosomosis. Partial Mantel test identified the present Northern limit of trypanosome vectors as the most significant landscape boundary influencing the genetic variability of Burkina Faso goat (p = 0.008). The contribution of Sahel goat genes to the goat populations in the Northern and Eastern parts of the Sudan-Sahel area of Burkina Faso was substantial. The presence of perennial streams explains the existence of trypanosome vectors. The South half of the Nakambé river (Southern Ouagadougou) and the Mouhoun river loop determined, respectively, the Eastern and Northern limits for the expansion of Sahelian goat genes. Furthermore, results from partial Mantel test suggest that the introgression of Sahelian goat genes into Djallonké goat using human-influenced genetic corridors has a limited influence when compared to the biological boundary defined by the northern limits for the distribution of the tsetse fly. However, the genetic differences found between the goat sampled in Bobo Dioulasso and the other populations located in the Sudan area of Burkina Faso may be explained by the broad goat trade favoured by the main road of the country. The current analysis clearly suggests that genetic variation in Burkina Faso goat: a) follows a North to South clinal; and b) is affected by the distribution of the tsetse fly that imposes a limit to the Sahelian goat expansion due to their trypanosusceptibility. Here we show how extensive surveys on livestock populations can be useful to indirectly assess the consequences of climate change and human action in developing countries.


COVID-19 spreading patterns in family clusters reveal gender roles in China.
Understanding different gender roles forms part of the efforts to reduce gender inequality. This paper analyses COVID-19 family clusters outside Hubei Province in mainland China during the 2020 outbreak, revealing significant differences in spreading patterns across gender and family roles. Results show that men are more likely to be the imported cases of a family cluster, and women are more likely to be infected within the family. This finding provides new supportive evidence of the 'men as breadwinner and women as homemaker' (MBWH) gender roles in China. Further analyses reveal that the MBWH pattern is stronger in eastern than in western China, stronger for younger than for elder people. This paper offers not only valuable references for formulating gender-differentiated epidemic prevention policies but also an exemplification for studying group differences in similar scenarios.


Splice site identification using probabilistic parameters and SVM classification.
Recent advances and automation in DNA sequencing technology has created a vast amount of DNA sequence data. This increasing growth of sequence data demands better and efficient analysis methods. Identifying genes in this newly accumulated data is an important issue in bioinformatics, and it requires the prediction of the complete gene structure. Accurate identification of splice sites in DNA sequences plays one of the central roles of gene structural prediction in eukaryotes. Effective detection of splice sites requires the knowledge of characteristics, dependencies, and relationship of nucleotides in the splice site surrounding region. A higher-order Markov model is generally regarded as a useful technique for modeling higher-order dependencies. However, their implementation requires estimating a large number of parameters, which is computationally expensive. The proposed method for splice site detection consists of two stages: a first order Markov model (MM1) is used in the first stage and a support vector machine (SVM) with polynomial kernel is used in the second stage. The MM1 serves as a pre-processing step for the SVM and takes DNA sequences as its input. It models the compositional features and dependencies of nucleotides in terms of probabilistic parameters around splice site regions. The probabilistic parameters are then fed into the SVM, which combines them nonlinearly to predict splice sites. When the proposed MM1-SVM model is compared with other existing standard splice site detection methods, it shows a superior performance in all the cases. We proposed an effective pre-processing scheme for the SVM and applied it for the identification of splice sites. This is a simple yet effective splice site detection method, which shows a better classification accuracy and computational speed than some other more complex methods.


The repressor activity of Even-skipped is highly conserved, and is sufficient to activate engrailed and to regulate both the spacing and stability of parasegment boundaries.
During segmentation of the Drosophila embryo, even skipped is required to activate engrailed stripes and to organize odd-numbered parasegments. A 16 kb transgene containing the even skipped coding region can rescue normal engrailed expression, as well as all other aspects of segmentation, in even skipped null mutants. To better understand its mechanism of action, we functionally dissected the Even-skipped protein in the context of this transgene. We found that Even-skipped utilizes two repressor domains to carry out its function. Each of these domains can function autonomously in embryos when fused with the Gal4 DNA-binding domain. A chimeric protein consisting only of the Engrailed repressor domain and the Even-skipped homeodomain, but not the homeodomain alone, was able to restore function, indicating that the repression of target genes is sufficient for even skipped function at the blastoderm stage, while the homeodomain is sufficient to recognize those target genes. When Drosophila Even skipped was replaced by its homologs from other species, including a mouse homolog, they could provide substantial function, indicating that these proteins can recognize similar target sites and also provide repressor activity. Using this rescue system, we show that broad, early even skipped stripes are sufficient for activation of both odd- and even-numbered engrailed stripes. Furthermore, these 'unrefined' stripes organize odd-numbered parasegments in a dose-dependent manner, while the refined, late stripes, which coincide cell-for-cell with parasegment boundaries, are required to ensure the stability of the boundaries.


Computed tomography-quantified body composition predicts short-term outcomes after gastrectomy in gastric cancer.
Malnutrition is a common and critical problem that influences outcome in cancer patients. Body composition reflects a patient's metabolic profile and physiologic reserves, which might be the true determinant of prognosis. In the present study, which aimed to identify valuable new prognostic indicators, we investigated the association between computed tomography-quantified body composition and short-term outcomes after gastrectomy for gastric cancer. Skeletal muscle index, mean muscle attenuation, and ratio of visceral-to-subcutaneous adipose tissue area (vsr) were calculated from preoperative computed tomography images. Low skeletal muscle index, low mean muscle attenuation, and high vsr were respectively termed "sarcopenia," "myosteatosis," and "visceral obesity." The association of body composition with postoperative complications and serum markers of nutrition and inflammation after radical gastrectomy were analyzed. The overall complication rate was significantly higher in the sarcopenia (62.5% vs. 27.3%, p = 0.001) and myosteatosis groups (38.2% vs. 4%, p = 0.002). Patients with visceral obesity had a higher incidence of inflammatory complications (20.3% vs. 6.5%, p = 0.01). Multivariate logistic regression analysis demonstrated that sarcopenia (p = 0.013), myosteatosis (p = 0.017), and low serum retinol-binding protein (p = 0.019) were independent risk factors for overall complications. Compared with control subjects, patients with sarcopenia had lower postoperative levels of serum retinol-binding protein (p = 0.007), and patients with visceral obesity had higher levels of C-reactive protein (p = 0.026). Sarcopenia, myosteatosis, and visceral obesity were significantly associated with increased rates of postoperative complications and affected the postoperative nutrition and inflammation status of patients with gastric cancer.


Walking balance and compensatory gait mechanisms in surgically treated patients with adult spinal deformity.
Gait patterns and their relationship to demographic and radiographic data in patients with adult spinal deformity (ASD) have not been fully documented. This study aimed to assess gait pattern in patients with ASD and the effect of corrective spinal surgery on gait. This is a prospective case series. The gait patterns of 33 consecutive women with ASD (age 67.1 years; body mass index [BMI] 22.5±2.5 kg/m2, Cobb angle 46.8±18.2°, coronal vertical axis [CVA] 1.5±3.7 cm, C7 sagittal vertical axis [SVA] 9.1±6.4 cm, pelvic incidence minus lumbar lordosis [PI-LL] 38.2±22.1°, and lean volume of the lower leg, 5.5±0.6 kg) before and after corrective surgery were compared with those of 33 age- and gender-matched healthy volunteers. Scoliosis Research Society Patient Questionnaire (SRS22r), Oswestry Disability Index (ODI), and forceplate analysis. All subjects underwent gait analysis on a custom-built forceplate using optical markers placed on all joints and spinal processes. Dual X-ray absorptiometry scores were used to calculate the lean composition of the lower legs. Subjects with ASD were followed for at least 2 years post operation. Preop mean values showed that patients with ASD had a significantly worse gait velocity (54±10 m/min vs. 70.7±12.9 m/min, p<.01) and stride (97.8±13.4 cm vs. 115.3±15.1 cm, p<.01), but no difference was observed in the stance-to-swing ratio. The right and left ground reaction force vectors were also discordant in the ASD group (vertical direction; r=0.84 vs. r=.97, p=.01). The hip range of motion (ROM) was also significantly decreased in ASD. Correlation coefficient showed moderate correlations between the preoperative gait velocity and the gravity line (GL), PI, ROM of the lower extremity joints, and lean volume, and between the stride and the lean volume, GL, and PI-LL. Gait pattern, stride, and velocity all improved significantly in the patients with ASD after surgery, but were still not as good as in healthy volunteers. The SRS22r satisfaction domain correlated moderately with postoperative gait velocity (r=0.34). The patients with ASD had an asymmetric gait pattern and impaired gait ability compared with healthy volunteers. Gait ability correlated significantly with the GL, spinopelvic alignment, lower extremity joint ROM, and lean volume. The surgical correction of spinopelvic alignment and exercises to build muscle strength may improve the gait pattern and ability in patients with ASD.


Is there pain in champagne? Semantic involvement of words within words during sense-making.
In an ERP experiment, we examined whether listeners, when making sense of spoken utterances, take into account the meaning of spurious words that are embedded in longer words, either at their onsets (e.g., pie in pirate) or at their offsets (e.g., pain in champagne). In the experiment, Dutch listeners heard Dutch words with initial or final embeddings presented in a sentence context that did or did not support the meaning of the embedded word, while equally supporting the longer carrier word. The N400 at the carrier words was modulated by the semantic fit of the embedded words, indicating that listeners briefly relate the meaning of initial- and final-embedded words to the sentential context, even though these words were not intended by the speaker. These findings help us understand the dynamics of initial sense-making and its link to lexical activation. In addition, they shed new light on the role of lexical competition and the debate concerning the lexical activation of final-embedded words.


Serum C-reactive protein on the prognosis of oncology patients with acute renal failure: an observational cohort study.
We undertook this study to evaluate the significance of the C-reactive protein level (CRP) as a prognostic factor in oncology patients with acute renal failure (ARF) during nephrology consultation. The study was comprised of a cohort of 375 consecutive oncology patients who had been admitted to a university-affiliated hospital between March 1998 and April 2006 and had been diagnosed with ARF. One hundred and fifty nine patients with ARF who matched at least one of the RIFLE criteria on increased serum creatinine were included for subsequent analysis. We used a Cox proportional hazard model. Clinical pathological variables were compared among patients with serum CRP levels > or =8 mg/dL (exposed group; cut-off point: median) and patients with serum CRP level <8 mg/dL (control group). In-hospital mortality rates associated with CRP levels were 53.8% for > or =8 mg/dL and 21.5% for <8 mg/dL (p <0.001). After adjusted analysis, the presence of a CRP level > or =8 mg/dL was significantly associated with an increased in-hospital mortality (HR 2.10; 95% CI: 1.17-3.78) than in those patients with similar Liano scoring, the same RIFLE classes, and the same treatment for ARF. In addition, each increment of 1 mg/dL of serum CRP was associated with an adjusted 4% increment of in-hospital mortality (HR 1.04, 95% CI: 1.01-1.06). CRP levels at nephrology consultation were an independent predictor of death in this cohort of oncology patients with ARF. Patients with levels > or =8 mg/dL may be considered at higher risk of death.


Group II introns break new boundaries: presence in a bilaterian's genome.
Group II introns are ribozymes, removing themselves from their primary transcripts, as well as mobile genetic elements, transposing via an RNA intermediate, and are thought to be the ancestors of spliceosomal introns. Although common in bacteria and most eukaryotic organelles, they have never been reported in any bilaterian animal genome, organellar or nuclear. Here we report the first group II intron found in the mitochondrial genome of a bilaterian worm. This location is especially surprising, since animal mitochondrial genomes are generally distinct from those of plants, fungi, and protists by being small and compact, and so are viewed as being highly streamlined, perhaps as a result of strong selective pressures for fast replication while establishing germ plasm during early development. This intron is found in the mtDNA of an annelid worm, (an undescribed species of Nephtys), where the complete sequence revealed a 1819 bp group II intron inside the cox1 gene. We infer that this intron is the result of a recent horizontal gene transfer event from a viral or bacterial vector into the mitochondrial genome of Nephtys sp. Our findings hold implications for understanding mechanisms, constraints, and selective pressures that account for patterns of animal mitochondrial genome evolution.


Association between severe drought and HIV prevention and care behaviors in Lesotho: A population-based survey 2016-2017.
A previous analysis of the impact of drought in Africa on HIV demonstrated an 11% greater prevalence in HIV-endemic rural areas attributable to local rainfall shocks. The Lesotho Population-Based HIV Impact Assessment (LePHIA) was conducted after the severe drought of 2014-2016, allowing for reevaluation of this relationship in a setting of expanded antiretroviral coverage. LePHIA selected a nationally representative sample between November 2016 and May 2017. All adults aged 15-59 years in randomly selected households were invited to complete an interview and HIV testing, with one woman per household eligible to answer questions on their experience of sexual violence. Deviations in rainfall for May 2014-June 2016 were estimated using precipitation data from Climate Hazards Group InfraRed Precipitation with Station Data (CHIRPS), with drought defined as <15% of the average rainfall from 1981 to 2016. The association between drought and risk behaviors as well as HIV-related outcomes was assessed using logistic regression, incorporating complex survey weights. Analyses were stratified by age, sex, and geography (urban versus rural). All of Lesotho suffered from reduced rainfall, with regions receiving 1%-36% of their historical rainfall. Of the 12,887 interviewed participants, 93.5% (12,052) lived in areas that experienced drought, with the majority in rural areas (7,281 versus 4,771 in urban areas). Of the 835 adults living in areas without drought, 520 were in rural areas and 315 in urban. Among females 15-19 years old, living in a rural drought area was associated with early sexual debut (odds ratio [OR] 3.11, 95% confidence interval [CI] 1.43-6.74, p = 0.004), and higher HIV prevalence (OR 2.77, 95% CI 1.19-6.47, p = 0.02). It was also associated with lower educational attainment in rural females ages 15-24 years (OR 0.44, 95% CI 0.25-0.78, p = 0.005). Multivariable analysis adjusting for household wealth and sexual behavior showed that experiencing drought increased the odds of HIV infection among females 15-24 years old (adjusted OR [aOR] 1.80, 95% CI 0.96-3.39, p = 0.07), although this was not statistically significant. Migration was associated with 2-fold higher odds of HIV infection in young people (aOR 2.06, 95% CI 1.25-3.40, p = 0.006). The study was limited by the extensiveness of the drought and the small number of participants in the comparison group. Drought in Lesotho was associated with higher HIV prevalence in girls 15-19 years old in rural areas and with lower educational attainment and riskier sexual behavior in rural females 15-24 years old. Policy-makers may consider adopting potential mechanisms to mitigate the impact of income shock from natural disasters on populations vulnerable to HIV transmission.


Electronic structure and bandgap of γ-Al2O3 compound using mBJ exchange potential.
γ-Al2O3 is a porous metal oxide and described as a defective spinel with some cationic vacancies. In this work, we calculate the electronic density of states and band structure for the bulk of this material. The calculations are performed within the density functional theory using the full potential augmented plan waves plus local orbital method, as embodied in the WIEN2k code. We show that the modified Becke-Johnson exchange potential, as a semi-local method, can predict the bandgap in better agreement with the experiment even compared to the accurate but much more expensive green function method. Moreover, our electronic structure analysis indicates that the character of the valence band maximum mainly originates from the p orbital of those oxygen atoms that are close to the vacancy. The charge density results show that the polarization of the oxygen electron cloud is directed toward aluminum cations, which cause Al and O atoms to be tightly connected by a strong dipole bond.


Whither the urban diaspora? The spatial redistribution of Latino origin groups in metropolitan America since 1990.
Our research advances what is known about the urban portion of the Latino diaspora, focusing on the extent to which Hispanic country-of-origin groups have spread throughout metropolitan America. Analyzing 1990-2010 census data for the seven largest origin groups, we find that all seven have become more evenly dispersed across metro areas, with group shares declining in primary gateways and increasing in other types of destinations. At the same time, Dominicans and Cubans remain highly concentrated in New York and Miami, respectively, and certain pairs of groups (e.g., Mexicans and Dominicans) continue to inhabit different metropolises despite a modest trend toward convergent settlement among most pairs. All groups have experienced some growth in exposure to ethnoracial diversity, particularly in primary gateway settings. However, Mexicans are less exposed than any other origin group to African Americans. The variation in our results by group attests to the delicate balance between the forces driving spatial concentration and dispersion. We conclude that multiple diasporas are underway rather than a single, uniform one. This pattern has relevance both for diversity within local Hispanic communities and for relations between Hispanics and other panethnic populations, most notably Whites and Blacks.


Intensification of hydroxyl radical production in sonochemical reactors.
The efficacy of sonochemical reactors in chemical processing applications has been well established in the laboratory scale of operation though at a given set of operating parameters and no efforts have been directed in terms of maximizing the free radical production. In the present work, the effect of different operating parameters viz. pH, power dissipation into the system, effect of additives such as air, haloalkanes, titanium dioxide, iron and oxygen on the extent of hydroxyl radical formation in a sonochemical reactor have been investigated using salicylic acid dosimetry. Possible mechanisms for oxidation of salicylic acid in the presence of different additives have also been established. It has been observed that acidic conditions under optimized power dissipation in the presence of iron powder and oxygen result in maximum liberation of hydroxyl radicals as quantified by the kinetic rate constant for production of 2,5- and 2,3-dihydroxybenzoic acid. The study has enabled the optimization of the conditions for maximum efficacy of sonochemical reactors where free radical attack is the controlling mechanism for the chemical processing applications.


Bisexuality and the problem of its social acceptance.
Professor Austin explores four main areas in this paper. First of all he outlines the physical development of sex differentiation in the embryo. He develops this by describing the clinical manifestations of abnormality which can appear at that stage. Professor Austin points out that there are relatively few people with abnormalities and that those who do show homosexual tendencies are not noticeably different from the norm in terms of their sexual equipment and hormone levels. It is much more likely that their psychological and social development has a greater influence in differentiating them sexually. The last section of the paper is a synopsis of society's reactions to homosexuality or bisexuality which term in Professor Austin's opinion is more accurate and descriptive of the condition.


Synthesis of partially and fully fused polyaromatics by annulative chlorophenylene dimerization.
Since the discovery by Ullmann and Bielecki in 1901, reductive dimerization (or homocoupling) of aryl halides has been extensively exploited for the generation of a range of biaryl-based functional molecules. In contrast to the single-point connection in these products, edge-sharing fused aromatic systems have not generally been accessible from simple aryl halides via annulation cascades. Here we report a single-step synthesis of fused aromatics with a triphenylene core by the palladium-catalyzed annulative dimerization of structurally and functionally diverse chlorophenylenes through double carbon-hydrogen bond activation. The partially fused polyaromatics can be transformed into fully fused, small graphene nanoribbons, which are otherwise difficult to synthesize. This simple, yet powerful, method allows access to functional π-systems of interest in optoelectronics research.


Brachial and lumbar neuropathies.
Sporadic acute brachial plexus neuropathy occurs in approximately 1.64/100,000 population, but may present in epidemic form. Sporadic lumbosacral plexus neuropathy is far less common and has to be distinguished from more common disorders affecting the plexus and roots such as diabetes. Early this century, when serum therapy became popular to treat or prevent prevalent infectious diseases, it became apparent that a plexopathy could follow treatment. It has thus been assumed that many of the cases are due to an autoimmune or inflammatory lesion of the plexus. A wide variety of vaccines, infections and medications seem able to precipitate the disorder. Recent work has shown that cultured lymphocytes from affected patients, but not controls, are able to mount a blastogenic response to components of cadaver brachial plexus. This response seems to be selective not only to the brachial plexus, but also to discrete components of the plexus. The recovery rate in brachial plexus neuropathy is good, being almost 90% at 3 years. Recovery with lumbosacral disease is less satisfactory. Histological material and descriptions of acute brachial plexus neuropathy are rare. There is some evidence that an inflammatory process is present, but the role of demyelination and axonal atrophy in producing the observed clinical signs, is still uncertain. Virtually nothing is known about the histological changes in lumbosacral plexus neuropathy. Treatment is mainly supportive, but important in limiting disability. Steroids may help relieve pain in the acute stages, but do not seem to alter the prognosis.


Practical application of fundamental concepts in exercise physiology.
The collection of primary data in laboratory classes enhances undergraduate practical and critical thinking skills. The present article describes the use of a lecture program, running in parallel with a series of linked practical classes, that emphasizes classical or standard concepts in exercise physiology. The academic and practical program ran under the title of a particular year II module named Sports Performance: Physiology and Assessment, and results are presented over a 3-yr period (2004-2006), based on an undergraduate population of 31 men and 34 women. The module compared laboratory-based indexes of endurance (e.g., ventilatory threshold and exercise economy) and high-intensity exercise (e.g., anaerobic power), respectively, with measures of human performance (based on 20-m shuttle run tests). The specific experimental protocols reinforced the lecture content to improve student understanding of the physiological and metabolic responses (and later adaptations) to exercise. In the present study, the strongest relationship with endurance performance was the treadmill velocity at maximal aerobic power (r = +0.88, P < 0.01, n = 51); in contrast, the strongest relationship with high-intensity exercise performance was the mean power output (in W/kg) measured during a 30-s all-out cycle ergometer sprint (r = +0.80, P < 0.01, n = 48). In class student data analysis improved undergraduate indepth or critical thinking during seminars and enhanced computer and data presentation skills. The endurance-based laboratories are particularly useful for examining the underlying scientific principles that determine aerobic performance but could equally well be adapted to investigate other topics, e.g., differences in the exercise response between men and women.


Do psychiatric comorbidities influence inpatient death, adverse events, and discharge after lower extremity fractures?
Psychiatric comorbidity is known to contribute to illness (the state of feeling unwell/unable to rely on one's body) and increased use of healthcare resources, but the effect on inpatient outcomes in fracture care is relatively unexplored. Our primary null hypothesis is that a concomitant diagnosis of depression, anxiety, dementia, or schizophrenia is not associated with (1) discharge to another care facility rather than home after lower extremity fractures. Secondary study questions address the associations between psychiatric comorbidity and (2) longer inpatient stay and inpatient (3) adverse events; (4) blood transfusion; and (5) mortality after lower extremity fractures. Using the National Hospital Discharge Survey database, we analyzed a total estimated number of 10,669,449 patients with lower limb fractures from 1990 to 2007. Sixty-four percent were women, and the mean±SD age was 67±22 years. The prevalence in the study population was 3.2% for depression, 1.6% for anxiety, 0.6% for schizophrenia, and 2.9% for dementia. A discharge diagnosis of psychiatric comorbidity was associated with a lower rate of discharge to home after accounting for an association with greater medical comorbidity (schizophrenia: odds ratio [OR], 5.6, 95% confidence interval [CI], 5.5-5.8; dementia: OR, 1.3, 95% CI, 1.2-1.3; depression: OR, 1.2, 95% CI, 1.2-1.3; anxiety: OR, 1.04, 95% CI, 1.02-1.06). Hospital stay was longer for patients with schizophrenia and dementia but shorter in patients with depression or anxiety compared with patients without any mental disorders. Schizophrenia was associated with more in-hospital adverse events and depression and anxiety with fewer events. A diagnosis of depression was associated with blood transfusion. Psychiatric comorbidity was not associated with a higher risk of in-hospital death. Optimal inpatient management of patients with lower extremity fractures should account for the influence of psychiatric comorbidities, dementia and schizophrenia in particular.


Soft Miniaturized Actuation and Sensing Units for Dynamic Force Control of Cardiac Ablation Catheters.
Recently, there has been active research in finding robotized solutions for the treatment of atrial fibrillation (AF) by augmenting catheter systems through the integration of force sensors at the tip. However, limited research has been aimed at providing automatic force control by also integrating actuation of the catheter tip, which can significantly enhance safety in such procedures. This article solves the demanding challenge of miniaturizing both actuation and sensing for integration into flexible catheters. Fabrication strategies are presented for a series of novel soft thick-walled cylindrical actuators, with embedded sensing using eutectic gallium-indium. The functional catheter tips have a diameter in the range of 2.6-3.6 mm and can both generate and detect forces in the range of < 0.4 N, with a bandwidth of 1-2 Hz. The deformation modeling of thick-walled cylinders with fiber reinforcement is presented in the article. An experimental setup developed for static and dynamic characterization of these units is presented. The prototyped units were validated with respect to the design specifications. The preliminary force control results indicate that these units can be used in tracking and control of contact force, which has the potential to make AF procedures much safer and more accurate.


Transport, nutritional and metabolic studies of taurine in staphylococci.
A specific, Na+-dependent, energy-requiring transport system for taurine has been reported recently in the Staphylococcus aureus M strain. Taurine was taken up vigorously by all S. aureus strains tested. The system was Na+-dependent, and Na+ decreased the Km but had no effect on the Vmax of the transport system. Among coagulase-negative staphylococci, the Staphylococcus epidermidis group (a taxonomically related group of species associated with humans or other primates) and the free-living, wide-ranging species Staphylococcus sciuri showed vigorous taurine uptake. Somewhat lower rates were found in the Staphylococcus saprophyticus group. Low or barely detectable uptake rates were noted in other staphylococcal species that were primarily of animal origin. No taurine uptake was detected in a variety of other bacterial species tested. Taurine uptake, which was not Na+-dependent, occurred in a Pseudomonas aeruginosa strain grown on taurine as sole energy, carbon, nitrogen, and sulphur source, but not when it was grown in a gluconate/salts medium. In nutritional studies we were unable to demonstrate a role for taurine as a sulphur source for S. aureus. [1,2-14C]- and [35S]taurine were taken up during overnight growth of cells, and radioactivity was distributed similarly among cellular fractions, indicating that the carbon and sulphur atoms of taurine were not cleaved and had the same fate. We were unable to demonstrate any catabolism of taurine in radiorespirometric experiments to detect evolution of 14CO2 by cells incubated with [1,2-14C]taurine. Thus, we found no evidence for a role of taurine in the energy, carbon and sulphur metabolism of S. aureus.


Morbidity management and surveillance of lymphatic filariasis disease and acute dermatolymphangioadenitis attacks using a mobile phone-based tool by community health volunteers in Ghana.
Morbidity burden of lymphatic filariasis (LF) relies on the information from the Mass Drug Administration (MDA) programme where Community Health Volunteers (CHVs) passively report cases identified. Consequently, the exact prevalence of morbidity cases is not always accurate. The use of mobile phone technology to report morbidity cases was piloted in Ghana using a text-based short messaging service (SMS) tool by CHVs. Though successful, illiterate CHVs could not effectively use the SMS tool. The aim of this study was to evaluate the use of a mobile phone-based Interactive Voice Response System (mIVRS) by CHVs in reporting LF morbidity cases and acute dermatolymphangioadenitis (ADLA) attacks in Ghana. The mIVRS was designed as a surveillance tool to capture LF data in Kassena Nankana Districts of Ghana. One hundred CHVs were trained to identify and report lymphedema and hydrocele cases as well as ADLA attacks by calling a hotline linked to the mIVRS. The system asked a series of questions about the disease condition. The ability of the CHV to report accurately was assessed and the data from the mIVRS were compared with the paper records from the CHVs and existing MDA programme records from the same communities and period. Higher numbers of lymphedema and hydrocele cases were recorded by the CHVs using the mIVRS (n = 590 and n = 103) compared to the paper-based reporting (n = 417 and n = 76) and the MDA records (n = 154 and n = 84). Female CHVs, CHVs above 40 years, and CHVs with higher educational levels were better at paper-based reporting (P = 0.007, P = 0.001, P = 0.049 respectively). The system, when fully developed and linked to national databases, may help to overcome underreporting of morbidity cases and ADLA attacks in endemic communities. The system has the potential to be further expanded to other diseases.


Characterizing the Burden of Occupational Chemical Exposures by Sociodemographic Groups in the United States, 2021.
Objectives. To estimate the number and prevalence of workers in the United States exposed to chemical hazards available in the Canadian job-exposure matrix (CANJEM) database and examine exposure disparities across sociodemographic groups. Methods. We merged US worker demographic data from the Current Population Survey with CANJEM to characterize the burden and sociodemographic distribution of 244 chemical exposures in the United States in 2021. An interactive version of the full data set is available online (https://deohs.washington.edu/us-exposure-burden). Results. Of the chemical exposures examined, the most prevalent were cleaning and antimicrobial agents (14.7% of workforce estimated exposed), engine emissions (12.8%), organic solvents (12.1%), polycyclic aromatic hydrocarbons (10.1%), and diesel engine emissions (8.3%). Racial and ethnic minoritized groups, persons with lower educational attainment, foreign-born noncitizens, and males were generally overrepresented in exposure to work-related chemical hazards. Conclusions. In the United States, marginalized sociodemographic groups are estimated to experience an inequitable burden to many chemical exposures because of occupational segregation. Data from this analysis can inform occupational and public health research, policy, and interventions aimed at reducing the burden of disease and health inequities in the United States. (Am J Public Health. 2024;114(1):57-67. https://doi.org/10.2105/AJPH.2023.307461).


Coital frequency and condom use in monogamous and concurrent sexual relationships in Cape Town, South Africa.
A decreased frequency of unprotected sex during episodes of concurrent relationships may dramatically reduce the role of concurrency in accelerating the spread of HIV. Such a decrease could be the result of coital dilution - the reduction in per-partner coital frequency from additional partners - and/or increased condom use during concurrency. To study the effect of concurrency on the frequency of unprotected sex, we examined sexual behaviour data from three communities with high HIV prevalence around Cape Town, South Africa. We conducted a cross-sectional survey from June 2011 to February 2012 using audio computer-assisted self-interviewing to reconstruct one-year sexual histories, with a focus on coital frequency and condom use. Participants were randomly sampled from a previous TB and HIV prevalence survey. Mixed effects logistic and Poisson regression models were fitted to data from 527 sexually active adults reporting on 1210 relationship episodes to evaluate the effect of concurrency status on consistent condom use and coital frequency. The median of the per-partner weekly average coital frequency was 2 (IQR: 1-3), and consistent condom use was reported for 36% of the relationship episodes. Neither per-partner coital frequency nor consistent condom use changed significantly during episodes of concurrency (aIRR=1.05; 95% confidence interval (CI): 0.99-1.24 and aOR=1.01; 95% CI: 0.38-2.68, respectively). Being male, coloured, having a tertiary education, and having a relationship between 2 weeks and 9 months were associated with higher coital frequencies. Being coloured, and having a relationship lasting for more than 9 months, was associated with inconsistent condom use. We found no evidence for coital dilution or for increased condom use during concurrent relationship episodes in three communities around Cape Town with high HIV prevalence. Given the low levels of self-reported consistent condom use, our findings suggest that if the frequency of unprotected sex with each of the sexual partners is sustained during concurrent relationships, HIV-positive individuals with concurrent partners may disproportionately contribute to onward HIV transmission.


Use and role of monoclonal antibodies and other biologics in preventive cardiology.
Biotechnological advances now enable the design of fully human antibodies to target specific antigens in a growing number of diseases. Monoclonal antibodies (mAbs) differ from traditional small chemical molecules in several ways: (1) biological production ‒ they are grown in and extracted from cell cultures; (2) specificity ‒ they demonstrate high target specificity, with a low risk of drug-drug interactions; (3) administration ‒ they are delivered parenterally (intravenously or subcutaneously); (4) dosage interval ‒ their extended half-lives generally allow for spaced dosing (from weekly to monthly). In cardiology, fully human mAbs directed against proprotein convertase subtilisin / kexin type 9 (PCSK9) have shown to be effective in reducing low-density lipoprotein cholesterol (LDL-C) in phase II clinical trials among patients with familial hypercholesterolaemia (FH). PCSK9 inhibitors have just received approval for the treatment of FH and clinical atherosclerotic disease, and patients not at target under maximally tolerated statin therapy or intolerant to statins. Large-scale phase III trials are currently assessing the role of PCSK9 inhibitors in the secondary prevention setting for patients with acute coronary syndromes (ACS) and poorly controlled LDL-C under evidence-based therapies. Another area currently under investigation for fully human mAbs in secondary prevention is their potential ability to inhibit inflammatory pathways. In this context, canakinumab, a specific mAb inhibiting interleukin-1β (IL-1β), has already received approval for the treatment of systemic juvenile idiopathic arthritis. The canakinumab anti-inflammatory thrombosis outcomes trial (CANTOS) is an ongoing trial assessing whether inhibition of IL-1β could reduce the occurrence of cardiovascular adverse events in 17,200 patients with ACS and with defined persisting inflammation.


Latissimus Dorsi Flap in the Treatment of Thoracic Wall Defects After Medial Sternotomy.
Background: This study aimed to describe the subjective and objective results of the latissimus dorsi muscle flap and propose it as a reconstructive option for postoperative thoracic defects. Methods: A systematic search for cases with pedicle-based latissimus dorsi flaps performed after medial sternotomy was conducted, and all cases occurred between 2010 and August 2017. Preoperative, intraoperative, and postoperative factors were retrospectively analyzed and then the correlations between prognostic factors and outcomes of flap surgery were calculated. Furthermore, an evaluation of the subjective quality of life after flap surgery was performed using questionnaires. Results: A total of 25 cases were identified (8 female and 17 male patients) with the mean age of 75.28 years (range, 55-88 years). The average survival rate was 39.63 ± 23.03 months. The proportion of patients with a survival rate of 1 year was 84.00% (21 patients), and the proportion of patients with a 2-year survival rate was 80.00% (20 patients). While 24% of all patients who had latissimus dorsi flap operations experienced no complications, 64% of them developed minor complications (non-life-threatening, Clavien-Dindo grades I-IIIb) and 12% of them developed major complications (life-threatening, Clavien-Dindo grades IV-V). There was a significant correlation between the low survival rate and risk factors such as a positive history of smoking (P = .034), renal insufficiency (P = .022), metabolic syndrome (P = .004), and the presence of postoperative complications (P < .00002). No significant correlation was observed between the survival rate and obesity (P = .396), hyperlipoproteinemia (P = .684), arterial hypertonia (P = .0450), diabetes (P = .891), cardiovascular comorbidities (P = .794), the interval between sternotomy and latissimus flap surgery (P = .075), the duration of flap surgery (P = .207), sternal osteitis (P = .78), and intraoperative application of norepinephrine (P = .818). We identified metabolic syndrome (hazard ratio: 6.27), renal insufficiency (hazard ratio: 3.935), and the presence of postoperative complications (hazard ratio: 2.965) as high-risk prognostic factors. The subjective evaluations revealed positive reports from the patients with an average score of 1.86 ± 1.03 (1.0 = very good; 5.0 = poor). Conclusions: The majority of the patients with defects after median sternotomy were treated successfully with the latissimus dorsi flap. High survival rates, low rates of severe complications, and subjective scoring of improved life quality make this procedure relative safe and reliable. However, some prognostic risk factors limit the outcome, so these factors should be considered during surgical planning.


Three-dimensional transperineal sonographic characteristics of the anal sphincter complex in nulliparous women.
To explore the morphological characteristics and normal biometry of the anal sphincter complex in nulliparous Chinese women using three-dimensional (3D) transperineal ultrasound. 3D sonographic data from 55 nulliparous Chinese women (aged 19-38 years) who had no pelvic organ prolapse and no symptoms of pelvic floor dysfunction were retrieved from an image dataset and analyzed by offline post-processing. The morphological characteristics of the external and internal anal sphincters, puborectalis muscle and perineal body were assessed in the sagittal, coronal and axial views. The external anal sphincter had three sonographic components: the circular main body, a subcutaneous part and an extension portion. It was significantly thinner at 12 o'clock than at the 3, 6 and 9 o'clock positions. The internal anal sphincter was seen as dark echolucent strips of equal thickness. In the mid-sagittal view, it started from the anal verge and ended at the anorectal junction. The perineal body was an ovoid structure covering the upper margin of the external sphincter, while the puborectalis muscle was banana-shaped in the sagittal view and was located behind the anorectal junction, extending downward along the inferior margin of the posterior external sphincter extension. Sonographic characteristics of the anal sphincter complex did not vary with age, weight, height or body mass index. 3D transperineal ultrasound clearly demonstrates the spatial relationships of each component of the anal sphincter complex. This should allow standardized measurement of the complex for investigations of its function.


Are people living with HIV less productive at work?
Health problems may cause decreased productivity among working people. It is unclear if this also applies for people living with HIV (PLWH). This cross-sectional study compares data of PLWH of one of the main HIV treatment centres in the Netherlands (n = 298) to data of the general working population from a previously conducted study (n = 986). We investigate whether productivity at work differs between these groups. The questionnaires used in these studies contained a core of identical questions regarding productivity losses, in the form of absenteeism and presenteeism, over a four-week period and a variety of baseline characteristics, including health status measured with EQ-5D. For PLWH additional clinical data were collected from patient records. From the data, descriptive statistics were computed to characterize the samples. Pearson correlations were used to explore significant associations of productivity with baseline characteristics. A two-part model was used to evaluate both the occurrence and of size of productivity losses in working PLWH and an aggregated sample of PLWH and the general population. It was observed that, on average, total productivity losses do not differ significantly between working PWLH and the general working population, but that the occurrence and size of absenteeism and presenteeism were different. Furthermore, more health problems were associated with higher productivity losses. HIV status was not significantly associated with productivity losses. We conclude that among working people, health status was related to productivity losses but HIV status was not. However, further research is needed into the relation between HIV status and unemployment.


Solubilization of immune precipitates by six isolated alternative pathway proteins.
Immune precipitates were solubilized by the alternative pathway of complement assembled from isolated proteins, i.e., C3, factor B, factor D, properdin, C3b inactivator (C3bINA), and beta 1H. The kinetic curves of solubilization in the isolated system and in EGTA-serum were virtually indistinguishable. No requirement of other factors was apparent. Deletion of C3bINA and beta 1H from the complete mixture caused total consumption of C3 in the fluid phase and resulted in neither C3 binding to the complexes nor solubilization. Thus, the presence of a regulated fluid-phase reaction is essential for efficient fixation of C3 and the consequent solubilization. In addition, properdin plays an essential role in the complement-mediated solubilization in the presence of the two regulators. A large amount of C3 was incorporated into the antigen-antibody lattice. Solubilization of immune complexes started after the binding of one C3 molecule to one antibody molecule in the complexes, and the molar ratio of C3:antibody in the solubilized complexes also is approximately 1.


Direct adenovirus-mediated insulin-like growth factor I gene transfer enhances transplant chondrocyte function.
Cell-based cartilage-resurfacing procedures may be enhanced by the addition of insulin-like growth factor I (IGF-I) to the transplant biomatrix. Given the relatively short half-life of IGF-I in biological systems, however, maintenance of effective concentrations of this peptide necessitates either high initial doses, or repeated treatment. This study investigated IGF-I delivery via adenoviral gene therapy, targeting graftable articular chondrocytes. Cultured articular chondrocytes were infected with an E1-deleted adenoviral vector containing IGF-I-coding sequence under CMV promoter control. Increased adenovirus-IGF-I concentrations resulted in coordinate increase in IGF-I mRNA and ligand expression; however, chondrocyte matrix synthesis was maximized by the lower adenovirus-IGF-I concentration (100 MOI) without additional increase at 200 or 500 MOI. Using 100 MOI, infected monolayers produced medium IGF-I content of at least 10 ng/ml in each 48-hr period for 28 days, reaching a day 4 peak concentration of 66 +/- 4.0 ng/ml. These concentrations were sufficient to produce significant stimulation of normal cartilage matrix gene expression. The concentration of secreted matrix products in medium from infected monolayers was increased up to 8-fold over uninfected control cultures. Moreover, compared with uninfected cultures, cells in infected cultures were more resistant to de-differentiation over time under serum-starved conditions, maintaining a normal chondrocyte molecular phenotype for at least 28 days. These data indicate that cultured chondrocytes are readily transduced by recombinant adenoviral vectors. The adenoviral-IGF transgene is abundantly expressed and its product secreted at therapeutic concentrations for at least 28 days, resulting in increased matrix biosynthesis and maintenance of the chondrocytic phenotype. Combined, this information suggests that there may be significant value in preimplantation adenoviral-IGF gene therapy for chondrocytes destined for cartilage resurfacing.


Bicarbonate and CO2 transport across the skin of the leopard frog, Rana pipiens: effect of PGF2alpha.
The amphibian skin represents an important organ for osmoregulation and, like the mammalian kidney, maintains acid-base balance by secreting protons or base. However, the lack of a reliable and accurate method to measure the contribution of unidirectional fluxes of HCO3- ions to this mechanism has been an obstacle for the determination of the role of bicarbonate in epithelial acid-base homeostasis. Recently, one of us developed a method that allows for the reliable determination of transepithelial fluxes of bicarbonate, and this method was applied to determine unidirectional fluxes of (14)CO2 and H(14)CO3 under a variety of conditions. We report that the combined CO2 and HCO3- mucosal-to-serosal flux under 5% CO2 was 40% larger than the opposing flux, giving a net flux in the mucosal-to-serosal direction. This net flux was inhibited by acetazolamide. In CO2-free conditions, there was no detectable net flux; however, acetazolamide and PGF(2alpha) attenuated the mucosal-to-serosal flux and established an apparent secretion of HCO3-. A model is presented that depicts twelve vectors or components to the CO2 plus HCO3- fluxes in the frog skin. This model can accurately reproduce the experimental values measured from unidirectional fluxes of CO2 and HCO3- under a variety of conditions and can explain the effects of PGF(2alpha) on unidirectional 14C-labeled fluxes as a consequence of inhibition of H+ secretion to the apical bath, similar to what was previously suggested by our laboratory using a different methodological approach. The present method, utilizing radiolabeled HCO3-, may be useful as a means to evaluate the mechanism of action of hormones and drugs that may regulate acid-base homeostasis by altering proton and bicarbonate transport processes.


Activation of cyclin D1 by estradiol and spermine in MCF-7 breast cancer cells: a mechanism involving the p38 MAP kinase and phosphorylation of ATF-2.
Estradiol (E2) and the naturally occurring polyamines (putrescine, spermidine, and spermine) play important roles in breast cancer cell growth and differentiation. We examined the effects of E2 and spermine on the phosphorylation and DNA binding of activating transcription factor-2 (ATF-2) in MCF-7 breast cancer cells. ATF-2 is a transcription factor involved in estrogenic regulation of cyclin D1 gene, and thereby cell cycle progression. DNA affinity immunoblot assays showed a six- to eightfold increase in the binding of ATF-2 to a 74-mer ATF/CRE oligonucleotide (ODN1) from cyclin D1 promoter in the presence of 4 nM E2 and 0.5 mM spermine, compared to untreated control. Individual treatments with E2 or spermine caused a twofold or lower increase in ATF-2 binding to ODN1. Immunoblotting with phospho-ATF-2 antibody showed that increased DNA binding of ATF-2 was associated with its phosphorylation. A p38 MAP kinase inhibitor, PD169316, inhibited ATF-2 phosphorylation. In contrast, the MEK-ERK1/2 inhibitor, PD98059, or the JNK inhibitor, SP600125, had no significant effect on DNA binding of ATF-2. Cyclin D1 promoter (-1745CD1) activity increased by approximately 12-fold (above control) in the presence of E2 and spermine, compared to a sixfold increase in the presence of E2 alone and a twofold increase with spermine. Cells transfected with a dominant negative mutant of ATF-2 showed decreased transactivation of cyclin D1 promoter in response to E2 and spermine. These results indicate that spermine can enhance E2-induced cell signaling and cyclin D1 transcription by activation of the p38 MAP kinase and phosphorylation of ATF-2, contributing to breast cancer cell proliferation.


Estimating the child health equity potential of improved sanitation in Nepal.
Access to improved sanitation plays an important role in child health through its impact on diarrheal mortality and malnutrition. Inequities in sanitation coverage translate into health inequities across socio-economic groups. This paper presents the differential impact on child mortality and diarrheal incidence of expanding sanitation coverage across wealth quintiles in Nepal. We modeled three scale up coverage scenarios at the national level and at each of the 5 wealth quintiles for improved sanitation in Nepal in the Lives Saved Tool (LiST): equal for all quintiles, realistically pro-poor and ambitiously pro-poor. The results show that equal improvement in sanitation coverage can save a total of 226 lives (10.7% of expected diarrhea deaths), while a realistically pro-poor program can save 451 child lives (20.5%) and the ambitiously pro-poor program can save 542 lives (24.6%). Pro-poor policies for expanding sanitation coverage have the ability to reduce population level health inequalities which can translate into reduced child diarrheal mortality.


Association of bioimpedance spectroscopy-based volume estimation with postdialysis hypotension in patients receiving hemodialysis.
Clinical examination to determine the dry weight of patients on hemodialysis (HD) has been problematic, with studies showing discordance between physician assessment and objective measures of volume status.We studied the association between predialysis bioimpedance spectroscopy (BIS)-based estimates of fluid overload and postdialysis hypotension in 635 patients in the United States Renal Data System ACTIVE/ADIPOSE (A Cohort study To Investigate the Value of Exercise/Analyses Designed to Investigate the Paradox of Obesity and Survival in ESRD) study receiving HD in 2009-2011. We recorded predialysis and postdialysis weight and blood pressures over 3 consecutive HD sessions and performed BIS before a single session. Using a previously reported method of estimating normohydration weight, we estimated postdialysis fluid overload (FOpost ) in liters. We used logistic regression with extracellular water/total body water (ECW/TBW) or estimated FOpost as the primary predictor and 1 or more postdialysis systolic blood pressures less than 110 mmHg as the dependent variable. Models were adjusted for age, sex, race, ultrafiltration rate per kilogram of body weight, end-stage renal disease vintage, diabetes mellitus, heart failure, and albumin. Higher ECW/TBW was associated with lower odds of postdialysis hypotension (odds ratio [OR] 0.35, 95% confidence interval [CI] 0.15-0.84 per 0.1, P = 0.02). Every liter of FOpost was associated with lower adjusted odds of postdialysis hypotension (OR 0.86, 95% CI 0.79-0.95, P = 0.003). Prospective studies are needed to determine whether this application of BIS could improve current clinical efforts to minimize episodes of postdialysis hypotension without leading to volume overload.


Genetic and phenotypic determinants of blood pressure and other cardiovascular risk factors (GAPP).
The pathogenesis of elevated blood pressure and other cardiovascular risk factors in the population and their progression over time is still incompletely understood, especially in young and healthy adults. The genetic and phenotypic determinants of blood pressure and other cardiovascular risk factors (GAPP) study is a population-based prospective cohort study involving a representative sample of healthy adults aged 25-41 years in the Principality of Liechtenstein. Exclusion criteria are any cardiovascular disease, diabetes, obstructive sleep apnoea syndrome, daily intake of nonsteroidal anti-inflammatory drugs and a body mass index >35 kg/m². Examinations include detailed assessment of personal, medical, lifestyle and nutritional factors, standardised assessment of weight, height and waist circumference, blood pressure measurement (clinic and 24-hour ambulatory monitoring), electrocardiography (12-lead and 24-hour Holter monitoring), bioimpedance analysis, blood, urinary and genetic sampling, spirometry and sleep pulse oximetry with nasal flow measurement. Baseline examination is still ongoing. Follow-up examinations are scheduled every 3-5 years. Since June 2010, 1,333 participants have been enrolled. Mean age of the participants was 36.7 ± 4.9 years and 47.5% of all participants were male. Mean body mass index was 26.1 ± 3.1 kg/m2 in men and 23.5 ± 3.9 kg/m2 in women. The prevalence of hypertension and prediabetes was 24.7% and 32.1% in men and 6% and 23% in women respectively. Mean LDL levels were 3.34 ± 0.9 mmol/l in men and 2.75 ± 0.7 mmol/l in women. Median hsCRP was 0.9 (0.5; 1.8) mg/l with no gender differences. GAPP affords an excellent opportunity to assess genetic and phenotypic predictors of cardiovascular risk factors and their progression over time in young and healthy adults from the general population.


Ratio of Autoantibodies of Tumor Suppressor AIMP2 and Its Oncogenic Variant Is Associated with Clinical Outcome in Lung Cancer.
Aminoacyl-tRNA synthetase-interacting multi-functional protein 2 (AIMP2) works as potent tumor suppressor, while its splicing variant lacking exon 2 (AIMP2-DX2) competes with AIMP2 for binding to target proteins and compromises its anti-tumor activity. Assuming that AIMP2 and its variant AIMP2-DX2 could be released out to human sera in pathological condition, we investigated the diagnostic and prognostic usefulness of autoantibodies against AIMP2 and AIMP2-DX2 by measuring their serum levels in 80 normal and lung cancer samples that were matched in age, gender and smoking status. The area under the curve of AIMP2-DX2, AIMP2, and AIMP2-DX2/AIMP2 autoantibody ratio was low (0.416, 0.579, and 0.357, respectively), suggesting limited diagnostic value. A total of 165 lung cancer patients were classified into low and high AIMP2-DX2, AIMP2, and AIMP2-DX2/AIMP2 based on the median expression of each parameter. The high AIMP2-DX2 group was older and had larger tumors (>3 cm) than the low AIMP2-DX2 group. The high AIMP2-DX2/AIMP2 group had higher CYFRA-21 levels and significantly shorter overall survival than the low AIMP2-DX2/AIMP2 group (18.6 vs. 48.9 months, P = 0.021, Log Rank Test). Taken together, autoantibodies against AIMP2-DX2 and AIMP2 are detectable in the human blood and the increased ratio of AIMP2-DX2/AIMP2 is related to poor clinical outcome of lung cancer.


Transforming growth factor beta receptor type II inactivation induces the malignant transformation of intestinal neoplasms initiated by Apc mutation.
The transforming growth factor-beta (TGF-beta) signaling pathway is a tumor-suppressor pathway that is commonly inactivated in colon cancer. TGF-beta is a secreted ligand that mediates its effects through a transmembrane heteromeric receptor complex, which consists of type I (TGFBR1) and type II subunits (TGFBR2). Approximately 30% of colon cancers carry TGFBR2 mutations, demonstrating that it is a common target for mutational inactivation in this cancer. To assess the functional role of TGFBR2 inactivation in the multistep progression sequence of colon cancer, we generated a mouse model that recapitulates two common genetic events observed in human colon cancer by mating Apc(1638N/wt) mice with mice that are null for Tgfbr2 in the intestinal epithelium, Villin-Cre;Tgfbr2(E2flx/E2flx) mice. In this model, we observed a dramatic increase in the number of intestinal adenocarcinomas in the Apc(1638N/wt);Villin-Cre;Tgfbr2(E2flx/E2flx) mice (called Apc(1638N/wt);Tgfbr2(IEKO)) compared with those mice with intact Tgfbr2 (Apc(1638N/wt);Tgfbr2(E2flx/E2flx)). Additionally, in vitro analyses of epithelial tumor cells derived from the Apc(1638N/wt);Tgfbr2(IEKO) mice showed enhanced expression and activity of matrix metalloproteinase MMP-2 and MMP-9, as well as increased TGF-beta1 secretion in the conditioned medium. Similarly, primary tumor tissues from the Apc(1638N/wt);Tgfbr2(IEKO) mice also showed elevated amounts of TGF-beta1 as well as higher MMP-2 activity in comparison with Apc(1638N/wt);Tgfbr2(E2flx/E2flx)-derived tumors. Thus, loss of TGFBR2 in intestinal epithelial cells promotes the invasion and malignant transformation of tumors initiated by Apc mutation, providing evidence that Wnt signaling deregulation and TGF-beta signaling inactivation cooperate to drive the initiation and progression, respectively, of intestinal cancers in vivo.


Zinc supplementation for the prevention of type 2 diabetes mellitus in adults with insulin resistance.
Diabetes is associated with long-term damage, dysfunction and failure of various organs, especially the eyes, kidneys, nerves, heart and blood vessels. The risk of developing type 2 diabetes increases with age, obesity and lack of physical activity. Insulin resistance is a fundamental aspect of the aetiology of type 2 diabetes. Insulin resistance has been shown to be associated with atherosclerosis, dyslipidaemia, glucose intolerance, hyperuricaemia, hypertension and polycystic ovary syndrome. The mineral zinc plays a key role in the synthesis and action of insulin, both physiologically and in diabetes mellitus. Zinc seems to stimulate insulin action and insulin receptor tyrosine kinase activity. To assess the effects of zinc supplementation for the prevention of type 2 diabetes mellitus in adults with insulin resistance. This review is an update of a previous Cochrane systematic review published in 2007. We searched the Cochrane Library (2015, Issue 3), MEDLINE, EMBASE, LILACS and the ICTRP trial register (from inception to March 2015). There were no language restrictions. We conducted citation searches and screened reference lists of included studies. We included studies if they had a randomised or quasi-randomised design and if they investigated zinc supplementation compared with placebo or no intervention in adults with insulin resistance living in the community. Two review authors selected relevant trials, assessed risk of bias and extracted data. We included three trials with a total of 128 participants in this review. The duration of zinc supplementation ranged between four and 12 weeks. Risk of bias was unclear for most studies regarding selection bias (random sequence generation, allocation concealment) and detection bias (blinding of outcome assessment). No study reported on our key outcome measures (incidence of type 2 diabetes mellitus, adverse events, health-related quality of life, all-cause mortality, diabetic complications, socioeconomic effects). Evaluation of insulin resistance as measured by the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) showed neutral effects when comparing zinc supplementation with control (two trials; 114 participants). There were neutral effects for trials comparing zinc supplementation with placebo for total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol and triglycerides (2 studies, 70 participants). The one trial comparing zinc supplementation with exercise also showed neutral effects for total cholesterol, HDL and LDL cholesterol, and a mean difference in triglycerides of -30 mg/dL (95% confidence interval (CI) -49 to -10) in favour of zinc supplementation (53 participants). Various surrogate laboratory parameters were also analysed in the included trials. There is currently no evidence on which to base the use of zinc supplementation for the prevention of type 2 diabetes mellitus. Future trials should investigate patient-important outcome measures such as incidence of type 2 diabetes mellitus, health-related quality of life, diabetic complications, all-cause mortality and socioeconomic effects.


Nutrition and Physical Activity Strategies for Cancer Prevention in Current National Comprehensive Cancer Control Program Plans.
Obesity, diet and physical inactivity are risk factors for some cancers. Grantees of the National Comprehensive Cancer Control Program (NCCCP) in US states, tribes, and territories develop plans to coordinate funding and activities for cancer prevention and control. Including information and goals related to nutrition and physical activity (NPA) is a key opportunity for primary cancer prevention, but it is currently unclear to what extent NCCCP plans address these issues. We reviewed 69 NCCCP plans and searched for terms related to NPA. Plans were coded as (1) knowledge of NPA and cancer link; (2) goals to improve NPA behaviors; and (3) strategies to increase healthy NPA activities, environments, or systems changes. NPA content was consistently included in all cancer plans examined across all years. Only 4 (6 %) outlined only the relationship between NPA and cancer without goals or strategies. Fifty-nine plans (89 %) contained goals or strategies related to NPA, with 53 (82 %) including both. However, numbers of goals, strategies, and detail provided varied widely. All programs recognized the importance of NPA in cancer prevention. Most plans included NPA goals and strategies. Increasing the presence of NPA strategies that can be modified or adapted appropriately locally could help with more widespread implementation and measurement of NPA interventions.