An experimental test of the thermoregulatory hypothesis for the evolution of endothermy.
The thermoregulatory hypothesis proposes that endothermy in mammals and birds evolved as a thermoregulatory mechanism per se and that natural selection operated directly to increase body temperature and thermal stability through increments in resting metabolic rate. We experimentally tested this hypothesis by measuring the thermoregulatory consequences of increased metabolic rate in resting lizards (Varanus exanthematicus). A large metabolic increment was induced by feeding the animals and consequent changes in metabolic rate and body temperature were monitored. Although metabolic rate tripled at 32 degrees C and quadrupled at 35 degrees C, body temperature rose only about 0.5 degrees C. The rate of decline of body temperature in a colder environment did not decrease as metabolic rate increased. Thus, increasing the visceral metabolic rate of this ectothermic lizard established neither consequential endothermy nor homeothermy. These results are inconsistent with a thermoregulatory explanation for the evolution of endothermy.


Current Strategies of Endocrine Therapy in Elderly Patients with Breast Cancer.
Currently, the growing population of the elderly is one of biggest problems in terms of increase in geriatric diseases. Lack of data from large prospective studies on geriatric breast cancer patients often makes it difficult for clinicians to make treatments decisions for them. Because both benefit and risk of treatment should be taken into account, treatment is usually determined considering life expectancy or comorbidities in elderly patients. Treatment of breast cancer is differentiated according to histologic classifications, and hormone therapy is even adopted for patients with metastatic breast cancer if tumor tissue expresses hormone receptors. Endocrine therapy can offer great benefit to elderly patients considering its equivalent efficacy to chemotherapy with fewer toxicities if it is appropriately used. Aromatase inhibitors are usually prescribed agents in hormone therapy for elderly breast cancer patients due to their physiology after menopause. Here, endocrine therapy for elderly patients with breast cancer in neoadjuvant, adjuvant, and palliative setting is reviewed along with predictive adverse events resulting from the use of hormone agents.


Co-localization of mu opioid receptor and N-methyl-D-aspartate receptor in the trigeminal dorsal horn.
Antagonists acting at the N-methyl-D-aspartate (NMDA) receptor can block the development of tolerance to the analgesic effects of [mu ] opioid receptor (MOR) ligands, such as morphine, and can also enhance the analgesic efficacy of opioids. These findings have led to the hypothesis that interactions between NMDA receptor and MOR ligands may be due to the co-localization of these receptors on neurons in the dorsal horn. We used dual immunogold and immunoperoxidase immunocytochemistry for MOR1 and NMDAR1 to determine the degree of co-localization of these receptors in neurons of the trigeminal dorsal horn. By use of electron microscopy, we found that both receptors were primarily located in dendrites and to a lesser extent in perikarya, axons, axon terminals, and glia. With regard to the degree of co-localization in dendrites, 63% of MOR1-labeled dendrites also contained NMDAR1, whereas 61% of NMDAR1-labeled dendrites also contained MOR1. Most of the dual-labeled profiles (94%) were classified as dendrites, with the remainder being axons, axon terminals, or perikarya. These results suggest that direct interactions between MOR and NMDA receptor ligands are likely mediated through shared dendritic targets in the dorsal horn. Less frequently, we found evidence for modulation of afferents to MOR-containing neurons through presynaptic NMDA receptors.


Effects of Posidonia oceanica beach-cast on germination, growth and nutrient uptake of coastal dune plants.
Seagrass meadows play an important role in marine ecosystems. A part of seagrass production is also exported to adjacent coastal terrestrial systems, possibly influencing their functioning. In this work we experimentally analyzed the effect of Posidonia oceanica beach-cast on plant germination, growth, and nutrient uptake of two plant species (Cakile maritima and Elymus farctus) that grow on upper beaches and fore dunes along the Mediterranean coasts. We compared plants growing in simple sand (control) with those growing in a substrate enriched with P. oceanica wrack (treatment) in laboratory. P. oceanica wrack doubled the N substrate pool and kept the substrate humid. Plants growing in the treated substrate grew faster, were twice as large as those growing in the control substrate, while tissues were enriched in N and P (Cakile by the 1.3 fold in N and 2.5 fold in P; Elymus by 1.5 fold in N and 2 fold in P). Our results suggest a positive effect of seagrass litter for the enhancing of dune species, highlighting its role for the conservation of coastal dune ecosystems.


Reconstruction and finite element mesh generation of abdominal aortic aneurysms from computerized tomography angiography data with minimal user interactions.
Evaluating rupture risk of abdominal aortic aneurysms is critically important in reducing related mortality without unnecessarily increasing the rate of elective repair. According to the current clinical practice aneurysm rupture risk is (mainly) estimated from its maximum diameter and/or expansion rate; an approach motivated from statistics but known to fail often in individuals. In contrast, recent research demonstrated that patient specific biomechanical simulations can provide more reliable diagnostic parameters, however current structural model development is cumbersome and time consuming. This paper used 2D and 3D deformable models to reconstruct aneurysms from computerized tomography angiography data with minimal user interactions. In particular, formulations of frames and shells, as known from structural mechanics, were used to define deformable modes, which in turn allowed a direct mechanical interpretation of the applied set of reconstruction parameters. Likewise, a parallel finite element implementation of the models allows the segmentation of clinical cases on standard personal computers within a few minutes. The particular topology of the applied 3D deformable models supports a fast and simple hexahedral-dominated meshing of the arising generally polyhedral domain. The variability of the derived segmentations (luminal: 0.50(SD 0.19) mm; exterior 0.89(SD 0.45) mm) with respect to large variations in elastic properties of the deformable models was in the range of the differences between manual segmentations as performed by experts (luminal: 0.57(SD 0.24) mm; exterior: 0.77(SD 0.58) mm), and was particularly independent from the algorithm's initialization. The proposed interaction of deformable models and mesh generation defines finite element meshes suitable to perform accurate and efficient structural analysis of the aneurysm using mixed finite element formulations.


Burnout Is Associated with Reduced Parasympathetic Activity and Reduced HPA Axis Responsiveness, Predominantly in Males.
There is mounting evidence that burnout is a risk factor for cardiovascular disease (CVD). Stress-related dysregulation of the sympathetic and parasympathetic system and the hypothalamic pituitary adrenal (HPA) axis may explain the enhanced risk for CVD. To test this hypothesis, 55 patients (34 males and 21 females) with burnout on sickness absence and 40 healthy participants (16 males and 24 females) were exposed to a psychosocial stressor consisting of mental arithmetic and public speech. Physiological variables (i.e., blood pressure, heart rate, cardiac output, vascular resistance, cortisol, and alpha-amylase) were measured. Basal levels, reactivity, and recovery were compared between groups. In male patients, baseline systolic blood pressure was higher, whereas basal alpha-amylase and cortisol reactivity were lower than in healthy males. In female patients, a tendency for lower basal cortisol was found as compared to healthy females. Furthermore, reduced basal heart rate variability and a trend for elevated basal cardiac output were observed in both male and female patients. Burnout is characterised by dysregulation of the sympathetic and parasympathetic system and the HPA axis, which was more pronounced in males than in females. This study further supports burnout as being a risk factor for CVD through dysregulation of the sympathetic and parasympathetic system and the HPA axis.


Colombia's discharge fee program: incentives for polluters or regulators?
Colombia's discharge fee system for water effluents is often held up as a model of a well-functioning, economic incentive pollution control program in a developing country. Yet few objective evaluations of the program have appeared. Based on a variety of primary and secondary data, this paper finds that in its first 5 years, the program was beset by a number of serious problems including limited implementation in many regions, widespread noncompliance by municipal sewerage authorities, and a confused relationship between discharge fees and emissions standards. Nevertheless, in some watersheds, pollution loads dropped significantly after the program was introduced. While proponents claim the incentives that discharge fees created for polluters to cut emissions in a cost-effective manner were responsible, this paper argues that the incentives they created for regulatory authorities to improve permitting, monitoring, and enforcement were at least as important.


Towards molecular systems biology of gene transcription and regulation.
Ten years after the determination of the RNA polymerase II structure, the basic mechanism of mRNA synthesis during gene transcription is known. In the future, the initiation and regulation of transcription must be studied with a combination of structural biology, biochemistry, functional genomics, and computational methods. In this article, the efforts of our laboratory to move from an integrated structural biology of gene transcription towards molecular systems biology of gene regulation are reviewed.


Comparison of mean bone densities of three preparations of the distal portion of the equine third metacarpal bone measured by use of quantitative computed tomography.
To evaluate whether cutting equine subchondral bone to demarcate specific regions of interest (ROIs) influences the mean density for that bone as measured via quantitative computed tomography (QCT). Sample population-2 metacarpophalangeal joints from equine cadavers. The distal portion of the third metacarpal bone of each intact metacarpophalangeal joint was scanned via CT to simulate in vivo conditions. Each joint was subsequently disarticulated and dissected, and the distal portion of the dissected third metacarpal bone in air was scanned. Then, six 1-cm(2) areas representing ROIs were cut into the distal condylar surfaces to depths of approximately 1 cm, and the bone was scanned again. Three-dimensional CT models of the 3 bone preparations were generated for each third metacarpal bone on the basis of data from each set of scan images, and densities of the 6 ROIs were measured. Mean bone densities for the 6 ROIs were compared among models of intact, dissected, and cut third metacarpal bone scans. Mean bone density was significantly lower in cut bone preparations, compared with that in intact or dissected bone. Differences between mean bone densities for intact and dissected bone preparations were not significant. Cutting subchondral bone to demarcate specific ROIs prior to CT imaging significantly lowered mean bone density as measured via QCT and thus introduced substantial artifacts. These findings have direct implications on techniques for CT modeling of equine subchondral bone in the characterization of joint diseases in horses.


Discovery of a VHL and HIF1α interaction inhibitor with in vivo angiogenic activity via structure-based virtual screening.
We describe herein compound 1, which is similar to many known natural products, as an inhibitor of the VHL-HIF1α interaction via structure-based virtual screening. Compound 1 disrupts VHL-mediated HIF1α degradation, leading to significantly increased VEGF expression. To our knowledge, compound 1 is a member of only the second class of small molecule inhibitors of the VHL-HIF1α interaction.


Coenzyme Q10 in neuromuscular and neurodegenerative disorders.
Coenzyme Q10 (CoQ10, or ubiquinone) is an electron carrier of the mitochondrial respiratory chain (electron transport chain) with antioxidant properties. In view of the involvement of CoQ10 in oxidative phosphorylation and cellular antioxidant protection a deficiency in this quinone would be expected to contribute to disease pathophysiology by causing a failure in energy metabolism and antioxidant status. Indeed, a deficit in CoQ10 status has been determined in a number of neuromuscular and neurodegenerative disorders. Primary disorders of CoQ10 biosynthesis are potentially treatable conditions and therefore a high degree of clinical awareness about this condition is essential. A secondary loss of CoQ10 status following HMG-Coa reductase inhibitor (statins) treatment has be implicated in the pathophysiology of the myotoxicity associated with this pharmacotherapy. CoQ10 and its analogue, idebenone, have been widely used in the treatment of neurodegenerative and neuromuscular disorders. These compounds could potentially play a role in the treatment of mitochondrial disorders, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, Friedreich's ataxia, and other conditions which have been linked to mitochondrial dysfunction. This article reviews the physiological roles of CoQ10, as well as the rationale and the role in clinical practice of CoQ10 supplementation in different neurological and muscular diseases, from primary CoQ10 deficiency to neurodegenerative disorders. We also briefly report a case of the myopathic form of CoQ10 deficiency.


Fertility after bilateral cryptorchidism. Evaluation by paternity, hormone, and semen data.
Evaluation of the fertility of a cohort of formerly bilaterally cryptorchid men in comparison with a group of formerly unilaterally cryptorchid men, and a group of control men. Using a detailed questionnaire concerning paternity and factors related to paternity, a cohort of formerly bilateral cryptorchid men were studied and compared with men who had undergone orchiopexy for unilateral cryptorchidism, and a group of control men. All study subjects had had surgery at the Children's Hospital of Pittsburgh, Pittsburgh, Pa., between 1955 and 1975. A subset of the full cohort underwent clinical evaluation that included a physical examination, serum hormonal determination and semen analyses. Paternity rates are significantly lower among the formerly bilaterally cryptorchid men who have attempted to father a child (65.3%) as compared to the formerly unilaterally cryptorchid (89.7%; p < 0.001) and control men (93.2%; p < 0.001). Differences in the ability to father children are also apparent when semen and hormone levels are compared between the three groups. The bilateral group has significantly lower sperm density and inhibin B levels, and higher FSH and LH levels, than the unilateral and control groups. Men born with bilateral cryptorchidism have severely compromised fertility in adulthood. This reduction in fertility is clearly shown in comparisons of both paternity rates, and in semen and hormone analyses, between the formerly bilateral, formerly unilateral, and control groups.


Risk factors for type 2 diabetes mellitus: An exposure-wide umbrella review of meta-analyses.
Type 2 diabetes mellitus (T2DM) is a global epidemic associated with increased health expenditure, and low quality of life. Many non-genetic risk factors have been suggested, but their overall epidemiological credibility has not been assessed. We searched PubMed to capture all meta-analyses and Mendelian randomization studies for risk factors of T2DM. For each association, we estimated the summary effect size, its 95% confidence and prediction interval, and the I2 metric. We examined the presence of small-study effects and excess significance bias. We assessed the epidemiological credibility through a set of predefined criteria. We captured 86 eligible papers (142 associations) covering a wide range of biomarkers, medical conditions, and dietary, lifestyle, environmental and psychosocial factors. Adiposity, low hip circumference, serum biomarkers (increased level of alanine aminotransferase, gamma-glutamyl transferase, uric acid and C-reactive protein, and decreased level of adiponectin and vitamin D), an unhealthy dietary pattern (increased consumption of processed meat and sugar-sweetened beverages, decreased intake of whole grains, coffee and heme iron, and low adherence to a healthy dietary pattern), low level of education and conscientiousness, decreased physical activity, high sedentary time and duration of television watching, low alcohol drinking, smoking, air pollution, and some medical conditions (high systolic blood pressure, late menarche age, gestational diabetes, metabolic syndrome, preterm birth) presented robust evidence for increased risk of T2DM. A healthy lifestyle pattern could lead to decreased risk for T2DM. Future randomized clinical trials should focus on identifying efficient strategies to modify harmful daily habits and predisposing dietary patterns.


Validity and reliability of sincerity test for dynamic trunk motions.
Marras et al. developed a technique to evaluate sincerity of effort during dynamic trunk motion performance. The validity and reliability of the technique have not been evaluated. Therefore, the objective of this study was to first determine whether or not a sincerity of effort measure correctly identified those giving a sincere effort in a blinded randomized control trial and second to quantify inter-rater and test-retest reliability. This article reports the findings of a two phase study. In phase one, the blinded evaluation, participants were randomly assigned to either a sincere or insincere performance condition. An examiner tested participants without knowledge of the participant's group membership. In the second phase, two examiners evaluated each participant twice to quantify inter-rater and test-retest reliability. In the blinded phase the specificity was 100% and sensitivity was 90% for identifying sincere and insincere effort, respectively. Phase two results showed no significant difference in probability of sincere effort between raters or between testing sessions. A performance criterion that accurately identifies sincere vs insincere group membership during functional evaluations was identified. There were no significant differences between raters or between testing sessions. These findings indicate that this test is reliable and possesses good predictive validity in assessing sincerity of effort.


Computational modeling of the effects of auditory nerve dysmyelination.
Our previous study showed that exposure to loud sound leading to hearing loss elongated the auditory nerve (AN) nodes of Ranvier and triggered notable morphological changes at paranodes and juxtaparanodes. Here we used computational modeling to examine how theoretical redistribution of voltage gated Na(+), Kv3.1, and Kv1.1 channels along the AN may be responsible for the alterations of conduction property following acoustic over-exposure. Our modeling study infers that changes related to Na(+) channel density (rather than the redistribution of voltage gated Na(+), Kv3.1, and Kv1.1 channels) is the likely cause of the decreased conduction velocity and the conduction block observed after acoustic overexposure (AOE).


Equity improvements in maternal and newborn care indicators: results from the Bardiya district of Nepal.
Community-based maternal and newborn care interventions have been shown to improve neonatal survival and other key health indicators. It is important to evaluate whether the improvement in health indicators is accompanied by a parallel increase in the equitable distribution of the intervention activities, and the uptake of healthy newborn care practices. We present an analysis of equity improvements after the implementation of a Community Based Newborn Care Package (CB-NCP) in the Bardiya district of Nepal. The package was implemented alongside other programs that were already in place within the district. We present changes in concentration indices (CIndices) as measures of changes in equity, as well as percentage changes in coverage, between baseline and endline. The CIndices were derived from wealth scores that were based on household assets, and they were compared usingt-tests. We observed statistically significant improvements in equity for facility delivery [CIndex: -0.15 (-0.24, -0.06)], knowledge of at least three newborn danger signs [-0.026(-0.06, -0.003)], breastfeeding within 1 h [-0.05(-0.11, -0.0001)], at least one antenatal visit with a skilled provider [-0.25(-0.04, -0.01)], at least four antenatal visits from any provider [-0.15(-0.19, -0.10)] and birth preparedness [-0.09(-0.12, -0.06)]. The largest increases in practices were observed for facility delivery (50%), immediate drying (34%) and delayed bathing (29%). These results and those of similar studies are evidence that community-based interventions delivered by female community health volunteers can be instrumental in improving equity in levels of facility delivery and other newborn care behaviours. We recommend that equity be evaluated in other similar settings within Nepal in order to determine if similar results are observed.


The sensitivity and specificity of p16(INK4a) cytology vs HPV testing for detecting high-grade cervical disease in the triage of ASC-US and LSIL pap cytology results.
We analyzed the performance of p16(INK4a) immunocytochemistry on a series of 810 retrospectively collected atypical squamous cells of undetermined significance (ASC-US) and low-grade squamous intraepithelial lesion (LSIL) cases with available biopsy follow-up data, including 94 cases of cervical intraepithelial neoplasia (CIN) 2 and 128 cases of CIN 3. Human papillomavirus (HPV) testing was performed from the same residual liquid-based cytologic specimen, and results for both tests were correlated with histologic follow-up data. Sensitivity values for high-grade CIN (HGCIN) confirmed on biopsy within 6 months were 92.6% (ASC-US) and 92.2% (LSIL) for cytotechnologists' reviews of p16 cytology and 90.1% (ASC-US) and 95.7% (LSIL) for HPV testing. Sensitivity rates of initial pathologists' reviews were slightly lower, 76.4% to 80.1%, with levels comparable to cytotechnologists' results after adjudication. The specificity of p16 cytology for HGCIN detection was significantly higher than for HPV testing for cytotechnologists and pathologists: 63.2% to 71.1% (p16 cytology) vs 37.8% for HPV in ASC-US (P < .001) and 37.3% to 53.3% (p16 cytology) vs 18.5% for HPV in LSIL (P < .001). This evaluation of the diagnostic performance of p16 cytology confirms the potential of this stain for the efficient triage of ASC-US and LSIL cytologic results.


Effects of body orientation and rotation axis on pitch visual-vestibular interaction.
Spatial transformations of the vestibular-optokinetic system must account for changes in head position with respect to gravity in order to produce compensatory oculomotor responses. The purpose of this experiment was to study the influence of gravity on the vestibulo-ocular reflex (VOR) in darkness and on visual-vestibular interaction in the pitch plane in human subjects using two different comparisons: (1) Earth-horizontal axis (EHA) rotation about an upright versus a supine body orientation, and (2) Earth-horizontal versus Earth-vertical (EVA) rotation axes. Visual-vestibular responses (VVR) were evaluated by measuring the slow phase velocity of nystagmus induced during sinusoidal motion of the body in the pitch plane (at 0.2 Hz and 0.8 Hz) combined with a constant-velocity vertical optokinetic stimulation (at +/- 36 degrees/s). The results showed no significant effect on the gain or phase of the VOR in darkness or on the VVR responses at 0.8 Hz between EHA upright and EHA supine body orientations. However, there was a downward shift in the VOR bias in darkness in the supine orientation. There were systematic changes in VOR and VVR between EHA and EVA for 0.2 Hz, including a reduced modulation gain, increased phase lead, and decreased bias during EVA rotation. The same trend was also observed at 0.8 Hz, but at a lesser extent, presumably due to the effects of eccentric rotation in our EVA condition and/or to the different canal input across frequencies. The change in the bias at 0.2 Hz between rotation in darkness and rotation with an optokinetic stimulus was greater than the optokinetic responses without rotation. During EHA, changes in head position relative to gravity preserve graviceptor input to the VVR regardless of body orientation. However, the modifications in VVR gain and phase when the rotation axis is aligned with gravity indicate that this graviceptive information is important for providing compensatory eye movements during visual-vestibular interaction in the pitch plane.


Longitudinal course of posttraumatic stress disorder and posttraumatic stress disorder symptoms in a community sample of adolescents and young adults.
Few studies have focused on the natural course of posttraumatic stress disorder (PTSD) and its determinants in samples of the general population. The authors examined determinants of remission and chronicity of PTSD and associations with other disorders in a prospective community sample. The data were drawn from a prospective, longitudinal epidemiological study of adolescents and young adults (age 14-24 years) in Munich, Germany (N=2,548). The course of PTSD from baseline to follow-up 34-50 months later was studied in 125 respondents with DSM-IV PTSD or subthreshold PTSD at baseline. Although 52% of the PTSD cases remitted during the follow-up period, 48% showed no significant remission of PTSD symptoms. Respondents with a chronic course were more likely to experience new traumatic event(s) during follow-up (odds ratio=5.21, 95% confidence interval [CI]=1.95-13.92), to have higher rates of avoidant symptoms at baseline (odds ratio=10.16, 95% CI=1.73-59.51), and to report more help seeking (odds ratio=5.50, 95% CI=1.04-29.05), compared to respondents with remission. Rates of incident somatoform disorder (odds ratio=4.24, 95% CI=1.60-11.19) and other anxiety disorders (odds ratio=4.07, 95% CI=1.15-14.37) were also significantly associated with a chronic course. PTSD is often a persistent and chronic disorder. Specific symptom clusters--especially avoidant symptoms--might be associated with the course of PTSD. In addition, the occurrence of new traumatic events differentiates PTSD cases with a chronic course from those with remission.


Psychosocial interventions for self-harm in adults.
Self-harm (SH; intentional self-poisoning or self-injury regardless of degree of suicidal intent or other types of motivation) is a growing problem in most counties, often repeated, and associated with suicide. There has been a substantial increase in both the number of trials and therapeutic approaches of psychosocial interventions for SH in adults. This review therefore updates a previous Cochrane Review (last published in 2016) on the role of psychosocial interventions in the treatment of SH in adults. To assess the effects of psychosocial interventions for self-harm (SH) compared to comparison types of care (e.g. treatment-as-usual, routine psychiatric care, enhanced usual care, active comparator) for adults (aged 18 years or older) who engage in SH. We searched the Cochrane Common Mental Disorders Specialised Register, the Cochrane Library (Central Register of Controlled Trials [CENTRAL] and Cochrane Database of Systematic reviews [CDSR]), together with MEDLINE, Ovid Embase, and PsycINFO (to 4 July 2020). We included all randomised controlled trials (RCTs) comparing interventions of specific psychosocial treatments versus treatment-as-usual (TAU), routine psychiatric care, enhanced usual care (EUC), active comparator, or a combination of these, in the treatment of adults with a recent (within six months of trial entry) episode of SH resulting in presentation to hospital or clinical services. The primary outcome was the occurrence of a repeated episode of SH over a maximum follow-up period of two years. Secondary outcomes included treatment adherence, depression, hopelessness, general functioning, social functioning, suicidal ideation, and suicide. We independently selected trials, extracted data, and appraised trial quality. For binary outcomes, we calculated odds ratio (ORs) and their 95% confidence intervals (CIs). For continuous outcomes, we calculated mean differences (MDs) or standardised mean differences (SMDs) and 95% CIs. The overall quality of evidence for the primary outcome (i.e. repetition of SH at post-intervention) was appraised for each intervention using the GRADE approach. We included data from 76 trials with a total of 21,414 participants. Participants in these trials were predominately female (61.9%) with a mean age of 31.8 years (standard deviation [SD] 11.7 years). On the basis of data from four trials, individual cognitive behavioural therapy (CBT)-based psychotherapy may reduce repetition of SH as compared to TAU or another comparator by the end of the intervention (OR 0.35, 95% CI 0.12 to 1.02; N = 238; k = 4; GRADE: low certainty evidence), although there was imprecision in the effect estimate. At longer follow-up time points (e.g., 6- and 12-months) there was some evidence that individual CBT-based psychotherapy may reduce SH repetition. Whilst there may be a slightly lower rate of SH repetition for dialectical behaviour therapy (DBT) (66.0%) as compared to TAU or alternative psychotherapy (68.2%), the evidence remains uncertain as to whether DBT reduces absolute repetition of SH by the post-intervention assessment. On the basis of data from a single trial, mentalisation-based therapy (MBT) reduces repetition of SH and frequency of SH by the post-intervention assessment (OR 0.35, 95% CI 0.17 to 0.73; N = 134; k = 1; GRADE: high-certainty evidence). A group-based emotion-regulation psychotherapy may also reduce repetition of SH by the post-intervention assessment based on evidence from two trials by the same author group (OR 0.34, 95% CI 0.13 to 0.88; N = 83; k = 2; moderate-certainty evidence). There is probably little to no effect for different variants of DBT on absolute repetition of SH, including DBT group-based skills training, DBT individual skills training, or an experimental form of DBT in which participants were given significantly longer cognitive exposure to stressful events. The evidence remains uncertain as to whether provision of information and support, based on the Suicide Trends in At-Risk Territories (START) and the SUicide-PREvention Multisite Intervention Study on Suicidal behaviors (SUPRE-MISS) models, have any effect on repetition of SH by the post-intervention assessment. There was no evidence of a difference for psychodynamic psychotherapy, case management, general practitioner (GP) management, remote contact interventions, and other multimodal interventions, or a variety of brief emergency department-based interventions. Overall, there were significant methodological limitations across the trials included in this review. Given the moderate or very low quality of the available evidence, there is only uncertain evidence regarding a number of psychosocial interventions for adults who engage in SH. Psychosocial therapy based on CBT approaches may result in fewer individuals repeating SH at longer follow-up time points, although no such effect was found at the post-intervention assessment and the quality of evidence, according to the GRADE criteria, was low. Given findings in single trials, or trials by the same author group, both MBT and group-based emotion regulation therapy should be further developed and evaluated in adults. DBT may also lead to a reduction in frequency of SH. Other interventions were mostly evaluated in single trials of moderate to very low quality such that the evidence relating to the use of these interventions is inconclusive at present.


Two-sided ubiquitin binding of NF-κB essential modulator (NEMO) zinc finger unveiled by a mutation associated with anhidrotic ectodermal dysplasia with immunodeficiency syndrome.
Hypomorphic mutations in the X-linked human NEMO gene result in various forms of anhidrotic ectodermal dysplasia with immunodeficiency. NEMO function is mediated by two distal ubiquitin binding domains located in the regulatory C-terminal domain of the protein: the coiled-coil 2-leucine zipper (CC2-LZ) domain and the zinc finger (ZF) domain. Here, we investigated the effect of the D406V mutation found in the NEMO ZF of an ectodermal dysplasia with immunodeficiency patients. This point mutation does not impair the folding of NEMO ZF or mono-ubiquitin binding but is sufficient to alter NEMO function, as NEMO-deficient fibroblasts and Jurkat T lymphocytes reconstituted with full-length D406V NEMO lead to partial and strong defects in NF-κB activation, respectively. To further characterize the ubiquitin binding properties of NEMO ZF, we employed di-ubiquitin (di-Ub) chains composed of several different linkages (Lys-48, Lys-63, and linear (Met-1-linked)). We showed that the pathogenic mutation preferentially impairs the interaction with Lys-63 and Met-1-linked di-Ub, which correlates with its ubiquitin binding defect in vivo. Furthermore, sedimentation velocity and gel filtration showed that NEMO ZF, like other NEMO related-ZFs, binds mono-Ub and di-Ub with distinct stoichiometries, indicating the presence of a new Ub site within the NEMO ZF. Extensive mutagenesis was then performed on NEMO ZF and characterization of mutants allowed the proposal of a structural model of NEMO ZF in interaction with a Lys-63 di-Ub chain.


Emission enhancement of laser-induced breakdown spectroscopy by localized surface plasmon resonance for analyzing plant nutrients.
We demonstrate the monitoring of plant nutrients in leaves of Citrus unshiu and Rhododendron obtusum using low-energy (<1 mJ) laser-induced breakdown spectroscopy. The raw plant leaf was successfully ablated without desiccation before laser irradiation, by applying metallic colloidal particles to the leaf surface. The emission intensity with the metallic particles was larger than that without the particles. This result indicates an improvement of the sensitivity and the detection limit of laser-induced breakdown spectroscopy. The emission enhancement was caused by localized surface plasmon resonance and was dependent on the size and material of metallic particles.


Molecular identification of algal endosymbionts in large miliolid Foraminifera: 2. Dinofiagellates.
Large miliolid foraminifers of the subfamily Soritinae bear symbiotic dinoflagellates morphologically similar to the species of the "Symbiodinium" complex, commonly found in corals and other marine invertebrates. Soritid foraminifers are abundant in coral reefs and it has been proposed that they share their symbionts with other dinoflagellate-bearing reef dwellers. In order to test this hypothesis, we have analysed partial large subunit ribosomal DNA sequences from dinoflagellates symbionts obtained from 28 foraminiferal specimens, and compared them to the corresponding sequences of Symbiodinium-like endosymbionts from various groups of invertebrates. Phylogenetic analysis of our data shows that all soritid symbionts belong to the "Symbiodinium" species complex, within which they form seven different molecular types (Frl-Fr7). Only one of these types (Fr1) branches within a group of invertebrate symbionts, previously described as type C. The remaining six types form sister groups to coral symbionts previously designed as types B, C, and D. Our data indicate a high genetic diversity and specificity of Symbiodinium-like symbionts in soritids. Except for type C, we have found no evidence for the transmission of symbionts between foraminifers and other symbiont-bearing invertebrates from the same localities. However, exchanges must have occurred frequently between the different species of Soritinae, as suggested by the lack of host specificity and some biogeographical patterns observed in symbiont distribution. Our data suggest that members of the subfamily Soritinae acquired their symbionts at least three times during their history, each acquisition being followed by a rapid diversification and independent radiation of symbionts within the foraminiferal hosts.


Emotional imagery: assessing pleasure and arousal in the brain's reward circuitry.
Research on emotional perception and learning indicates appetitive cues engage nucleus accumbens (NAc) and medial prefrontal cortex (mPFC), whereas amygdala activity is modulated by the emotional intensity of appetitive and aversive cues. This study sought to determine patterns of functional activation and connectivity among these regions during narrative emotional imagery. Using event-related fMRI, we investigate activation of these structures when participants vividly imagine pleasant, neutral, and unpleasant scenes. Results indicate that pleasant imagery selectively activates NAc and mPFC, whereas amygdala activation was enhanced during both pleasant and unpleasant imagery. NAc and mPFC activity were each correlated with the rated pleasure of the imagined scenes, while amygdala activity was correlated with rated emotional arousal. Functional connectivity of NAc and mPFC was evident throughout imagery, regardless of hedonic content, while correlated activation of the amygdala with NAc and mPFC was specific to imagining pleasant scenes. These findings provide strong evidence that pleasurable text-driven imagery engages a core appetitive circuit, including NAc, mPFC, and the amygdala.


JOURNAL CLUB: Scatter Radiation Dose From Digital Screening Mammography Measured in a Representative Patient Population.
The purpose of this study was to quantify the amount of scatter radiation received at the skin surface overlying the thyroid gland, salivary gland, lens of the eye, sternum, and uterus during a routine screening digital mammographic examination measured in a representative patient population. The subjects were 207 women without symptoms with varied body mass indexes who underwent annual screening mammography while wearing six optically stimulated luminescence dosimeters placed at the bridge of the nose, right submandibular gland, right and left thyroid lobes, mid sternum, and 2 cm caudal to the umbilicus to assess scatter radiation dose to the skin. The average scatter radiation doses at the skin surface during digital screening mammography in the representative population of women were as follows: overlying the right lobe of the thyroid, 0.24 mGy; left lobe of the thyroid, 0.25 mGy; salivary gland, 0.2 mGy; bridge of the nose, 0.025 mGy; sternum, 0.87 mGy; and umbilicus, 0.011 mGy. The scatter radiation doses at the umbilicus and the bridge of the nose were too low to measure with statistical confidence. Scatter radiation dose increased with increasing body mass index and increasing breast compression thickness. Scatter radiation dose at the skin overlying organs of interest is a small fraction of the entrance skin dose to the breast. The low levels of scatter radiation measured do not support delaying clinically indicated mammography during early pregnancy.


Mutations in CNGA3 impair trafficking or function of cone cyclic nucleotide-gated channels, resulting in achromatopsia.
CNGA3 encodes the A-subunit of the cone photoreceptor cyclic nucleotide-gated (CNG) channel, which is a crucial component of the phototransduction cascade in cone outer segments. Mutations in the CNGA3 gene have been associated with complete and incomplete forms of achromatopsia (ACHR), a congenital, autosomal recessively inherited retinal disorder characterized by lack of color discrimination, reduced visual acuity, nystagmus, and photophobia. Here we report the identification of three novel CNGA3 missense mutations in ACHR patients: c.682G>A (p.E228 K), c.1315C>T (p.R439W), and c.1405G>A (p.A469 T), and the detailed functional analyses of these new as well as five previously reported mutations (R283Q, T291R, F547L, G557R, and E590 K), in conjunction with clinical data of patients carrying these mutations, to establish genotype-phenotype correlations. The functional characterization of mutant CNGA3 channels was performed with calcium imaging and patch clamp recordings in a heterologous HEK293 cell expression system. Results were corroborated by immunostaining and colocalization experiments of the channel protein with the plasma membrane. Several mutations evoked pronounced alterations of the apparent cGMP sensitivity of mutant channels. These functional defects were fully or partially compensated by coexpressing the mutant CNGA3 subunit with the wild-type CNGB3 subunit for channels with the mutations R439W, A469 T, F547L, and E590 K. We could show that several mutant channels with agonist dose-response relationships similar to the wild-type exhibited severely impaired membrane targeting. In addition, this study presents the positive effect of reduced cell culture temperature on surface expression and functional performance of mutant CNG channels with protein folding or trafficking defects.


Patient education program to enhance decision autonomy in multiple sclerosis relapse management: a randomized-controlled trial.
Contrary to strong recommendations for high-dose intravenous corticosteroid treatment for relapses in multiple sclerosis (MS), uncertainty remains about most aspects of relapse management. Oral corticosteroids administered by physicians or patients themselves or no corticosteroids also appear justifiable. To evaluate an education program that aims to involve patients with MS in decisions on relapse management. In three German MS centers, 150 patients with relapsing MS were randomly assigned to a single, 4-h group session or a standard information leaflet. The primary outcome measure was the proportion of relapses with oral or no corticosteroid therapy as an indicator of patient autonomy in treatment decision making. Other outcomes included perceived decision autonomy, quality of life, and disability status. In the intervention group (IG), 108/139 (78%) relapses were treated with oral or no corticosteroids compared with 101/179 (56%) in the control group; P < 0.0001. Patients' perceived autonomy of treatment decision making was significantly higher in the IG; P < 0.0001. Quality of life, disability status, and adverse events of corticosteroid therapies were comparable. The patient education program led to more autonomous decision making in patients with relapsing MS. Relevant changes in relapse management were observed.


Listening to music primes space: pianists, but not novices, simulate heard actions.
Musicians sometimes report twitching in their fingers or hands while listening to music. This anecdote could be indicative of a tendency for auditory-motor co-representation in musicians. Here, we describe two studies showing that pianists (Experiment 1), but not novices (Experiment 2) automatically generate spatial representations that correspond to learned musical actions while listening to music. Participants made one-handed movements to the left or right from a central location in response to visual stimuli while listening to task-irrelevant auditory stimuli, which were scales played on a piano. These task-irrelevant scales were either ascending (compatible with rightward movements) or descending (compatible with leftward movements). Pianists were faster to respond when the scale direction was compatible with the direction of response movement, whereas novices' movements were unaffected by the scale. These results are in agreement with existing research on action-effect coupling in musicians, which draw heavily on common coding theory. In addition, these results show how intricate auditory stimuli (ascending or descending scales) evoke coarse, domain-general spatial representations.


Structural and Functional Characterization of the Bacterial Type III Secretion Export Apparatus.
Bacterial type III protein secretion systems inject effector proteins into eukaryotic host cells in order to promote survival and colonization of Gram-negative pathogens and symbionts. Secretion across the bacterial cell envelope and injection into host cells is facilitated by a so-called injectisome. Its small hydrophobic export apparatus components SpaP and SpaR were shown to nucleate assembly of the needle complex and to form the central "cup" substructure of a Salmonella Typhimurium secretion system. However, the in vivo placement of these components in the needle complex and their function during the secretion process remained poorly defined. Here we present evidence that a SpaP pentamer forms a 15 Å wide pore and provide a detailed map of SpaP interactions with the export apparatus components SpaQ, SpaR, and SpaS. We further refine the current view of export apparatus assembly, consolidate transmembrane topology models for SpaP and SpaR, and present intimate interactions of the periplasmic domains of SpaP and SpaR with the inner rod protein PrgJ, indicating how export apparatus and needle filament are connected to create a continuous conduit for substrate translocation.


Melting down the Ice Queen: an integrative treatment of anorexia nervosa.
A 23-year-old woman with anorexia nervosa (AN) and a strong need for control was offered an integrative treatment, empowering the patient to be an active participant and advocating shared decision-making. To emphasise this, both the therapist and patient describe their views on the therapy. The integrative treatment resulted in more psychological flexibility and behavioural improvements, as is evident from an increased weight, a decreased dietary restriction and an increased valued action. The strength of this integrative treatment is based on accepting and encouraging patient's self-chosen treatment method, within healthy limits, and thereby creating a flexible, supportive and empowering therapeutic alliance. More research is needed to test the efficacy of combining complementary therapies within conventional treatments of AN.


Exposure to the BPA-Substitute Bisphenol S Causes Unique Alterations of Germline Function.
Concerns about the safety of Bisphenol A, a chemical found in plastics, receipts, food packaging and more, have led to its replacement with substitutes now found in a multitude of consumer products. However, several popular BPA-free alternatives, such as Bisphenol S, share a high degree of structural similarity with BPA, suggesting that these substitutes may disrupt similar developmental and reproductive pathways. We compared the effects of BPA and BPS on germline and reproductive functions using the genetic model system Caenorhabditis elegans. We found that, similarly to BPA, BPS caused severe reproductive defects including germline apoptosis and embryonic lethality. However, meiotic recombination, targeted gene expression, whole transcriptome and ontology analyses as well as ToxCast data mining all indicate that these effects are partly achieved via mechanisms distinct from BPAs. These findings therefore raise new concerns about the safety of BPA alternatives and the risk associated with human exposure to mixtures.


Characterization of the structural ensembles of p53 TAD2 by molecular dynamics simulations with different force fields.
Intrinsically disordered regions (IDRs) or proteins (IDPs), which play crucial biological functions in essential biological processes of life, do not have well-defined secondary or tertiary structures when isolated in solution. The highly dynamic properties and conformational heterogeneity of IDPs make them challenging to study with traditional experimental techniques. As a powerful complementary tool for experiments, all-atom molecular dynamics simulation can obtain detailed conformational information on IDPs, but the limitation of force field accuracy is a challenge for reproducing IDP conformers. Here, we compared five empirical all-atom force fields AMBER03, AMBER99SB-ILDN, CHARMM27, OPLS-AA/L and CHARMM36m in modeling the conformational ensembles of wild-type peptide TAD2(41-62) from the human p53 tumor suppressor. Our results show that for the model peptide, the newest force field CHARMM36m produces more expanded coil ensemble followed by AMBER99SB-ILDN; CHARMM27 displays a predominant propensity for a helical structure; whereas OPLS-AA/L exhibits a apparent preference for a β-sheet structure and yields the most compact conformation. In the comparison of the simulated dimensions with theoretical prediction and the back-calculated chemical shifts with experimental measurements, AMBER99SB-ILDN gives a more consistent agreement than the other force fields. In addition, the region from residues 47 to 55, which commonly forms an amphipathic α-helix upon binding target proteins according to experimental observation, could form a helical structure with a different probability population in our simulations with different force fields. This implies that the binding process might be conducted by, or partly by "conformation selection" for this peptide. This work indicates that force field development for modeling general IDPs accurately has a long way to go, and more detailed experimental data of IDPs are also in demand.


In vitro inhibition of endothelial cell growth by the antiangiogenic drug AGM-1470 (TNP-470) and the anti-endoglin antibody TEC-11.
Angiogenesis plays a key role in tumor growth, progression and metastasis. The modulation of angiogenesis represents a potentially useful target for novel forms of anticancer therapy. Two such modulators are AGM-1470 (TNP-470, angioinhibin), which is a synthetic analog of the antibiotic fumagallin, and the monoclonal antibody TEC-11 to endoglin. We investigated the mechanisms of action of these modulators on human microvascular and macrovascular endothelial cells and on the transformed endothelial cell line ECV-304 in vitro. The administration of AGM-1470 or TEC-11 resulted in a significant inhibition of cell proliferation in all cell types used; this effect was reversible upon removal of these compounds from the culture medium. Furthermore, biochemical and morphological analyses showed that neither AGM-1470 or TEC-11 induce apoptosis. Both AGM-1470 and TEC-11 inhibited the production of urokinase-type plasminogen activator (u-PA), an enzyme involved in the early steps of neovascularization. Finally, the incubation of endothelial cells with both AGM-1470 and TEC-11 did not produce an additive effect on growth cell inhibition, apoptosis or u-PA production. Since both AGM 1470 and TEC-11 inhibit crucial events such as endothelial cell growth and protease production, our results provide a basis for their therapeutic use as angiostatic molecules in cancer.


Complications following internal fixation of unstable distal radius fracture with a palmar locking-plate.
The increasing number of fixed-angle plate systems used to treat distal radius fractures carries with it the problem of determining the optimal fixation for unstable fractures. Our goal was to analyze the clinical and radiological outcomes of patients with displaced, unstable distal radius fractures treated with a palmar fixed-angle plate. Prospective protocol; multicenter clinical study; retrospective analysis. Level 1 university trauma centers. Over a mean 15-month period (range, 12 to 27 months), 141 consecutive patients were treated for an unstable dorsally displaced distal radius fracture of which 114 or 81% were followed for 1 year or longer. Open reduction and palmar internal fixation with a fixed-angle plate (2.4 mm LCP Distal Radius Plates; Synthes, Salzburg, Austria). Indication for surgical treatment was the inability to obtain or maintain fracture or articular alignment after initial closed reduction. In a follow-up period, which had to be longer than 12 months, objective and subjective functional results (active range of motion; strength; Disabilities of the Arm, Shoulder, and Hand (DASH) score; visual analog scale (VAS); Green and O'Brien Score) and radiographic assessment (palmar tilt, radial inclination, ulnar variance, fracture union) were assessed. Potentials for complications were given special attention. In the 114 patients followed for a minimum of 12 months, there were 21 men and 93 women with a mean age of 57 years (17 to 79 years). Fractures were classified according to the AO/ASIF classification system as type A2 (n = 39), A3 (n = 16), C1 (n = 24), C2 (n = 30), or C3 (n = 5). The modified Green and O'Brien Score revealed 31 excellent, 54 good, 23 fair, and 6 poor results. Active wrist motion averaged 54 degrees extension (82% as compared with the uninjured side) and 46 degrees flexion (72% as compared with the uninjured side). The average pronation was 81 degrees (95% as compared with the uninjured side), and the average supination was 82 degrees (95% as compared with the uninjured side). Mean grip strength at final follow-up was 70% of the uninjured side. Low residual pain values in the wrist were demonstrated: 81 patients (71%) were pain free, 17 patients (15%) had mild pain, 10 patients (9%) had moderate pain, and 6 patients (5%) had severe pain. The DASH score averaged 13 points (range, 0 to 39 points). Fracture union was achieved in all patients. A mean loss of palmar tilt of 3.4 degrees (range, 0 to 8 degrees), radial inclination of 0.4 degrees (range 0 to 2 degrees), and of the ulnar variance of 1.2 mm (range, 0 to 6 mm) was measured. The overall complication rate was 27% (31/114). The most frequent problems were flexor and extensor tendon irritation (57% of the total number of complications), including 2 ruptures of the flexor pollicis longus tendon, 2 ruptures of the extensor pollicis longus tendon, 4 cases of extensor tendon tenosynovitis, and 9 cases of flexor tendon tenosynovitis. Carpal tunnel syndrome was observed in 3 patients, and complex regional pain syndrome occurred in 5 patients. In 2 cases, loosening of a single screw was seen. Delayed fracture union occurred in 3 patients, and intraoperative intraarticular screw displacement was recognized in 1 patient. Neither clinical outcome nor complication rate were dependent on fracture type (intraarticular versus extraarticular). Fixation of unstable dorsally displaced distal radius fractures with a fixed angle plate provides sufficient stability with minimal loss of reduction. Nevertheless, very distal palmar plate position can interfere with the flexor tendon system, too long screws can penetrate the extensor compartments, and distal screws in comminuted fracture patterns can cut through the subchondral bone and penetrate into the radiocarpal joint. Mindful of these problems, we consider that the complex fracture pattern of an unstable distal radius fracture cannot be treated by a single plate system and approach.


Surgical treatment of rectourethral fistulae.
9 male patients with rectourethral fistula were treated. Fistulae were congenital in 1 case, iatrogenic in 6 cases and traumatic in 2 cases. In 8 cases we used an abdominoperineal approach with omentoplasty or peritoneal flap; in 1 case a perineal approach was made. In 2 cases it was also necessary to use a transpubic approach to the posterior urethra. Good results were obtained in all cases. The importance of a proper radiological investigation of the fistulous tract and the use of omentoplasty are both emphasized.


Multiple Membrane Transporters and Some Immune Regulatory Genes are Major Genetic Factors to Gout.
Gout is a common form of inflammatory arthritis caused by hyperuricemia and the deposition of Monosodium Urate (MSU) crystals. It is also considered as a complex disorder in which multiple genetic factors have been identified in association with its susceptibility and/or clinical outcomes. Major genes that were associated with gout include URAT1, GLUT9, OAT4, NPT1 (SLC17A1), NPT4 (SLC17A3), NPT5 (SLC17A4), MCT9, ABCG2, ABCC4, KCNQ1, PDZK1, NIPAL1, IL1β, IL-8, IL-12B, IL-23R, TNFA, MCP-1/CCL2, NLRP3, PPARGC1B, TLR4, CD14, CARD8, P2X7R, EGF, A1CF, HNF4G and TRIM46, LRP2, GKRP, ADRB3, ADH1B, ALDH2, COMT, MAOA, PRKG2, WDR1, ALPK1, CARMIL (LRRC16A), RFX3, BCAS3, CNIH-2, FAM35A and MYL2-CUX2. The proteins encoded by these genes mainly function in urate transport, inflammation, innate immunity and metabolism. Understanding the functions of gout-associated genes will provide important insights into future studies to explore the pathogenesis of gout, as well as to develop targeted therapies for gout.


'Witch's milk'. Galactorrhea in the newborn.
For a five month period, infants examined on admission and discharge from the newborn nursery and at two-week and two-month well-baby visits were examined for breast nodule size and the presence of galactorrhea. Nine hundred eighty-four examinations were performed on 640 children. Forty-five examinations (4.6%) on 38 infants revealed galactorrhea. "Witch's milk" was noted at all ages studied, including 1.8% of examinations at 2 months of age. All the infants with galactorrhea were born at term, with neither sex predominating. Children with galactorrhea had breast nodules significantly larger than those of children without galactorrhea. None of these infants was hypothyroid. This study concludes that witch's milk is a common occurrence, associated with larger than average breast nodules, and may persist until 2 months of age in normal newborns.


Protection of Hippocampal CA1 Neurons Against Ischemia/Reperfusion Injury by Exercise Preconditioning via Modulation of Bax/Bcl-2 Ratio and Prevention of Caspase-3 Activation.
Ischemia leads to loss of neurons by apoptosis in specific brain regions, especially in the hippocampus. The purpose of this study was investigating the effects of exercise preconditioning on expression of Bax, Bcl-2, and caspase-3 proteins in hippocampal CA1 neurons after induction of cerebral ischemia. Male rats weighing 260-300 g were randomly allocated into three groups (sham, exercise, and ischemia). The rats in exercise group were trained to run on a treadmill 5 days a week for 4 weeks. Ischemia was induced by the occlusion of both common carotid arteries (CCAs) for 20 min. Levels of expression of Bax, Bcl-2, and caspase-3 proteins in CA1 area of hippocampus were determined by immunohistochemical staining . The number of active caspase-3-positive neurons in CA1 area were significantly increased in ischemia group, compared to sham-operated group (P<0.001), and exercise preconditioning significantly reduced the ischemia/reperfusion-induced caspase-3 activation, compared to the ischemia group (P<0.05). Also, results indicated a significant increase in Bax/Bcl-2 ratio in ischemia group, compared to sham-operated group (P<0.001). This study indicated that exercise has a neuroprotective effects against cerebral ischemia when used as preconditioning stimuli.


Glutamate uptake disguises neurotoxic potency of glutamate agonists in cerebral cortex in dissociated cell culture.
The pharmacological properties of glutamate agonists were compared in astrocyte-rich and astrocyte-poor cultures derived from embryonic rat cerebral cortex. The object of this investigation was to determine the extent to which glutamate uptake might influence the receptor-mediated neurotoxic actions of these compounds. In astrocyte-rich cultures, using 30 min exposures, we observed that the potencies of the poorly transported agonists NMDA (35 microM) and D-glutamate (89 microM) were higher than that of L-glutamate (205 microM). In astrocyte-poor cultures, L-glutamate was much more potent, with an EC50 of 5 +/- 4 microM (3-12 microM), for a 30 min exposure, whereas the potencies of NMDA and D-glutamate were essentially unchanged. L- and D-aspartate were also more effective in astrocyte-poor cultures, again with EC50 values of approximately 6-10 microM, as compared with 130 and 108 microM, respectively, in astrocyte-rich cultures. In other experiments, blocking sodium-dependent glutamate uptake in astrocyte-rich cultures, by using a sodium-free medium, made glutamate as potent an agonist as in astrocyte-poor cultures. Finally, we directly assessed the glutamate uptake system in astrocyte-rich and astrocyte-poor cultures and found that uptake was reduced approximately 25-fold in the astrocyte-poor cultures. These results show that in the presence of abundant astrocytes the neurotoxic potencies of L-glutamate, L-aspartate, and D-aspartate are substantially under-estimated.


Selective trafficking of non-cell-autonomous proteins mediated by NtNCAPP1.
In plants, cell-to-cell communication is mediated by plasmodesmata and involves the trafficking of non-cell-autonomous proteins (NCAPs). A component in this pathway, Nicotiana tabacum NON-CELL-AUTONOMOUS PATHWAY PROTEIN1 (NtNCAPP1), was affinity purified and cloned. Protein overlay assays and in vivo studies showed that NtNCAPP1 is located on the endoplasmic reticulum at the cell periphery and displays specificity in its interaction with NCAPs. Deletion of the NtNCAPP1 amino-terminal transmembrane domain produced a dominant-negative mutant that blocked the trafficking of specific NCAPs. Transgenic tobacco plants expressing this mutant form of NtNCAPP1 and plants in which the NtNCAPP1 gene was silenced were compromised in their ability to regulate leaf and floral development. These results support a model in which NCAP delivery to plasmodesmata is both selective and regulated.


The B cell response is redundant and highly focused on V1V2 during early subtype C infection in a Zambian seroconverter.
High-titer autologous neutralizing antibody responses have been demonstrated during early subtype C human immunodeficiency virus type 1 (HIV-1) infection. However, characterization of this response against autologous virus at the monoclonal antibody (MAb) level has only recently begun to be elucidated. Here we describe five monoclonal antibodies derived from a subtype C-infected seroconverter and their neutralizing activities against pseudoviruses that carry envelope glycoproteins from 48 days (0 month), 2 months, and 8 months after the estimated time of infection. Sequence analysis indicated that the MAbs arose from three distinct B cell clones, and their pattern of neutralization compared to that in patient plasma suggested that they circulated between 2 and 8 months after infection. Neutralization by MAbs representative of each B cell clone was mapped to two residues: position 134 in V1 and position 189 in V2. Mutational analysis revealed cooperative effects between glycans and residues at these two positions, arguing that they contribute to a single epitope. Analysis of the cognate gp120 sequence through homology modeling places this potential epitope near the interface between the V1 and V2 loops. Additionally, the escape mutation R189S in V2, which conferred resistance against all three MAbs, had no detrimental effect on virus replication in vitro. Taken together, our data demonstrate that independent B cells repeatedly targeted a single structure in V1V2 during early infection. Despite this assault, a single amino acid change was sufficient to confer complete escape with minimal impact on replication fitness.


Experiencing new forms of genetic choice: findings from an ethnographic study of preimplantation genetic diagnosis.
Contemporary scientific and clinical knowledges and practices continue to make available new forms of genetic information, and to create new forms of reproductive choice. For example, couples at high risk of passing on a serious genetic condition to their offspring in Britain today have the opportunity to use Preimplantation Genetic Diagnosis (PGD) to select embryos that are unaffected by serious genetic disease. This information assists these couples in making reproductive choices. This article presents an analysis of patients' experiences of making the decision to undertake PGD treatment and of making reproductive choices based on genetic information. We present qualitative interview data from an ethnographic study of PGD based in two British clinics which indicate how these new forms of genetic choice are experienced by patients. Our data suggest that PGD patients make decisions about treatment in a complex way, taking multiple variables into account, and maintaining ongoing assessments of the multiple costs of engaging with PGD. Patients are aware of broader implications of their decisions, at personal, familial, and societal levels, as well as clinical ones. Based on these findings we argue that the ethical and social aspects of PGD are often as innovative as the scientific and medical aspects of this technique, and that in this sense, science cannot be described as "racing ahead" of society.


Colonic healing requires Wnt produced by epithelium as well as Tagln+ and Acta2+ stromal cells.
Although Wnt signaling is clearly important for the intestinal epithelial homeostasis, the relevance of various sources of Wnt ligands themselves remains incompletely understood. Blocking the release of Wnt in distinct stromal cell types suggests obligatory functions of several stromal cell sources and yields different observations. The physiological contribution of epithelial Wnt to tissue homeostasis remains unclear. We show here that blocking epithelial Wnts affects colonic Reg4+ epithelial cell differentiation and impairs colonic epithelial regeneration after injury in mice. Single-cell RNA analysis of intestinal stroma showed that the majority of Wnt-producing cells were contained in transgelin (Tagln+) and smooth muscle actin α2 (Acta2+) expressing populations. We genetically attenuated Wnt production from these stromal cells using Tagln-Cre and Acta2-CreER drivers, and found that blockage of Wnt release from either epithelium or Tagln+ and Acta2+ stromal cells impaired colonic epithelial healing after chemical-induced injury. Aggregated blockage of Wnt release from both epithelium and Tagln+ or Acta2+ stromal cells drastically diminished epithelial repair, increasing morbidity and mortality. These results from two uncharacterized stromal populations suggested that colonic recovery from colitis-like injury depends on multiple Wnt-producing sources.


The Marine Mammal Class II Major Histocompatibility Complex Organization.
Sirenians share with cetaceans and pinnipeds several convergent traits selected for the aquatic lifestyle. Living in water poses new challenges not only for locomotion and feeding but also for combating new pathogens, which may render the immune system one of the best tools aquatic mammals have for dealing with aquatic microbial threats. So far, only cetaceans have had their class II Major Histocompatibility Complex (MHC) organization characterized, despite the importance of MHC genes for adaptive immune responses. This study aims to characterize the organization of the marine mammal class II MHC using publicly available genomes. We located class II sequences in the genomes of one sirenian, four pinnipeds and eight cetaceans using NCBI-BLAST and reannotated the sequences using local BLAST search with exon and intron libraries. Scaffolds containing class II sequences were compared using dotplot analysis and introns were used for phylogenetic analysis. The manatee class II region shares overall synteny with other mammals, however most DR loci were translocated from the canonical location, past the extended class II region. Detailed analysis of the genomes of closely related taxa revealed that this presumed translocation is shared with all other living afrotherians. Other presumptive chromosome rearrangements in Afrotheria are the deletion of DQ loci in Afrosoricida and deletion of DP in E. telfairi. Pinnipeds share the main features of dog MHC: lack of a functional pair of DPA/DPB genes and inverted DRB locus between DQ and DO subregions. All cetaceans share the Cetartiodactyla inversion separating class II genes into two subregions: class IIa, with DR and DQ genes, and class IIb, with non-classic genes and a DRB pseudogene. These results point to three distinct and unheralded class II MHC structures in marine mammals: one canonical organization but lacking DP genes in pinnipeds; one bearing an inversion separating IIa and IIb subregions lacking DP genes found in cetaceans; and one with a translocation separating the most diverse class II gene from the MHC found in afrotherians and presumptive functional DR, DQ, and DP genes. Future functional research will reveal how these aquatic mammals cope with pathogen pressures with these divergent MHC organizations.


An electrostatic selection mechanism controls sequential kinase signaling downstream of the T cell receptor.
The sequence of events that initiates T cell signaling is dictated by the specificities and order of activation of the tyrosine kinases that signal downstream of the T cell receptor. Using a platform that combines exhaustive point-mutagenesis of peptide substrates, bacterial surface-display, cell sorting, and deep sequencing, we have defined the specificities of the first two kinases in this pathway, Lck and ZAP-70, for the T cell receptor ζ chain and the scaffold proteins LAT and SLP-76. We find that ZAP-70 selects its substrates by utilizing an electrostatic mechanism that excludes substrates with positively-charged residues and favors LAT and SLP-76 phosphosites that are surrounded by negatively-charged residues. This mechanism prevents ZAP-70 from phosphorylating its own activation loop, thereby enforcing its strict dependence on Lck for activation. The sequence features in ZAP-70, LAT, and SLP-76 that underlie electrostatic selectivity likely contribute to the specific response of T cells to foreign antigens.


Benefit-risk tradeoff preferences for chronic hand eczema treatments.
Hand eczema affects approximately 16% of the US population. The long-term prognosis is poor, and 5-7% experience severe chronic hand eczema (sCHE) that interferes with daily activities. Treatments for CHE may be ineffective or associated with adverse events (AEs) that may dissuade patients from pursuing or continuing treatment. For quantification of patient experiences and benefit-risk preferences for outcomes associated with CHE treatments, a web-based discrete choice experiment survey was administered to patients in the United States with a self-reported physician diagnosis of CHE and severe symptoms not resolved with topical agents. Respondents answered a series of treatment choice questions, each requiring evaluation of a pair of hypothetical profiles of medications for sCHE defined by efficacy and risk of several AEs. Improvement in CHE clearing of 25-50% was rated from 1.5 to 3.1 times as important as eliminating a 5% risk of permanent bone problems. The mean maximum acceptable risk of permanent vision problems in exchange for an improvement in CHE clearing of 25-50% ranged from 3.4% to 4.8%. This study demonstrated that patients with CHE rated efficacy improvements associated with treatment of sCHE as more important than eliminating the risks of specific AEs.


Global health and foreign policy.
Health has long been intertwined with the foreign policies of states. In recent years, however, global health issues have risen to the highest levels of international politics and have become accepted as legitimate issues in foreign policy. This elevated political priority is in many ways a welcome development for proponents of global health, and it has resulted in increased funding for and attention to select global health issues. However, there has been less examination of the tensions that characterize the relationship between global health and foreign policy and of the potential effects of linking global health efforts with the foreign-policy interests of states. In this paper, the authors review the relationship between global health and foreign policy by examining the roles of health across 4 major components of foreign policy: aid, trade, diplomacy, and national security. For each of these aspects of foreign policy, the authors review current and historical issues and discuss how foreign-policy interests have aided or impeded global health efforts. The increasing relevance of global health to foreign policy holds both opportunities and dangers for global efforts to improve health.


The influence of lifelong musicianship on neurophysiological measures of concurrent sound segregation.
The ability to separate concurrent sounds based on periodicity cues is critical for parsing complex auditory scenes. This ability is enhanced in young adult musicians and reduced in older adults. Here, we investigated the impact of lifelong musicianship on concurrent sound segregation and perception using scalp-recorded ERPs. Older and younger musicians and nonmusicians were presented with periodic harmonic complexes where the second harmonic could be tuned or mistuned by 1-16% of its original value. The likelihood of perceiving two simultaneous sounds increased with mistuning, and musicians, both older and younger, were more likely to detect and report hearing two sounds when the second harmonic was mistuned at or above 2%. The perception of a mistuned harmonic as a separate sound was paralleled by an object-related negativity that was larger and earlier in younger musicians compared with the other three groups. When listeners made a judgment about the harmonic stimuli, the perception of the mistuned harmonic as a separate sound was paralleled by a positive wave at about 400 msec poststimulus (P400), which was enhanced in both older and younger musicians. These findings suggest attention-dependent processing of a mistuned harmonic is enhanced in older musicians and provides further evidence that age-related decline in hearing abilities are mitigated by musical training.


Quantified Mechanical Properties of the Deltoid Muscle Using the Shear Wave Elastography: Potential Implications for Reverse Shoulder Arthroplasty.
The deltoid muscle plays a critical role in the biomechanics of shoulders undergoing reverse shoulder arthroplasty (RSA). However, both pre- and postoperative assessment of the deltoid muscle quality still remains challenging. The purposes of this study were to establish a novel methodology of shear wave elastography (SWE) to quantify the mechanical properties of the deltoid muscle, and to investigate the reliability of this technique using cadaveric shoulders for the purpose of RSA. Eight fresh-frozen cadaveric shoulders were obtained. The deltoid muscles were divided into 5 segments (A1, A2, M, P1 and P2) according to the muscle fiber orientation and SWE values were measured for each segment. Intra- and inter-observer reliability was evaluated using intraclass correlation coefficient (ICC). To measure the response of muscle tension during RSA, the humeral shaft was osteotomized and subsequently elongated by an external fixator (intact to 15 mm elongation). SWE of the deltoid muscle was measured under each stretch condition. Intra- and inter-observer reliability of SWE measurements for all regions showed 0.761-0.963 and 0.718-0.947 for ICC(2,1). Especially, SWE measurements for segments A2 and M presented satisfactory repeatability. Elongated deltoid muscles by the external fixator showed a progressive increase in passive stiffness for all muscular segments. Especially, SWE outcomes of segments A2 and M reliably showed an exponential growth upon stretching (R2 = 0.558 and 0.593). Segmental measurements using SWE could be reliably and feasibly used to quantitatively assess the mechanical properties of the deltoid muscle, especially in the anterior and middle portions. This novel technique based on the anatomical features may provide helpful information of the deltoid muscle properties during treatment of RSA.


Health trajectories across the work exit transition in the 1990s, 2000s, and 2010s: the role of working conditions and policy.
We examined health trajectories of Dutch older workers across their exit from the workforce in the 1990s, 2000s, and 2010s, testing the hypothesis that pre-post-exit health trajectories of workers with favourable and unfavourable working conditions increasingly diverged over time due to policy measures to extend working life. The Longitudinal Aging Study Amsterdam includes baseline samples in 1992/1993, 2002/2003 and 2012/2013 with two 3-year follow-up waves each. Selected respondents were aged 55 years and over who exited from a paid job within the first or second 3-year interval, up to and including the statutory retirement age (N = 522). Pre-post-exit trajectories were modelled using Generalized Estimating Equations with outcomes self-rated health and physical limitations and determinants physical demands, psychosocial demands, and psychosocial resources. Average work exit age rose from 60.7 in the 1990s to 62.9 in the 2010s. On average, self-rated health decreased somewhat over successive periods and did not show pre-post-exit change; average physical limitations increased substantially both over successive periods and from pre- to post-exit. No support is found for our hypothesis. However, regardless of work exposures, we found sharp pre-post-exit increases in physical limitations in the 2010s. Although these findings provide no support for our hypothesis of diverging health trajectories over time based on work exposure, they show that exiting at a higher age is linked to poorer pre- and post-exit health and to pre-post-exit increases in physical limitations, suggesting greater health care costs in the near future.


Rituximab Retreatment in Rheumatoid Arthritis in a Real-life Cohort: Data from the CERERRA Collaboration.
Several aspects of rituximab (RTX) retreatment in rheumatoid arthritis (RA) need to be further elucidated. The aim of this study was to describe the effect of repeated courses of RTX on disease activity and to compare 2 retreatment strategies, fixed-interval versus on-flare retreatment, in a large international, observational, collaborative study. In the first analysis, patients with RA who received at least 4 cycles with RTX were included. In the second analysis, patients who received at least 1 RTX retreatment and for whom information about the strategy for retreatment was available were identified. Two retreatment strategies (fixed-interval vs on-flare) were compared by fitting-adjusted, mixed-effects models of 28-joint Disease Activity Score (DAS28) over time for first and second retreatment. A total of 1530 patients met the eligibility criteria for the first analysis. Significant reductions of mean DAS28 between the starts of subsequent treatment cycles were observed (at start of first treatment cycle: 5.5; second: 4.3; third: 3.8; and fourth: 3.5), suggesting improved response after each additional cycle (p < 0.0001 for all pairwise comparisons). A total of 800 patients qualified for the second analysis: 616 were retreated on flare and 184 at fixed interval. For the first retreatment, the fixed-interval retreatment group yielded significantly better results than the on-flare group (estimated marginal mean DAS28 = 3.8, 95% CI 3.6-4.1 vs 4.6, 95% CI 4.5-4.7, p < 0.0001). Similar results were found for the second retreatment. Repeated treatment with RTX leads to further clinical improvement after the first course of RTX. A fixed-interval retreatment strategy seems to be more effective than on-flare retreatment.


Complex signatures of natural selection at the Duffy blood group locus.
The Duffy blood group locus (FY) has long been considered a likely target of natural selection, because of the extreme pattern of geographic differentiation of its three major alleles (FY*B, FY*A, and FY*O). In the present study, we resequenced the FY region in samples of Hausa from Cameroon (fixed for FY*O), Han Chinese (fixed for FY*A), Italians, and Pakistanis. Our goals were to characterize the signature of directional selection on FY*O in sub-Saharan Africa and to understand the extent to which natural selection has also played a role in the extreme geographic differentiation of the other derived allele at this locus, FY*A. The data from the FY region are compared with the patterns of variation observed at 10 unlinked, putatively neutral loci from the same populations, as well as with theoretical expectations from the neutral-equilibrium model. The FY region in the Hausa shows evidence of directional selection in two independent properties of the data (i.e., level of sequence variation and frequency spectrum), observations that are consistent with the FY*O mutation being the target. The Italian and Chinese FY data show patterns of variation that are very unusual, particularly with regard to frequency spectrum and linkage disequilibrium, but do not fit the predictions of any simple model of selection. These patterns may represent a more complex and previously unrecognized signature of positive selection.


Probing the dynamics of complexed local anesthetics via neutron scattering spectroscopy and DFT calculations.
Since potential changes in the dynamics and mobility of drugs upon complexation for delivery may affect their ultimate efficacy, we have investigated the dynamics of two local anesthetic molecules, bupivacaine (BVC, C18H28N2O) and ropivacaine (RVC, C17H26N2O), in both their crystalline forms and complexed with water-soluble oligosaccharide 2-hydroxypropyl-β-cyclodextrin (HP-β-CD). The study was carried out by neutron scattering spectroscopy, along with thermal analysis, and density functional theory computation. Mean square displacements suggest that RVC may be less flexible in crystalline form than BVC, but both molecules exhibit very similar dynamics when confined in HP-β-CD. The use of vibrational analysis by density functional theory (DFT) made possible the identification of molecular modes that are most affected in both molecules by insertion into HP-β-CD, namely those of the piperidine rings and methyl groups. Nonetheless, the somewhat greater structure in the vibrational spectrum at room temperature of complexed RVC than that of BVC, suggests that the effects of complexation are more severe for the latter. This unique approach to the molecular level study of encapsulated drugs should lead to deeper understanding of their mobility and the respective release dynamics.


An outbreak of pyrogenic reactions in chronic hemodialysis patients associated with hemodialyzer reuse.
In February 1992, 22 patients undergoing chronic hemodialysis at an outpatient dialysis center experienced pyrogenic reactions (PR). The PR rate was significantly greater (p < 0.001) during the epidemic (February 3-5) than the pre-epidemic period (November 1, 1992-February 1, 1992). All patients with PR used dialyzers that had been manually reprocessed either on February 1 or 3. These dialyzers contained up to 120.8 EU/ml of endotoxin in the blood compartment. The only dialyzer reprocessed before February 1 that was available for analysis was found to contain no detectable endotoxin, while dialyzers reprocessed during the epidemic period contained a median endotoxin concentration of 52.8 EU/ml. The bioburden of water used to prepare dialysate was in excess of the Association for the Advancement of Medical Instrumentation (AAMI) standard for water, < or = 200 colony forming units (CFU)/ml. Samples of treated water collected in the reuse area were within AAMI standards at the time of the investigation (February 11 and February 26), but before the investigation, water samples were assayed with a culture method that could not detect microbial concentrations below 10(3) CFU/ml. In addition, the treated water feed line to the disinfectant container may never have been disinfected. However, no samples were collected from this line during the investigation. This outbreak emphasizes the need to use water that meets the AAMI bacteriologic and endotoxin standards of < or = to 200 CFU/ml and/or 5 EU/ml, respectively, for reprocessing hemodialyzers nad to ensure that appropriate culture techniques are used for treated water dialysate.


Study protocol to investigate the effect of a lifestyle intervention on body weight, psychological health status and risk factors associated with disease recurrence in women recovering from breast cancer treatment [ISRCTN08045231].
Breast cancer survivors often encounter physiological and psychological problems related to their diagnosis and treatment that can influence long-term prognosis. The aim of this research is to investigate the effects of a lifestyle intervention on body weight and psychological well-being in women recovering from breast cancer treatment, and to determine the relationship between changes in these variables and biomarkers associated with disease recurrence and survival. Following ethical approval, a total of 100 patients will be randomly assigned to a lifestyle intervention (incorporating dietary energy restriction in conjunction with aerobic exercise training) or normal care control group. Patients randomised to the dietary and exercise intervention will be given individualised healthy eating dietary advice and written information and attend moderate intensity aerobic exercise sessions on three to five days per week for a period of 24 weeks. The aim of this strategy is to induce a steady weight loss of up to 0.5 Kg each week. In addition, the overall quality of the diet will be examined with a view to (i) reducing the dietary intake of fat to approximately 25% of the total calories, (ii) eating at least 5 portions of fruit and vegetables a day, (iii) increasing the intake of fibre and reducing refined carbohydrates, and (iv) taking moderate amounts of alcohol. Outcome measures will include body weight and body composition, psychological health status (stress and depression), cardiorespiratory fitness and quality of life. In addition, biomarkers associated with disease recurrence, including stress hormones, estrogen status, inflammatory markers and indices of innate and adaptive immune function will be monitored. This research will provide valuable information on the effectiveness of a practical, easily implemented lifestyle intervention for evoking positive effects on body weight and psychological well-being, two important factors that can influence long-term prognosis in breast cancer survivors. However, the added value of the study is that it will also evaluate the effects of the lifestyle intervention on a range of biomarkers associated with disease recurrence and survival. Considered together, the results should improve our understanding of the potential role that lifestyle-modifiable factors could play in saving or prolonging lives.


Linking Housing Policy, Housing Typology, and Residential Energy Demand in the United States.
Residential energy demand can be greatly influenced by the types of housing structures that households live in, but few studies have assessed changes in the composition of housing stocks as a strategy for reducing residential energy demand or greenhouse gas (GHG) emissions. In this paper we examine the effects of three sequenced federal policies on the share of new housing construction by type in the U.S., and estimate the cumulative influence of those policies on the composition of the 2015 housing stock. In a counterfactual 2015 housing stock without the policy effects, 14 million housing units exist as multifamily rather than single-family, equal to 14.1% of urban housing. Accompanied by floor area reductions of 0-50%, the switch from single- to multifamily housing reduces energy demand by 27-47% per household, and total urban residential energy by 4.6-8.3%. This paper is the first to link federal policies to housing outcomes by type and estimate associated effects on residential energy and GHG emissions. Removing policy barriers and disincentives to multifamily housing can unlock a large potential for reducing residential energy demand and GHG emissions in the coming decades.


Malignant mesothelioma of the tunica vaginalis.
Malignant mesothelioma involving the tunica vaginalis is an extremely rare tumor. We describe a case of a 39-year-old man who initially presented with discomfort in the left testis and underwent resection of a hydrocele in the left testis. A pathology examination of a frozen section of a lesion on the tunica identified the lesion as mesothelioma, which was confirmed by a second pathology examination. No metastatic disease was found. The patient subsequently underwent a left radical orchiectomy and a partial scrotectomy, and has been disease free for 7 years. The first case of malignant mesothelioma involving the tunica vaginalis, a structure embryologically derived from a layer of reflected peritoneum known as the "processus vaginalis," was reported in 1957. Only 73 cases were reported in the literature between 1966 and 1997. In up to 41% of cases, there is a positive history of asbestos exposure. Young age and localized disease are associated with a better prognosis. Radical orchiectomy limits recurrence, which usually occurs within 2 years, but may occur up to 15 years after surgery.


Genome-wide real-time in vivo transcriptional dynamics during Plasmodium falciparum blood-stage development.
Genome-wide analysis of transcription in the malaria parasite Plasmodium falciparum has revealed robust variation in steady-state mRNA abundance throughout the 48-h intraerythrocytic developmental cycle (IDC), suggesting that this process is highly dynamic and tightly regulated. Here, we utilize rapid 4-thiouracil (4-TU) incorporation via pyrimidine salvage to specifically label, capture, and quantify newly-synthesized RNA transcripts at every hour throughout the IDC. This high-resolution global analysis of the transcriptome captures the timing and rate of transcription for each newly synthesized mRNA in vivo, revealing active transcription throughout all IDC stages. Using a statistical model to predict the mRNA dynamics contributing to the total mRNA abundance at each timepoint, we find varying degrees of transcription and stabilization for each mRNA corresponding to developmental transitions. Finally, our results provide new insight into co-regulation of mRNAs throughout the IDC through regulatory DNA sequence motifs, thereby expanding our understanding of P. falciparum mRNA dynamics.


Citrus reticulata peel oil inhibits non-small cell lung cancer cell proliferation in culture and implanted in nude mice.
Non-small cell lung cancer (NSCLC) accounts for most cases of lung cancer. The peel oil of mandarin Citrus reticulata Blanco cv. Dancy (MPO) is a natural source of essential oils and carotenoids. Volatile and non-volatile lipid compounds were characterized by chromatographic methods. We demonstrate that MPO causes a dose-dependent growth inhibition of NSCLC model cells (A549) in culture and tumour growth in vivo of the same cells implanted in nude mice fed with MPO-supplemented diets. MPO induced cell cycle arrest mainly at the G0/G1 phase and reduced the amount of membrane-bound Ras protein along with apoptosis induction. No toxicological effect was found in liver parameters analysed in treated mice and histopathological analyses of their organs did not show any morphological changes. In conclusion, the data suggest that MPO possesses significant antitumor activity without causing systemic toxicity, proposing it as a dietary supplement that may be helpful in cancer prevention.


Modified C-7 neurotization in the treatment of brachial plexus avulsion injury.
Contralateral C-7 transfer is often used in patients with brachial plexus avulsion injury. Traditionally, the contralateral C-7 root has only been transferred to a single nerve, such as the median or radial nerve. In this study, the authors aimed to evaluate the efficacy of contralateral C-7 transfer to 2 different recipient nerves in patients with brachial plexus avulsion injuries. Between 2004 and 2008, 10 patients with brachial plexus root avulsions underwent nerve reconstruction using a modified C-7 neurotization technique. In this procedure, the contralateral C-7 root was transferred via vascularized ulnar nerve grafts to both the musculocutaneous nerve and the median nerve on the affected side. The strength of the biceps muscles increased to M3 or M4 in 6 patients and to M2 in 2 patients. The median nerve transfers led to regained motor function and strength of the wrist and finger flexors with improvement to M3 in 5 patients. Seven patients showed notable gains of sensory function (≥ S3). Contralateral C-7 transfer to 2 different recipient nerves is a feasible and efficient approach in patients with brachial plexus avulsion injuries when the donor nerve is limited.


Modelling reaction kinetics inside cells.
In the past decade, advances in molecular biology such as the development of non-invasive single molecule imaging techniques have given us a window into the intricate biochemical activities that occur inside cells. In this chapter we review four distinct theoretical and simulation frameworks: (i) non-spatial and deterministic, (ii) spatial and deterministic, (iii) non-spatial and stochastic and (iv) spatial and stochastic. Each framework can be suited to modelling and interpreting intracellular reaction kinetics. By estimating the fundamental length scales, one can roughly determine which models are best suited for the particular reaction pathway under study. We discuss differences in prediction between the four modelling methodologies. In particular we show that taking into account noise and space does not simply add quantitative predictive accuracy but may also lead to qualitatively different physiological predictions, unaccounted for by classical deterministic models.


Physicians of ancient India.
A survey of Indian medical historiography will reveal no dearth of work on the systems of medicine and medical literature of ancient India. However, the people who were responsible for the healing have not received much attention. This article traces the evolution of the physician as a professional in ancient India. This article reviews the secondary literature on healing and medical practice in India, specifically pertaining to the individual medical practitioner, drawing from varied sources. The healers of ancient India hailed from different castes and classes. They were well-respected and enjoyed state patronage. They were held to the highest ethical standards of the day and were bound by a strict code of conduct. They underwent rigorous training in both medicine and surgery. Most physicians were multi-skilled generalists, and expected to be skilled in elocution and debate. They were reasonably well-off financially. The paper also briefly traces the evolution of medicinal ideas in ancient India.


Electrode-shaping for the excitation and detection of permitted arbitrary modes in arbitrary geometries in piezoelectric resonators.
This paper reports theoretical analysis and experimental results on a numerical electrode shaping design technique that permits the excitation of arbitrary modes in arbitrary geometries for piezoelectric resonators, for those modes permitted to exist by the nonzero piezoelectric coefficients and electrode configuration. The technique directly determines optimal electrode shapes by assessing the local suitability of excitation and detection electrode placement on two-port resonators without the need for iterative numerical techniques. The technique is demonstrated in 61 different electrode designs in lead zirconate titanate (PZT) thin film on silicon RF micro electro-mechanical system (MEMS) plate, beam, ring, and disc resonators for out-of-plane flexural and various contour modes up to 200 MHz. The average squared effective electromechanical coupling factor for the designs was 0.54%, approximately equivalent to the theoretical maximum value of 0.53% for a fully electroded length-extensional mode beam resonator comprised of the same composite. The average improvement in S(21) for the electrode-shaped designs was 14.6 dB with a maximum improvement of 44.3 dB. Through this piezoelectric electrodeshaping technique, 95% of the designs showed a reduction in insertion loss.


Remyelination in multiple sclerosis: from basic science to clinical translation.
The treatment of multiple sclerosis has been transformed by the successful development of immunotherapies that efficiently reduce disease activity and related clinical relapses during the relapsing-remitting phase of the disease. However, the prevention of disability progression, which is due to axonal and neuronal damage and loss, has yet to be achieved and is therapeutically challenging, particularly during the progressive phase of the disease. One strategy to counteract neurodegeneration is to promote neuroprotection by enhancing myelin regeneration, hence restoring nerve conduction and metabolic support to the axon. Animal studies have provided targets for interventions to improve brain and spinal cord remyelination, paving the way for the translation of this research to humans. From these initial and promising forays, further problems have emerged, including questions on how best to design these clinical trials and appropriately measure the outcomes. Solving these problems will need additional work before efficacious pro-remyelination therapies will be ready for people with multiple sclerosis, but there is a real sense of hope that researchers are getting closer to a successful therapy.