The Macrophage-Specific Promoter mfap4 Allows Live, Long-Term Analysis of Macrophage Behavior during Mycobacterial Infection in Zebrafish.
Transgenic labeling of innate immune cell lineages within the larval zebrafish allows for real-time, in vivo analyses of microbial pathogenesis within a vertebrate host. To date, labeling of zebrafish macrophages has been relatively limited, with the most specific expression coming from the mpeg1 promoter. However, mpeg1 transcription at both endogenous and transgenic loci becomes attenuated in the presence of intracellular pathogens, including Salmonella typhimurium and Mycobacterium marinum. Here, we describe mfap4 as a macrophage-specific promoter capable of producing transgenic lines in which transgene expression within larval macrophages remains stable throughout several days of infection. Additionally, we have developed a novel macrophage-specific Cre transgenic line under the control of mfap4, enabling macrophage-specific expression using existing floxed transgenic lines. These tools enrich the repertoire of transgenic lines and promoters available for studying zebrafish macrophage dynamics during infection and inflammation and add flexibility to the design of future macrophage-specific transgenic lines.


Engineering brain activity patterns by neuromodulator polytherapy for treatment of disorders.
Conventional drug screens and treatments often ignore the underlying complexity of brain network dysfunctions, resulting in suboptimal outcomes. Here we ask whether we can correct abnormal functional connectivity of the entire brain by identifying and combining multiple neuromodulators that perturb connectivity in complementary ways. Our approach avoids the combinatorial complexity of screening all drug combinations. We develop a high-speed platform capable of imaging more than 15000 neurons in 50ms to map the entire brain functional connectivity in large numbers of vertebrates under many conditions. Screening a panel of drugs in a zebrafish model of human Dravet syndrome, we show that even drugs with related mechanisms of action can modulate functional connectivity in significantly different ways. By clustering connectivity fingerprints, we algorithmically select small subsets of complementary drugs and rapidly identify combinations that are significantly more effective at correcting abnormal networks and reducing spontaneous seizures than monotherapies, while minimizing behavioral side effects. Even at low concentrations, our polytherapy performs superior to individual drugs even at highest tolerated concentrations.


Temporal polyethism and worker specialization in the wasp, Vespula germanica.
Temporal polyethism is a common mechanism of worker specialization observed in social insect species with large colony sizes, Vespula wasp colonies consist of thousands of monomorphic workers, yet studies based on small cohorts of workers report that temporal polyethism is either weak or completely absent in different Vespula species. Concerned that the small sample size of these studies precluded detection of temporal polyethism, several hundred, known-age Vespula germanica (F.) (Hymenoptera: Vespidae) workers were studied. High variability was found in the sequence and diversity of tasks workers perform, suggesting that V. germanica colonies exhibit weak temporal polyethism. The most common order in which tasks were taken up was 1) nest work, 2) pulp foraging, 3) carbohydrate foraging, and 4) protein foraging. However, only 61% of the wasps performed more than two of the tasks during their lives. Thorax size had a significant negative effect on the age at first foraging, but the magnitude of the effect was small. The daily ratio of task generalists to specialists was relatively constant despite the high turnover of workers, growth of the colony, and the colony's transition from rearing worker larvae to rearing reproductives. Over the course of their lives, 43% of the workers averaged more than one kind of task performed per day. Life history traits are identified that may explain why vespines with large colonies use a generalist strategy of labor division rather than the specialist strategy observed in honey bees (Apis mellifera) and large colonies of wasps (Polybia occidentalis).


Potential Developmental and Reproductive Impacts of Triclocarban: A Scoping Review.
Triclocarban (TCC) is an antimicrobial agent used in personal care products. Although frequently studied with another antimicrobial, triclosan, it is not as well researched, and there are very few reviews of the biological activity of TCC. TCC has been shown to be a possible endocrine disruptor, acting by enhancing the activity of endogenous hormones. TCC has been banned in the US for certain applications; however, many human populations, in and outside the US, exhibit exposure to TCC. Because of the concern of the health effects of TCC, we conducted a scoping review in order to map the current body of literature on the endocrine, reproductive, and developmental effects of TCC. The aim of this scoping review was to identify possible endpoints for future systematic review and to make recommendations for future research. A search of the literature until August 2017 yielded 32 relevant studies in humans, rodents, fish, invertebrates, and in vitro. Based on the robustness of the literature in all three evidence streams (human, animal, and in vitro), we identified three endpoints for possible systematic review: estrogenic activity, androgenic activity, and offspring growth. In this review, we describe the body of evidence and make recommendations for future research.


Nab-paclitaxel after docetaxel hypersensitivity reaction: case report and literature review.
Taxanes, including paclitaxel and docetaxel, are one of the most active cytotoxic agents in breast cancer treatment including Her-2 positive subtype characterized by aggressive clinical and pathological features since the early stage. However, their use is sometimes limited by the occurrence of hypersensivity reactions (HSRs) characterized by erythematous rashes, bronchospasm, respiratory distress, hypotension, and pulmonary edema. Cross-reactions between paclitaxel and docetaxel are described in literature with a rate ranging from 49% to 90%. Abraxane (nab-paclitaxel), an albumin-bound form of paclitaxel, has a different toxicity profile from solvent-based paclitaxel and a lower rate of HSRs. Interestingly, several authors have recently reported cases of patients who developed HSRs to taxanes, principally paclitaxel, and were then safety treated with Abraxane, suggesting the absence of cross-reactivity between these drugs. Based on these considerations, we report our clinical experience and perform a literature review on this topic with the aim to investigate the cross-reactivity between nab-paclitaxel and other taxanes, in particular with docetaxel.


Effects of a topically applied 2% delta-9-tetrahydrocannabinol ophthalmic solution on intraocular pressure and aqueous humor flow rate in clinically normal dogs.
To determine the effects of topically applied 2% delta-9-tetrahydrocannabinol (THC) ophthalmic solution on aqueous humor flow rate (AHFR) and intraocular pressure (IOP) in clinically normal dogs. 21 clinically normal dogs. A randomized longitudinal crossover design was used. Following acquisition of baseline IOP (morning and evening) and AHFR (afternoon only) data, dogs were randomly assigned to 2 treatment groups and received 1 drop of either 2% THC solution or a control treatment (olive oil vehicle) to 1 randomly selected eye every 12 hours for 9 doses. The IOPs and AHFRs were reassessed after the final treatment. Following a washout period of ≥ 7 days, dogs were administered the alternate treatment in the same eye, and measurements were repeated. Mean ± SD IOPs in the morning were 15.86 ± 2.48 mm Hg at baseline, 12.54 ± 3.18 mm Hg after THC treatment, and 13.88 ± 3.28 mm Hg after control treatment. Mean ± SD IOPs in the evening were 13.69 ± 3.36 mm Hg at baseline, 11.69 ± 3.94 mm Hg after THC treatment, and 12.13 ± 2.99 mm Hg after control treatment. Mean IOPs were significantly decreased from baseline after administration of THC solution but not the control treatment. Changes in IOP varied substantially among individual dogs. Mean ± SD AHFRs were not significantly different from baseline for either treatment. Topical application of 2% THC ophthalmic solution resulted in moderate reduction of mean IOP in clinically normal dogs. Further research is needed to determine efficacy in dogs with glaucoma.


Pre-Transplant Marital Status and Hematopoietic Cell Transplantation Outcomes
Evidence about the impact of marital status before hematopoietic cell transplantation (hct) on outcomes after hct is conflicting. We identified patients 40 years of age and older within the Center for International Blood and Marrow Transplant Research registry who underwent hct between January 2008 and December 2015. Marital status before hct was declared as one of: married or living with a partner, single (never married), separated or divorced, and widowed. We performed a multivariable analysis to determine the association of marital status with outcomes after hct. We identified 10,226 allogeneic and 5714 autologous hct cases with, respectively, a median follow-up of 37 months (range: 1-102 months) and 40 months (range: 1-106 months). No association between marital status and overall survival was observed in either the allogeneic (p = 0.58) or autologous (p = 0.17) setting. However, marital status was associated with grades 2-4 acute graft-versus-host disease (gvhd), p < 0.001, and chronic gvhd, p = 0.04. The risk of grades 2-4 acute gvhd was increased in separated compared with married patients [hazard ratio (hr): 1.13; 95% confidence interval (ci): 1.03 to 1.24], and single patients had a reduced risk of grades 2-4 acute gvhd (hr: 0.87; 95% ci: 0.77 to 0.98). The risk of chronic gvhd was lower in widowed compared with married patients (hr: 0.82; 95% ci: 0.67 to 0.99). Overall survival after hct is not influenced by marital status, but associations were evident between marital status and grades 2-4 acute and chronic gvhd. To better appreciate the effects of marital status and social support, future research should consider using validated scales to measure social support and patient and caregiver reports of caregiver commitment, and to assess health-related quality of life together with health care utilization.


Pavlovian-to-instrumental transfer in alcohol dependence: a pilot study.
Pavlovian processes are thought to play an important role in the development, maintenance and relapse of alcohol dependence, possibly by influencing and usurping ongoing thought and behavior. The influence of pavlovian stimuli on ongoing behavior is paradigmatically measured by pavlovian-to-instrumental transfer (PIT) tasks. These involve multiple stages and are complex. Whether increased PIT is involved in human alcohol dependence is uncertain. We therefore aimed to establish and validate a modified PIT paradigm that would be robust, consistent and tolerated by healthy controls as well as by patients suffering from alcohol dependence, and to explore whether alcohol dependence is associated with enhanced PIT. Thirty-two recently detoxified alcohol-dependent patients and 32 age- and gender-matched healthy controls performed a PIT task with instrumental go/no-go approach behaviors. The task involved both pavlovian stimuli associated with monetary rewards and losses, and images of drinks. Both patients and healthy controls showed a robust and temporally stable PIT effect. Strengths of PIT effects to drug-related and monetary conditioned stimuli were highly correlated. Patients more frequently showed a PIT effect, and the effect was stronger in response to aversively conditioned CSs (conditioned suppression), but there was no group difference in response to appetitive CSs. The implementation of PIT has favorably robust properties in chronic alcohol-dependent patients and in healthy controls. It shows internal consistency between monetary and drug-related cues. The findings support an association of alcohol dependence with an increased propensity towards PIT.


The first intravenous anaesthetic: how well was it managed and its potential realized?
Our speciality commonly traces its origin to a demonstration of the inhalation of ether by a patient undergoing surgery in Boston in 1846. Less well known is the demonstration of the i.v. injection of opium with alcohol into a dog in Oxford in 1656, leading to anaesthesia followed by full long-term recovery. After gaining i.v. access, a mixture of opium and alcohol was injected, resulting in a brief period of anaesthesia. After a period during which the dog was kept moving to assist recovery, a full recovery was made. Details from this momentous experiment allow us to compare the technique used with modern management. It is important to consider why there was a failure to translate the results into clinical practice and nearly 200 yr of potentially pain-free surgery. Possible factors include lack of equipment for i.v. access, lack of understanding of dose-response effects, and a climate of scientific discovery rather than clinical application. Given the current interest in total i.v. anaesthesia, it seems appropriate to identify its origins well before those of inhalation anaesthesia.


Feeding on multiple sources: towards a universal parameterization of the functional response of a generalist predator allowing for switching.
Understanding of complex trophic interactions in ecosystems requires correct descriptions of the rate at which predators consume a variety of different prey species. Field and laboratory data on multispecies communities are rarely sufficient and usually cannot provide an unambiguous test for the theory. As a result, the conventional way of constructing a multi-prey functional response is speculative, and often based on assumptions that are difficult to verify. Predator responses allowing for prey selectivity and active switching are thought to be more biologically relevant compared to the standard proportion-based consumption. However, here we argue that the functional responses with switching may not be applicable to communities with a broad spectrum of resource types. We formulate a set of general rules that a biologically sound parameterization of a predator functional response should satisfy, and show that all existing formulations for the multispecies response with prey selectivity and switching fail to do so. Finally, we propose a universal framework for parameterization of a multi-prey functional response by combining patterns of food selectivity and proportion-based feeding.


Zero-reflectivity homogeneous layers and high spatialfrequency surface-reliefgratings on lossy materials.
The required thickness and complex refractive index of single homogeneous layers on lossy substrates to produce zero reflectivity are calculated by a rigorous impedance matching approach. The analysis is applicable to both TE and TM polarization and to any angle of incidence. The filling factor and groove depth of a rectangular-groove grating, equivalent to a single homogeneous lossy layer in the long-wavelength limit, are calculated. The method reduces to that previously found for dielectric surface-relief gratings in the limit of no losses. The antireflection behavior of the gratings is verified using the rigorous (without approximations) coupled-wave analysis of metallic surface-relief grating diffraction. It is shown that multiple zeroreflectivity solutions exist for both TE and TM polarizations and for any angle of incidence for an arbitrary complex-refractive-index substrate. Example zero-reflectivity gold gratings for incident free space wavelengths from 0.44 to 12.0 microm are presented.


Cytofluorometric analysis of the kinetics of lymphocyte transformation after phytohemagglutinin stimulation: comparison with the kinetics of thymidine incorporation.
The technique of flow cytofluorometry has been employed to assess the response of unfractionated and highly purified human lymphocyte subpopulations to phytohemagglutinin (PHA) and pokeweed mitogen. Normal values for cytofluorometric responses were established and compared to the uptake of tritiated thymidine in simultaneous experiments. Cytofluorometric analysis offered the advantages of increased sensitivity and direct measurement of DNA content per cell, and provided percentages and absolute numbers of responding cells. B-cell responses to pokeweed mitogen were absent, but brisk T-cell responses were noted. Between 4% and 8% of highly purified human B cells were found to respond to PHA by increasing their DNA content; modest but significant uptake of tritiated thymidine by B cells following PHA stimulation was also observed.


Prospective analysis of clinical outcomes after percutaneous vertebroplasty for painful osteoporotic vertebral body fractures.
Previous studies have retrospectively reported the positive effects of percutaneous vertebroplasty. The purpose of our study was to evaluate prospectively the effects of vertebroplasty on mobility, analgesic use, pain, and SF-36 (short-form 36-item) scales for patients with painful vertebral compression fractures that are refractory to medical therapy. We prospectively followed 167 patients who received 207 vertebroplasty treatment sessions for stabilization of 264 symptomatic vertebral compression fractures between August 1999 and January 2003. The average age of patients was 74.6 years (SD = 12.2 years), and 76% were women. Pre- and postprocedural measurements of pain, mobility, analgesic use, and SF-36 scales were compared at 1 month after the procedure and between 6 months and 3 years after the procedure with the SF-36 scales. Respective pre- and post-treatment pain scores were 8.71 (SE = 0.1) and 2.77 (SE = 0.18; P < .00001). Respective pre- and post-treatment analgesic use scores were 2.93 (SE = 0.9) and 1.64 (SE = 0.09; P < .00001). Respective pre- and post-treatment activity levels were 2.66 (SE = 0.1) and 1.64 (SE = 0.11; P < .00001). There was a statistically significant improvement on nine of 10 SF-36 scales (P < .001) after 1 month and on eight of 10 SF-36 scales (P < .02) at long-term follow-up. Percutaneous vertebroplasty offers statistically significant benefits in decreasing pain, decreasing use of analgesics, and increasing mobility in appropriately selected patients. Percutaneous vertebroplasty also offers a statistically significant benefit in most SF-36 scales at both short- and long-term follow-up.


Interaction between maternal caffeine intake during pregnancy and CYP1A2 C164A polymorphism affects infant birth size in the Hokkaido study.
BackgroundCaffeine, 1,3,7-trimethylxanthine, is widely consumed by women of reproductive age. Although caffeine has been proposed to inhibit fetal growth, previous studies on the effects of caffeine on infant birth size have yielded inconsistent findings. This inconsistency may result from failure to account for individual differences in caffeine metabolism related to polymorphisms in the gene for CYP1A2, the major caffeine-metabolizing enzyme.MethodsFive hundred fourteen Japanese women participated in a prospective cohort study in Sapporo, Japan, from 2002 to 2005, and 476 mother-child pairs were included for final analysis.ResultsCaffeine intake was not significantly associated with mean infant birth size. When caffeine intake and CYP1A2 C164A genotype were considered together, women with the AA genotype and caffeine intake of ≥300 mg per day had a mean reduction in infant birth head circumference of 0.8 cm relative to the reference group after adjusting for confounding factors. In a subgroup analysis, only nonsmokers with the AA genotype and caffeine intake of ≥300 mg per day had infants with decreased birth weight (mean reduction, 277 g) and birth head circumference (mean reduction, 1.0 cm).ConclusionNonsmokers who rapidly metabolize caffeine may be at increased risk for having infants with decreased birth size when consuming ≥300 mg of caffeine per day.


Impact of malnutrition on survival and infections among pediatric patients with cancer: a retrospective study.
Recognizing and managing malnutrition among hospitalized children affected by cancer is a rising need. Awareness and consideration of malnutrition among clinicians are still largely insufficient. This can principally be explained by the lack of consciousness and the shortage of easy and objective tools to identify malnutrition status. The aim of this study is to explore the impact of malnutrition on survival and infections among a population of pediatric patients with cancer. All children aged between 3 and 18 years, newly diagnosed with a malignancy between August 2013 and April 2018, were included in our study. We assessed nutritional risk at diagnosis (with STRONGkids), then we evaluated anthropometric measurements (BMI Z-scores and weight loss), data about survival and number of hospitalization for febrile neutropenia (FN) in the first year after diagnosis. Cut-off values for malnourishment were chosen as BMI Z-score ≤-2.0. One hundred twenty-six pediatric cancer patients were included in the study. At diagnosis 36 pediatric cancer patients (28.6%) were at high risk of malnutrition (STRONGkids 4 or 5), whereas 6 (4.7%) others were malnourished (BMI Z-score≤-2.0). The risk of mortality and the rate of infections (≥3 hospitalizations for FN episodes) were significantly increased by malnutrition and rapid weight loss in the initial phase of treatment (3-6 months after diagnosis). Multivariate analysis confirmed the independent effect of weight loss≥ 5% at 3 months on both survival and infections, and the independent impact of a high risk of malnutrition at diagnosis on infections. A personalized evaluation of nutritional risk at diagnosis and a close monitoring of nutritional status during the initial phase of treatment are crucial for ensuring a timely and personalized nutritional intervention, which may potentially improve tolerance to chemotherapy and survival, and prevent prolonged hospitalization for infections in childhood cancer patients.


Early supported discharge after stroke in Bergen (ESD Stroke Bergen): a randomized controlled trial comparing rehabilitation in a day unit or in the patients' homes with conventional treatment.
As a result of demographic changes with a presumed rapidly increasing number of older people during the coming decades, a strong increase in the incidence and prevalence of stroke should be expected. Early supported discharge implies that the patients are discharged to their homes as soon as feasible and that rehabilitative treatment is offered after the discharge, with the patients being home-dwelling. This has proved beneficial in previous studies. The main objective of this study is to further characterize the important components of early supported discharge and to confirm superiority of early supported discharge over conventional treatment. The secondary aim will be to compare two different early supported discharge schemes. These early supported discharge schemes are composed of intensive rehabilitation treatment given by a multidisciplinary team in a day unit and, alternatively, the same treatment given in the patients' homes. The study is conducted as a randomized controlled trial with three arms: two different forms of early supported discharge and a control arm with conventional treatment. Patients with acute stroke admitted to our hospital's stroke unit and living in the Municipality of Bergen are considered for inclusion. A total of 350 stroke patients are expected. Primary outcome is modified Rankin Scale six-months after inclusion. Secondary outcomes include Barthel Index and National Institute of Health Stroke Scale at several points in time after inclusion, as well as many other schemes, questionnaires and physical tests. The study is registered in ClinicalTrials.gov registration number NCT00771771.


Rapid disease progression in HIV-1 subtype C-infected South African women.
Whereas human immunodeficiency virus (HIV) subtype B-infected individuals generally progress to AIDS within 8-10 years, limited data exist for other clades, especially from Africa. We investigated rates of HIV disease progression of clade C-infected South African women. Prospective seroincidence cohorts in KwaZulu-Natal were assessed for acute HIV infection monthly (n = 245) or every 3 months (n = 594) for up to 4 years. Rapid disease progression was defined as CD4 decline to <350 cells/µL by 2 years postinfection. Serial clinical and laboratory assessments were compared using survival analysis and logistic regression models. Sixty-two women were identified at a median of 42 days postinfection (interquartile range, 34-59), contributing 282 person-years of follow-up. Mean CD4 count dropped by 39.6% at 3 months and 46.7% at 6 months postinfection in women with preinfection measurements. CD4 decline to <350 cells/µL occurred in 31%, 44%, and 55% of women at 1, 2, and 3 years postinfection, respectively, and to <500 cells/µL in 69%, 79%, and 81% at equivalent timepoints. Predictors of rapid progression were CD4 count at 3 months postinfection (hazard ratio [HR], 2.07; 95% confidence interval [CI], 1.31-3.28; P = .002), setpoint viral load (HR, 3.82; 95% CI, 1.51-9.67; P = .005), and hepatitis B coinfection (HR, 4.54; 95% CI, 1.31-15.69; P = .017). Conversely, presence of any of HLAB*1302, B*27, B*57, B*5801, or B*8101 alleles predicted non-rapid progression (HR, 0.19; 95% CI, .05-.74; P = .016). Nearly half of subtype C-infected women progressed to a CD4 count <350 cells/µL within 2 years of infection. Implementing 2013 World Health Organization treatment guidelines (CD4 count <500 cells/µL) would require most individuals to start antiretroviral therapy within 1 year of HIV infection.


Mutational analysis of the conserved Asp2.50 and ERY motif reveals signaling bias of the urotensin II receptor.
Class A (rhodopsin-like) G protein-coupled receptors possess conserved residues and motifs that are important for their specific activity. In the present study, we examined the role of residue Asp97(2.50) as well as residues Glu147(3.49), Arg148(3.50), and Tyr149(3.51) of the ERY motif on the functionality of the urotensin II receptor (UT). Mutations D97(2.50)A, R148(3.50)A, and R148(3.50)H abolished the ability of UT to activate phospholipase C, whereas mutations E147(3.49)A and Y149(3.51)A reduced the ability to activate PLC by 50%. None of the mutants exhibited constitutive activity. However, R148(3.50)A and R148(3.50)H promoted ERK1/2 activation, which was abolished by 4-(3-chloroanilino)-6,7-dimethoxyquinazoline (AG1478), an inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase activity. Both these mutants were capable of directly activating EGFR, which confirmed that they activated the mitogen-activated protein kinase (MAPK) pathway by a Galpha(q/11)-independent transactivation of EGFR. The D97(2.50)A, R148(3.50)A, and R148(3.50)H mutants did not readily internalize and did not promote translocation or colocalize with beta-arrestin2-GFP. Finally, the agonist-induced internalization of the E147(3.49)A mutant receptor was significantly increased compared with wild-type receptor. This study highlights the major contribution of the conserved Asp(2.50) residue to the functionality of the UT receptor. The Arg residue in the ERY motif of UT is an important structural element in signaling crossroads that determine whether Galpha(q/11)-dependent and -independent events can occur.


Translating genomics in cancer care.
There is increasing enthusiasm for genomics and its promise in advancing personalized medicine. Genomic information has been used to personalize health care for decades, spanning the fields of cardiovascular disease, infectious disease, endocrinology, metabolic medicine, and hematology. However, oncology has often been the first test bed for the clinical translation of genomics for diagnostic, prognostic, and therapeutic applications. Notable hereditary cancer examples include testing for mutations in BRCA1 or BRCA2 in unaffected women to identify those at significantly elevated risk for developing breast and ovarian cancers, and screening patients with newly diagnosed colorectal cancer for mutations in 4 mismatch repair genes to reduce morbidity and mortality in their relatives. Somatic genomic testing is also increasingly used in oncology, with gene expression profiling of breast tumors and EGFR testing to predict treatment response representing commonly used examples. Health technology assessment provides a rigorous means to inform clinical and policy decision-making through systematic assessment of the evidentiary base, along with precepts of clinical effectiveness, cost-effectiveness, and consideration of risks and benefits for health care delivery and society. Although this evaluation is a fundamental step in the translation of any new therapeutic, procedure, or diagnostic test into clinical care, emerging developments may threaten this standard. These include "direct to consumer" genomic risk assessment services and the challenges posed by incidental results generated from next-generation sequencing (NGS) technologies. This article presents a review of the evidentiary standards and knowledge base supporting the translation of key cancer genomic technologies along the continuum of validity, utility, cost-effectiveness, health service impacts, and ethical and societal issues, and offers future research considerations to guide the responsible introduction of NGS technologies into health care. It concludes that significant evidentiary gaps remain in translating genomic technologies into routine clinical practice, particularly in efficacy, health outcomes, cost-effectiveness, and health services research. These caveats are especially germane in the context of NGS, wherein efforts are underway to translate NGS results despite their limited accuracy, lack of proven efficacy, and significant computational and counseling challenges. Further research across these domains is critical to inform the effective, efficient, and equitable translation of genomics into cancer care.


A Generic Transferable EEG Decoder for Online Detection of Error Potential in Target Selection.
Reliable detection of error from electroencephalography (EEG) signals as feedback while performing a discrete target selection task across sessions and subjects has a huge scope in real-time rehabilitative application of Brain-computer Interfacing (BCI). Error Related Potentials (ErrP) are EEG signals which occur when the participant observes an erroneous feedback from the system. ErrP holds significance in such closed-loop system, as BCI is prone to error and we need an effective method of systematic error detection as feedback for correction. In this paper, we have proposed a novel scheme for online detection of error feedback directly from the EEG signal in a transferable environment (i.e., across sessions and across subjects). For this purpose, we have used a P300-speller dataset available on a BCI competition website. The task involves the subject to select a letter of a word which is followed by a feedback period. The feedback period displays the letter selected and, if the selection is wrong, the subject perceives it by the generation of ErrP signal. Our proposed system is designed to detect ErrP present in the EEG from new independent datasets, not involved in its training. Thus, the decoder is trained using EEG features of 16 subjects for single-trial classification and tested on 10 independent subjects. The decoder designed for this task is an ensemble of linear discriminant analysis, quadratic discriminant analysis, and logistic regression classifier. The performance of the decoder is evaluated using accuracy, F1-score, and Area Under the Curve metric and the results obtained is 73.97, 83.53, and 73.18%, respectively.


The Arabidopsis Cop9 signalosome subunit 4 (CNS4) is involved in adventitious root formation.
The COP9 signalosome (CSN) is an evolutionary conserved multiprotein complex that regulates many aspects of plant development by controlling the activity of CULLIN-RING E3 ubiquitin ligases (CRLs). CRLs ubiquitinate and target for proteasomal degradation a vast number of specific substrate proteins involved in many developmental and physiological processes, including light and hormone signaling and cell division. As a consequence of CSN pleiotropic function, complete loss of CSN activity results in seedling lethality. Therefore, a detailed analysis of CSN physiological functions in adult Arabidopsis plants has been hampered by the early seedling lethality of csn null mutants. Here we report the identification and characterization of a viable allele of the Arabidopsis COP9 signalosome subunit 4 (CSN4). The allele, designated csn4-2035, suppresses the adventitious root (AR) phenotype of the Arabidopsis superroot2-1 mutant, potentially by altering its auxin signaling. Furthermore, we show that although the csn4-2035 mutation affects primary and lateral root (LR) formation in the 2035 suppressor mutant, CSN4 and other subunits of the COP9 complex seem to differentially control AR and LR development.


Multiple metallic-shell nanocylinders for surface-enhanced spectroscopes.
The optical properties of multiple dielectric-core-gold-shell nanocylinder pairs are investigated by two-dimensional finite difference time domain method. The core-shell cylinders are assumed to be of the same dimension and composition. For normal incidence, the diffraction spectra of multiple cylinder pairs contain the lightning-rod plasmon mode, and the electric field intensity is concentrated in the gap between the nanocylinder pairs in the infrared region. The resonance wavelength and local field enhancement of this plasmon mode can be tuned by varying the pair-distance between the pairs, the gap-distance between the pairs, and the optical constants of the dielectric-core and the surrounding medium. The results show that the multiple core-shell nanocylinder pair contains the plasmon mode same as that of the solid metallic cylinder pairs at the long wavelength part of the spectrum. The large electric field intensity in the infrared region at long wavelength makes multiple core-shell cylinders as ideal candidates for surface-enhanced spectroscopes.


Association of serum CD14 level and functional polymorphism C-159T in the promoter region of CD14 gene with allergic rhinitis.
Allergic rhinitis (AR) is an inflammatory disease of the upper respiratory tract affecting a significant number of the world's population. It occurs as an IgE-mediated immune response of the nasal mucosa to inhaled allergens. The human Cluster of Differentiation 14 (CD14) is a glycosyl-phosphatidylinositol-anchored molecule expressed on the surface of monocytes and macrophages and functions as a receptor to lipopolysaccharides and inhaled endotoxins that may stimulate interleukins production by antigen-presenting cells. Consequently, CD14 plays a substantial role in allergic diseases and may become one of their etiological causes. This study aimed to determine the association between C-159T polymorphism in the CD14 gene promoter region and serum CD14 levels and the risk of Allergic rhinitis Egyptian patients and to test the validity of serum CD14 level measurement in predicting AR. This case-control study included 45 patients with AR referred to Allergy and Immunology Unit, Zagazig University Hospital, Zagazig, Egypt, and 45 healthy subjects as controls. Serum CD14 levels were measured by ELISA. The polymerase chain reaction-restriction fragment length polymorphism technique was used to detect C-159T gene polymorphism in the CD14 promoter region. There was a significant association between CD14 serum levels and AR incidence (P < 0.001), with patients having higher serum CD14 levels than controls. In addition, a significant association (P < 0.001) was detected between serum CD14 levels and the severity of AR, as well as elevated serum CD14 levels in severe and the most severe cases. On the molecular level, there was a statistically significant relationship between patients and the control group regarding the CD14 genotype (P < 0.001), where CT and TT genotypes and T allele were primarily associated with the cases group, indicating that the risk of AR was significantly associated with the inheritance of the TT genotype. Additionally, a statistically significant association was found between the severity of AR and CD14 genotype (P < 0.001), where TT genotypes were mainly associated with severe and the most severe cases. In the studied groups, there was a statistically significant difference (P < 0.05) between the CD14 genotype and serum CD14 levels, with TT genotypes being associated with higher CD14 levels. The results obtained in this study revealed that serum CD14 level is a potential biomarker for the diagnosis of AR and, at the genetic level, a potential predictor of disease.


An estimate of the global reduction in mortality rates through doubling vitamin D levels.
The goal of this work is to estimate the reduction in mortality rates for six geopolitical regions of the world under the assumption that serum 25-hydroxyvitamin D (25(OH)D) levels increase from 54 to 110 nmol/l. This study is based on interpretation of the journal literature relating to the effects of solar ultraviolet-B (UVB) and vitamin D in reducing the risk of disease and estimates of the serum 25(OH)D level-disease risk relations for cancer, cardiovascular disease (CVD) and respiratory infections. The vitamin D-sensitive diseases that account for more than half of global mortality rates are CVD, cancer, respiratory infections, respiratory diseases, tuberculosis and diabetes mellitus. Additional vitamin D-sensitive diseases and conditions that account for 2 to 3% of global mortality rates are Alzheimer's disease, falls, meningitis, Parkinson's disease, maternal sepsis, maternal hypertension (pre-eclampsia) and multiple sclerosis. Increasing serum 25(OH)D levels from 54 to 110 nmol/l would reduce the vitamin D-sensitive disease mortality rate by an estimated 20%. The reduction in all-cause mortality rates range from 7.6% for African females to 17.3% for European females. Reductions for males average 0.6% lower than for females. The estimated increase in life expectancy is 2 years for all six regions. Increasing serum 25(OH)D levels is the most cost-effective way to reduce global mortality rates, as the cost of vitamin D is very low and there are few adverse effects from oral intake and/or frequent moderate UVB irradiance with sufficient body surface area exposed.


Novel hybrids derived from aspirin and chalcones potently suppress colorectal cancer in vitro and in vivo.
Colorectal cancer (CRC) remains the fourth leading cause of cancer deaths around the world despite the availability of many approved small molecules for treatment. The issues lie in the potency, selectivity and targeting of these compounds. Therefore, new strategies and targets are needed to optimize and develop novel treatments for CRC. Here, a group of novel hybrids derived from aspirin and chalcones were designed and synthesized based on recent reports of their individual benefits to CRC targeting and selectivity. The most active compound 7h inhibited proliferation of CRC cell lines with better potency compared to 5-fluorouracil, a currently used therapeutic agent for CRC. Importantly, 7h had 8-fold less inhibitory activity against non-cancer CCD841 cells. In addition, 7h inhibited CRC growth via the inhibition of the cell cycle in the G1 phase. Furthermore, 7h induced apoptosis by activating caspase 3 and PARP cleavage, as well as increasing ROS in CRC cells. Finally, 7h significantly retarded the CRC cell growth in a mouse xenograft model. These findings suggest that 7h may have potential to treat CRC.


Mechanism of the interaction of human platelet profilin with actin.
We have reexamined the interaction of purified platelet profilin with actin and present evidence that simple sequestration of actin monomers in a 1:1 complex with profilin cannot explain many of the effects of profilin on actin assembly. Three different methods to assess binding of profilin to actin show that the complex with platelet actin has a dissociation constant in the range of 1 to 5 microM. The value for muscle actin is similar. When bound to actin, profilin increases the rate constant for dissociation of ATP from actin by 1,000-fold and also increases the rate of dissociation of Ca2+ bound to actin. Kinetic simulation showed that the profilin exchanges between actin monomers on a subsecond time scale that allows it to catalyze nucleotide exchange. On the other hand, polymerization assays give disparate results that are inconsistent with the binding assays and each other: profilin has different effects on elongation at the two ends of actin filaments; profilin inhibits the elongation of platelet actin much more strongly than muscle actin; and simple formation of 1:1 complexes of actin with profilin cannot account for the strong inhibition of spontaneous polymerization. We suggest that the in vitro effects on actin polymerization may be explained by a complex mechanism that includes weak capping of filament ends and catalytic poisoning of nucleation. Although platelets contain only 1 profilin for every 5-10 actin molecules, these complex reactions may allow substoichiometric profilin to have an important influence on actin assembly. We also confirm the observation of I. Lassing and U. Lindberg (1985. Nature [Lond.] 318:472-474) that polyphosphoinositides inhibit the effects of profilin on actin polymerization, so lipid metabolism must also be taken into account when considering the functions of profilin in a cell.


Jejunal regulation of gastric motility patterns: effect of extrinsic neural continuity to stomach.
This study was designed to determine the role of extrinsic gastric innervation in mediating the inhibitory effects of jejunal infusion of mixed nutrients on canine interdigestive gastric motility patterns. Four dogs underwent transection of all extrinsic and intrinsic neural continuity to the stomach except for careful preservation of vagal innervation (stage 1). Antral manometry catheters, antral electrodes, intestinal electrodes, and a jejunal infusion catheter were placed. After a 2-wk recovery, stage 1 studies of myoelectric and contractile activity of the stomach and small bowel during fasting were recorded on four occasions during infusion of isomolar solutions of either nonnutrient NaCl (150 mM) or mixed nutrients (50% Meritene solution) into the jejunum at 2.9 ml/min for 6 h. Identical studies (stage 2) were repeated after completion of extrinsic denervation of the stomach by supradiaphragmatic vagotomy. In stage 1 studies, jejunal nutrients (83 kcal/h) inhibited the characteristic interdigestive cyclic motility patterns in the stomach and duodenum for greater than or equal to 172 min during jejunal infusion of mixed nutrients. After completion of extrinsic denervation (stage 2), jejunal infusion of nutrients had the same effects with inhibition of cyclic motility patterns in the stomach and small intestine. We concluded that inhibition of interdigestive gastric motility patterns by jejunally infused nutrients is mediated by hormonal mechanisms and not by nonvagal or vagal extrinsic neural input to the stomach.


Value-based purchasing and the doctor-patient relationship.
The Value-Based Purchasing (VBP) program was established by the Secretary of Health and Human Services, in accordance with mandates under the Patient Protection and Affordable Care Act of 2010. Under the VBP program, the Centers for Medicare & Medicaid Services will decrease payments for certain Diagnosis Related Group (DRG) payments. Of the approximately 3100 acute care hospitals affected by the reductions, which hospitals will be able to recoup some of the losses and which ones will be forfeiting the total amount will be decided by predetermined performance measures. Seventy percent of the VBP Total Performance Score (TPS) will involve the Process of Core Measures, which include quality measures of treatment of acute myocardial infarction, heart failure, pneumonia, healthcare-associated infections, and surgical care improvement. The remaining 30% of the TPS will be determined by patient satisfaction. Hospitals will be graded according to points awarded for quality achievement, improvement from baseline, and consistency.


Earthquake Exposure and Post-traumatic Stress Among Nepalese Mothers After the 2015 Earthquakes.
Introduction: Nepal suffered from major earthquakes in April 2015 resulting in great damage to the society. The objective of the current study is to describe the earthquake exposure, the impact on family's daily life and the symptoms of post-traumatic stress disorder (PTSD) and their association in Nepalese mothers 20 months following the earthquakes. Methods: In a clinical trial in Bhaktapur, Nepal, 558 mothers responded to an inventory on earthquake exposure and the Impact of Event Scale - Revised (IES-R) 20 months after the earthquakes. In multiple linear regression models, we estimated the associations between the earthquake exposure and the impact on the families' life and the IES-R score. Results: Over 60% reported that the earthquakes had a great deal of negative impact on their family's life. In 4.7%, close family members died, and in 10.5%, family members were injured. 24% had IES-R scores indicating PTSD symptoms within clinical concern or a possible diagnosis. Lower levels of education were associated with higher scores on the total IES-R. Mothers who report that the earthquakes had a great deal of negative impact had higher total IES-R scores [9.8, 95% CI (5.9, 13.6)] compared to mothers that reported no such negative impact. Mothers with family members who were killed had higher IES-R scores [3.6, 95% CI (1.6, 5.5)] than those with no family members who died. Mothers assisting in rescue efforts had lower IES-R scores [2.8, 95% CI (0.8, 4.8)] than those not assisting. Conclusion: Our study demonstrates high levels of exposure to traumatic events, large negative impact on the everyday life of the families, and a high level of PTSD symptoms. There was a consistent and graded association between the exposure variables and PTSD symptoms. The large impact of the earthquakes on these Nepalese mothers underscore the importance of awareness of mental disorders following major natural catastrophes for marginalized families.


Bilateral nucleus basalis of Meynert deep brain stimulation for dementia with Lewy bodies: A randomised clinical trial.
Dementia with Lewy bodies (DLB) is the second most common form of dementia. Current symptomatic treatment with medications remains inadequate. Deep brain stimulation of the nucleus basalis of Meynert (NBM DBS) has been proposed as a potential new treatment option in dementias. To assess the safety and tolerability of low frequency (20 Hz) NBM DBS in DLB patients and explore its potential effects on both clinical symptoms and functional connectivity in underlying cognitive networks. We conducted an exploratory randomised, double-blind, crossover trial of NBM DBS in six DLB patients recruited from two UK neuroscience centres. Patients were aged between 50 and 80 years, had mild-moderate dementia symptoms and were living with a carer-informant. Patients underwent image guided stereotactic implantation of bilateral DBS electrodes with the deepest contacts positioned in the Ch4i subsector of NBM. Patients were subsequently assigned to receive either active or sham stimulation for six weeks, followed by a two week washout period, then the opposite condition for six weeks. Safety and tolerability of both the surgery and stimulation were systematically evaluated throughout. Exploratory outcomes included the difference in scores on standardised measurements of cognitive, psychiatric and motor symptoms between the active and sham stimulation conditions, as well as differences in functional connectivity in discrete cognitive networks on resting state fMRI. Surgery and stimulation were well tolerated by all six patients (five male, mean age 71.33 years). One serious adverse event occurred: one patient developed antibiotic-associated colitis, prolonging his hospital stay by two weeks. No consistent improvements were observed in exploratory clinical outcome measures, but the severity of neuropsychiatric symptoms reduced with NBM DBS in 3/5 patients. Active stimulation was associated with functional connectivity changes in both the default mode network and the frontoparietal network. Low frequency NBM DBS can be safely conducted in DLB patients. This should encourage further exploration of the possible effects of stimulation on neuropsychiatric symptoms and corresponding changes in functional connectivity in cognitive networks. NCT02263937.


Homologous recombination DNA repair defects in PALB2-associated breast cancers.
Mono-allelic germline pathogenic variants in the Partner And Localizer of BRCA2 (PALB2) gene predispose to a high-risk of breast cancer development, consistent with the role of PALB2 in homologous recombination (HR) DNA repair. Here, we sought to define the repertoire of somatic genetic alterations in PALB2-associated breast cancers (BCs), and whether PALB2-associated BCs display bi-allelic inactivation of PALB2 and/or genomic features of HR-deficiency (HRD). Twenty-four breast cancer patients with pathogenic PALB2 germline mutations were analyzed by whole-exome sequencing (WES, n = 16) or targeted capture massively parallel sequencing (410 cancer genes, n = 8). Somatic genetic alterations, loss of heterozygosity (LOH) of the PALB2 wild-type allele, large-scale state transitions (LSTs) and mutational signatures were defined. PALB2-associated BCs were found to be heterogeneous at the genetic level, with PIK3CA (29%), PALB2 (21%), TP53 (21%), and NOTCH3 (17%) being the genes most frequently affected by somatic mutations. Bi-allelic PALB2 inactivation was found in 16 of the 24 cases (67%), either through LOH (n = 11) or second somatic mutations (n = 5) of the wild-type allele. High LST scores were found in all 12 PALB2-associated BCs with bi-allelic PALB2 inactivation sequenced by WES, of which eight displayed the HRD-related mutational signature 3. In addition, bi-allelic inactivation of PALB2 was significantly associated with high LST scores. Our findings suggest that the identification of bi-allelic PALB2 inactivation in PALB2-associated BCs is required for the personalization of HR-directed therapies, such as platinum salts and/or PARP inhibitors, as the vast majority of PALB2-associated BCs without PALB2 bi-allelic inactivation lack genomic features of HRD.


Manual rupture versus transvaginal ultrasound-guided aspiration of allanto-amniotic fluid in multiple pregnancies: a clinical approach to embryo reduction in dairy cattle.
To avoid the problems associated with twinning in dairy cattle, one of the embryos may be eliminated. This study compares the effect on pregnancy maintenance of two embryo reduction techniques, manual rupture (MR) and transvaginal ultrasound-guided aspiration (TUGA) of allanto-amniotic fluid, in Holstein-Friesian cows with multiple pregnancies. In the first experiment, 61 lactating cows bearing unilateral twins (n=27), bilateral twins (n=30) or triplets/quadruplets (n=4) were subjected to MR (n=45) or TUGA using a 17-G neddle (n=16) on day 28-34 of gestation. In 21 and 10 cows undergoing MR and TUGA embryo reduction, respectively, pregnancy loss occurred before day 90 (46.7 vs. 62.5%, P= 0.28). Through binary logistic regression, the type of pregnancy was identified as the only variable significantly affecting pregnancy maintenance (P=0.03). Based on the odds ratio, the risk of pregnancy loss was 4.1 times higher for unilateral twins than for bilateral twins (70.4 vs. 36.7%, respectively, P=0.01). No effect was detected on pregnancy maintenance of the technique used (P=0.17) or of the interaction technique by type of pregnancy (P=0.22). In the second experiment, a 22-G needle was used to perform TUGA on 22 lactating cows. The pregnancy loss rates were 44.4% (4/9), 18.2% (2/11) and 50% (1/2) for cows bearing unilateral twins, bilateral twins and triplets, respectively. The total pregnancy loss rate following TUGA using the 22-G needle tended to be lower than that using the 17-G needle (31.8 vs. 62.5%; P=0.06). Our results suggest that TUGA using a 22-G needle could be the method of choice to perform embryo reduction in cows carrying multiple pregnancies.


Virtual Reality Anterior Cervical Discectomy and Fusion Simulation on the Novel Sim-Ortho Platform: Validation Studies.
Virtual reality spine simulators are emerging as potential educational tools to assess and train surgical procedures in safe environments. Analysis of validity is important in determining the educational utility of these systems. To assess face, content, and construct validity of a C4-C5 anterior cervical discectomy and fusion simulation on the Sim-Ortho virtual reality platform, developed by OSSimTechTM (Montreal, Canada) and the AO Foundation (Davos, Switzerland). Spine surgeons, spine fellows, along with neurosurgical and orthopedic residents, performed a simulated C4-C5 anterior cervical discectomy and fusion on the Sim-Ortho system. Participants were separated into 3 categories: post-residents (spine surgeons and spine fellows), senior residents, and junior residents. A Likert scale was used to assess face and content validity. Construct validity was evaluated by investigating differences between the 3 groups on metrics derived from simulator data. The Kruskal-Wallis test was employed to compare groups and a post-hoc Dunn's test with a Bonferroni correction was utilized to investigate differences between groups on significant metrics. A total of 21 individuals were included: 9 post-residents, 5 senior residents, and 7 junior residents. The post-resident group rated face and content validity, median ≥4, for the overall procedure and at least 1 tool in each of the 4 steps. Significant differences (P < .05) were found between the post-resident group and senior and/or junior residents on at least 1 metric for each component of the simulation. The C4-C5 anterior cervical discectomy and fusion simulation on the Sim-Ortho platform demonstrated face, content, and construct validity suggesting its utility as a formative educational tool.


Amla Therapy as a Potential Modulator of Alzheimer's Disease Risk Factors and Physiological Change.
There is currently no effective treatment for Alzheimer's disease (AD), the most common form of dementia. It has been proposed, however, that a modest delay in onset can significantly reduce the number of cases. Thus, prevention and intervention strategies are currently the focus of much research. In the search for compounds that potentially confer benefit, the Amla fruit and its extracts have drawn attention. Amla preparations have been used for centuries in traditional Indian medicine systems such as Ayurveda, with various parts of the plant used to treat a variety of diseases. Here we review many animal-based studies, and some clinical trials, which have shown that Amla, and its extracts, exert many positive effects on dyslipidemia, hyperglycemia, inflammation, oxidative stress, apoptosis, and autophagy, that contribute to AD risk. Collectively, this evidence suggests that Amla may be of value as part of an effective disease-delaying treatment for AD.


Carrier effects on biological activity of amphotericin B.
Amphotericin B (AmB), the drug of choice for the treatment of most systemic fungal infections, is marketed under the trademark Fungizone, as an AmB-deoxycholate complex suitable for intravenous administration. The association between AmB and deoxycholate is relatively weak; therefore, dissociation occurs in the blood. The drug itself interacts with both mammalian and fungal cell membranes to damage cells, but the greater susceptibility of fungal cells to its effects forms the basis for its clinical usefulness. The ability of the drug to form stable complexes with lipids has allowed the development of new formulations of AmB based on this property. Several lipid-based formulations of the drug which are more selective in damaging fungal or parasitic cells than mammalian cells and some of which also have a better therapeutic index than Fungizone have been developed. In vitro investigations have led to the conclusion that the increase in selectivity observed is due to the selective transfer of AmB from lipid complexes to fungal cells or to the higher thermodynamic stability of lipid formulations. Association with lipids modulates AmB binding to lipoproteins in vivo, thus influencing tissue distribution and toxicity. For example, lipid complexes of AmB can be internalized by macrophages, and the macrophages then serve as a reservoir for the drug. Furthermore, stable AmB-lipid complexes are much less toxic to the host than Fungizone and can therefore be administered in higher doses. Experimentally, the efficacy of AmB-lipid formulations compared with Fungizone depends on the animal model used. Improved therapeutic indices for AmB-lipid formations have been demonstrated in clinical trials, but the definitive trials leading to the selection of an optimal formulation and therapeutic regimen have not been done.


IA Channels Encoded by Kv1.4 and Kv4.2 Regulate Circadian Period of PER2 Expression in the Suprachiasmatic Nucleus.
Neurons in the suprachiasmatic nucleus (SCN), the master circadian pacemaker in mammals, display daily rhythms in electrical activity with more depolarized resting potentials and higher firing rates during the day than at night. Although these daily variations in the electrical properties of SCN neurons are required for circadian rhythms in physiology and behavior, the mechanisms linking changes in neuronal excitability to the molecular clock are not known. Recently, we reported that mice deficient for either Kcna4 (Kv1.4(-/-)) or Kcnd2 (Kv4.2(-/-); but not Kcnd3, Kv4.3(-/-)), voltage-gated K(+) (Kv) channel pore-forming subunits that encode subthreshold, rapidly activating, and inactivating K(+) currents (IA), have shortened (0.5 h) circadian periods in SCN firing and in locomotor activity compared with wild-type (WT) mice. In the experiments here, we used a mouse (Per2(Luc)) line engineered with a bioluminescent reporter construct, PERIOD2::LUCIFERASE (PER2::LUC), replacing the endogenous Per2 locus, to test the hypothesis that the loss of Kv1.4- or Kv4.2-encoded IA channels also modifies circadian rhythms in the expression of the clock protein PERIOD2 (PER2). We found that SCN explants from Kv1.4(-/-)Per2(Luc) and Kv4.2(-/-) Per2(Luc), but not Kv4.3(-/-)Per2(Luc), mice have significantly shorter (by approximately 0.5 h) circadian periods in PER2 rhythms, compared with explants from Per2(Luc) mice, revealing that the membrane properties of SCN neurons feedback to regulate clock (PER2) expression. The combined loss of both Kv1.4- and Kv4.2-encoded IA channels in Kv1.4(-/-)/Kv4.2(-/-)Per2(Luc) SCN explants did not result in any further alterations in PER2 rhythms. Interestingly, however, mice lacking both Kv1.4 and Kv4.2 show a striking (approximately 1.8 h) advance in their daily activity onset in a light cycle compared with WT mice, suggesting additional roles for Kv1.4- and Kv4.2-encoded IA channels in controlling the light-dependent responses of neurons within and/or outside of the SCN to regulate circadian phase of daily activity.


Femoral arterial and central venous catheters in the trauma resuscitation room.
Arterial and central venous femoral catheters (fAC-CVC) use during the initial management of severe trauma patients is not a standard technique in most trauma centers. Arguments in favor of their use are: continuous monitoring of blood pressure, safe drug administration, easy blood sampling and potentially large bore venous access. The lack of evidence makes the practice heterogeneous. The aim of the present study was to describe the use and complications of fAC-CVC in the trauma bay in two centers where they are routinely used. This was a retrospective analysis of routine fAC-CVC use from two French trauma centers. All patients admitted directly to the trauma resuscitation room were included. Demographic, clinical and biological data were collected from the scene to discharge to describe the use of catheters during initial trauma management including infectious, mechanical and thrombotic complications. 243 pairs of femoral catheters were inserted among 692 patients admitted in both trauma centers. Femoral AC-CVC use was more frequent in critically ill patients with higher ISS 26 [17; 41] vs 13 [8; 24], p < 0.001(median [quartile 1-3]), severe traumatic brain injury (AIS head 1[0-4] vs 0[0-3], p < 0.001), lower systolic blood pressure, 92 (37) vs 113 (28) mmHg, p < 0.001 mean (standard deviation), lower haemoglobin on arrival, 10.9 (3) vs 13.3 (2.1) g/dL (p < 0.001), and higher blood lactate concentration, 4.0 (3.9) vs 2.1 (1.8) mmol/L (p < 0.001). In patients with fAC-CVC use time in the trauma room was longer, 46 [40;60] vs 30 [20;40] minutes (p < 0.05). In total 52 colonizations and 3 bloodstream infections were noted in 1000 catheter days. An incidence of 12% of mechanical complications and of 42% deep venous thromboses were observed. Of the latter none was associated with confirmed pulmonary embolism. Femoral AC-CVC appeared to be deployed more often in critically ill patients, presenting with shock and/or traumatic brain injury in particular. The observed rate of complications in this sample seems to be low compared to reported rates.


Absolute interferometric distance measurement using a FM-demodulation technique.
We propose an interferometric method for measuring absolute distances larger than the wavelength. A laser diode is used as a light source. The principle of operation is based on multiple-wavelength interferometry that uses a modulated light source. This method uses the fact that the wavelength of light emitted by the laser diode can be varied by means of the injection current. The modulation of the injection current in combination with the optical heterodyne technique causes a high-frequency phase-modulated detector signal. The phase deviation of the signal is a measure of the optical path difference in the interferometer. By FM demodulation of the detector output with a phase-locked loop demodulator, the optical path difference can be determined directly without the classical ambiguity problem of interferometry. The measuring range in the experiments was limited to 50 mm by the maximum travel range of the used specimen translation stage. Because of the inherent light sensitivity of the method described, the rangefinder can be used for three-dimensional profile measurements on a wide variety of objects, even on diffuse scattering surfaces.


Association of race and other potential risk factors with nonvertebral fractures in community-dwelling elderly women.
This study determined potential associations of sociodemographic, lifestyle, health, and drug use factors known to affect bone metabolism with incident nonvertebral fractures. The baseline sample consisted of 2,590 female, nonproxy subjects from the Duke Established Populations for Epidemiologic Studies of the Elderly, which focuses on five adjacent counties in the Piedmont area of North Carolina. Information about potential risk factors was collected during a baseline in-home interview during 1986-1987. Subsequent nonvertebral fractures were reported at follow-up interviews during the annual follow-up periods (1988-1993). The authors used multivariate analyses in which weighted data were adjusted for sampling design. After controlling for other potential confounding sociodemographic, lifestyle, health, and drug use factors, they found that African American race (adjusted odds ratio (OR) = 0.43, 95% confidence interval (CI) 0.31-0.58), age (adjusted OR = 1.04, 95% CI 1.01-1.06), alcohol consumption (adjusted OR = 1.61, 95% CI 1.01-2.57), being underweight (adjusted OR = 1.63, 95% CI 1.13-2.34), cognitive impairment (adjusted OR = 1.67, 95% CI 1.12-2.48), impaired mobility (adjusted OR = 1.15, 95% CI 1.03-1.29), and phenytoin use (adjusted OR = 2.93, 95% CI 1.04-8.30) were associated with first fracture occurrence. Similar findings were observed for nonhip, nonvertebral fractures. African Americans were less likely than Whites to have nonvertebral fractures, and these differences were not related to lifestyle or health factors examined in this study.


Changes in gene expression in macrophages infected with Mycobacterium tuberculosis: a combined transcriptomic and proteomic approach.
We investigated the changes which occur in gene expression in the human macrophage cell line, THP1, at 1, 6 and 12 hr following infection with Mycobacterium tuberculosis. The analysis was carried out at the transcriptome level, using microarrays consisting of 375 human genes generally thought to be involved in immunoregulation, and at the proteomic level, using two-dimensional gel electrophoresis and mass spectrometry. The analysis of the transcriptome using microarrays revealed that many genes were up-regulated at 6 and 12 hr. Most of these genes encoded proteins involved in cell migration and homing, including the chemokines interleukin (IL)-8, osteopontin, monocyte chemotactic protein-1 (MCP-1), macrophage inflammatory protein-1alpha (MIP-1alpha), regulated on activation, normal, T-cell expressed and secreted (RANTES), MIP-1beta, MIP-3alpha, myeloid progenitor inhibitory factor-1 (MPIF-1), pulmonary and activation regulated chemokine (PARC), growth regulated gene-beta (GRO-beta), GRO-gamma, MCP-2, I-309, and the T helper 2 (Th2) and eosinophil-attracting chemokine, eotaxin. Other genes involved in cell migration which were up-regulated included the matrix metalloproteinase MMP-9, vascular endothelial growth factor (VEGF) and its receptor Flk-1, the chemokine receptor CCR3, and the cell adhesion molecules vesicular cell adhesion molecule-1 (VCAM-1) and integrin a3. In addition to the chemokine response, genes encoding the proinflammatory cytokines IL-1beta (showing a 433-fold induction), IL-2 and tumour necrosis factor-alpha (TNF-alpha), were also found to be induced at 6 and/or 12 hr. It was more difficult to detect changes using the proteomic approach. Nevertheless, IL-1beta was again shown to be strongly up-regulated. The enzyme manganese superoxide dismutase was also found to be strongly up-regulated; this enzyme was found to be macrophage-, rather than M. tuberculosis, derived. The heat-shock protein hsp27 was found to be down-regulated following infection. We also identified a mycobacterial protein, the product of the atpD gene (thought to be involved in the regulation of cytoplasmic pH) in the infected macrophage extracts.


[Epidemiology of HIV].
Globally, an estimated 35 million people were living with HIV in 2012; of these, 69 % in sub-Saharan Africa. There were 2.3 million new HIV infections globally and 1.6 million AIDS deaths in 2012. As a result of large roll-out programs with integrated voluntary counselling and testing and prevention programs in resource limited settings, sexual transmission of HIV decreased substantially over the last years. However, the world is not on track to reduced HIV transmission among people who inject drugs. Especially in Eastern Europe and Asia prevention coverage for people who inject drugs remains low. In addition, effective prevention among these people is undermined by stigmatisation, discrimination, punitive policy frameworks and law enforcement practices, which discourage people from seeking the health and social services they need. Antiretroviral coverage among pregnant women living with HIV reached 62 % in 2012 resulting in a reduction of newly infected children by 35 % from 2009. In 2012, 9.7 million people in low and middle-income countries received antiretroviral therapy, representing 61 % of all who were eligible under the 2010 WHO HIV treatment guidelines. Under the 2013 guidelines, this represents only 34 % of the 28.3 million people eligible in 2013. A new concept to curb the HIV epidemic is "Test and Treat" which involves population-wide HIV tests with immediate initiation of antiretroviral therapy among all HIV infected individuals. However, there are concerns regarding the sustainability of such treatment programs for decades due to lost to follow up and insufficient adherence and the danger of a large increase of resistant HIV which jeopardize the effectiveness of affordable treatments.


Altering alpha-frequency brain oscillations with rapid analog feedback-driven neurostimulation.
Oscillations of the brain's local field potential (LFP) may coordinate neural ensembles and brain networks. It has been difficult to causally test this model or to translate its implications into treatments, because there are few reliable ways to alter LFP oscillations. We developed a closed-loop analog circuit to enhance brain oscillations by feeding them back into cortex through phase-locked transcranial electrical stimulation. We tested the system in a rhesus macaque with chronically implanted electrode arrays, targeting 8-15 Hz (alpha) oscillations. Ten seconds of stimulation increased alpha oscillatory power for up to 1 second after stimulation offset. In contrast, open-loop stimulation decreased alpha power. There was no effect in the neighboring 15-30 Hz (beta) LFP rhythm or on a neighboring array that did not participate in closed-loop feedback. Analog closed-loop neurostimulation might thus be a useful strategy for altering brain oscillations, both for basic research and the treatment of neuro-psychiatric disease.


The Brain Protective Effect of rTMS (Repetitive Transcranial Magnetic Stimulation) in Depression: A Mini-Review in Animal Studies.
There are rapidly replicating human data suggesting the therapeutic and neurorestorative role of repetitive transcranial magnetic stimulation (rTMS) in clinical depression. However there are only limited experimental studies in the literature and the neurobiological mechanisms of the technique are still unclear. Studies have suggested that modulating of either excitatory or inhibitory neural circuitry may be responsible for the mechanism of action of rTMS while it is still unclear whether rTMS exerts a neuroprotective effect. In the light of these findings, we aimed to review the neuroprotective effect of rTMS in animal models of depression. We have shown that rTMS may exert significant neuroprotective effect through acting on the oxidative injury, stress hormones, dopamine and serotonin levels, Brain Derived Neurotrophic Factor expression, neuroinflamation and hippocampal cell proliferation.


Practices of traditional birth attendants in Machakos District, kenya.
The aim of the study was to document TBAs practices as well as the indigenous herbal remedies they use to manage pre, intra and post partum complications in a rural Kenyan community. A cross sectional study was conducted on practicing TBAs and their clients living in the study area. Data was collected using structured questionnaires and interviews. Focused group discussions were held with the TBAs to supplement the interviews and questionnaire survey. Two hundred TBAs and 20 clients were interviewed. The majority of the TBAs were females 75% of them having attended to over 200 pregnant women over a period of 5 years and above compared to only 6% of the males. A total of 10 pregnancy related complications and symptoms including threatened abortion, labor complications, post partum hemorrhage and retained after birth were recorded. Fifty five plant species most of them belonging to Euphorbiaceae family were identified for the management of the complications. Traditional Birth Attendants still have a role to play in assisting pregnant women in rural communities. Their knowledge on herbal medicines is equally important and should be preserved for posterity.


Dry needling as a novel intervention for cervicogenic somatosensory tinnitus: a case study.
Tinnitus is defined as conscious perception of sound in the absence of a corresponding external stimulus. A condition that affects 10 - 15% of the adult population, tinnitus may be caused by an interaction between the somatosensory and auditory system, more formally known as somatosensory tinnitus. Cervicogenic somatosensory tinnitus is a subgroup of somatosensory tinnitus involving anatomical structures and physiological mechanisms associated with the cervical spine. A limited number of studies have reported inconsistent outcomes for treating cervicogenic somatosensory tinnitus with conservative treatment strategies such as manual therapy and exercise. However, dry needling is a skilled, manual therapy intervention that has recently gained popularity among the physical therapy profession that may be useful for both evaluating and treating the condition. The following case report describes the use of dry needling to evaluate and treat a patient with cervical somatosensory tinnitus and concurrent cervicogenic headaches. Physical therapy that targeted the muscles of the upper cervical spine with dry needling resulted in a meaningful reduction in cervicogenic somatosensory tinnitus, and the improvements persisted at 1-year follow-up. Further research, including randomized control trials, is warranted to fully determine the potential of dry needling to treat cervicogenic somatosensory tinnitus.


Anxiety disorders in 8-11-year-old children: motor skill performance and self-perception of competence.
This study investigates motor skill performance and self-perceived competence in children with anxiety disorders compared with children without psychiatric disorders. Motor skills and self-perception were assessed in 329 children aged 8 to 11 years, from the Bergen Child Study. The Kiddie-SADS PL diagnostic interview was employed to define a group of children with an anxiety disorder without comorbid diagnosis, and a control group (no diagnosis) matched according to gender, age, and full-scale IQ. Children in the anxiety disorder group displayed impaired motor skills and poor self-perceived peer acceptance and physical competence compared with the control group. Two-thirds of the anxious boys scored on the Motor Assessment Battery for Children (MABC) as having motor problems. The present study demonstrated impaired motor skills in boys with "pure" anxiety disorders. Anxious children also perceived themselves as being less accepted by peers and less competent in physical activities compared with children in the control group.


Sex-specific effects of mitochondrial haplotype on metabolic rate in Drosophila melanogaster support predictions of the Mother's Curse hypothesis.
Evolutionary theory proposes that maternal inheritance of mitochondria will facilitate the accumulation of mitochondrial DNA (mtDNA) mutations that are harmful to males but benign or beneficial to females. Furthermore, mtDNA haplotypes sampled from across a given species distribution are expected to differ in the number and identity of these 'male-harming' mutations they accumulate. Consequently, it is predicted that the genetic variation which delineates distinct mtDNA haplotypes of a given species should confer larger phenotypic effects on males than females (reflecting mtDNA mutations that are male-harming, but female-benign), or sexually antagonistic effects (reflecting mutations that are male-harming, but female-benefitting). These predictions have received support from recent work examining mitochondrial haplotypic effects on adult life-history traits in Drosophila melanogaster. Here, we explore whether similar signatures of male-bias or sexual antagonism extend to a key physiological trait-metabolic rate. We measured the effects of mitochondrial haplotypes on the amount of carbon dioxide produced by individual flies, controlling for mass and activity, across 13 strains of D. melanogaster that differed only in their mtDNA haplotype. The effects of mtDNA haplotype on metabolic rate were larger in males than females. Furthermore, we observed a negative intersexual correlation across the haplotypes for metabolic rate. Finally, we uncovered a male-specific negative correlation, across haplotypes, between metabolic rate and longevity. These results are consistent with the hypothesis that maternal mitochondrial inheritance has led to the accumulation of a sex-specific genetic load within the mitochondrial genome, which affects metabolic rate and that may have consequences for the evolution of sex differences in life history. This article is part of the theme issue 'Linking the mitochondrial genotype to phenotype: a complex endeavour'.


Bone marrow cells adopt the cardiomyogenic fate in vivo.
The possibility that adult bone marrow cells (BMCs) retain a remarkable degree of developmental plasticity and acquire the cardiomyocyte lineage after infarction has been challenged, and the notion of BMC transdifferentiation has been questioned. The center of the controversy is the lack of unequivocal evidence in favor of myocardial regeneration by the injection of BMCs in the infarcted heart. Because of the interest in cell-based therapy for heart failure, several approaches including gene reporter assay, genetic tagging, cell genotyping, PCR-based detection of donor genes, and direct immunofluorescence with quantum dots were used to prove or disprove BMC transdifferentiation. Our results indicate that BMCs engraft, survive, and grow within the spared myocardium after infarction by forming junctional complexes with resident myocytes. BMCs and myocytes express at their interface connexin 43 and N-cadherin, and this interaction may be critical for BMCs to adopt the cardiomyogenic fate. With time, a large number of myocytes and coronary vessels are generated. Myocytes show a diploid DNA content and carry, at most, two sex chromosomes. Old and new myocytes show synchronicity in calcium transients, providing strong evidence in favor of the functional coupling of these two cell populations. Thus, BMCs transdifferentiate and acquire the cardiomyogenic and vascular phenotypes restoring the infarcted heart. Together, our studies reveal that locally delivered BMCs generate de novo myocardium composed of integrated cardiomyocytes and coronary vessels. This process occurs independently of cell fusion and ameliorates structurally and functionally the outcome of the heart after infarction.


Non-suicidal self-injury (NSSI) disorder: a preliminary study.
Non-suicidal self-injury (NSSI) disorder has been suggested for inclusion into the Diagnostic and Statistical Manual of Mental Disorders (5th ed.; DSM-5; American Psychiatric Association, in preparation), yet there is concern that NSSI is primarily a function of high borderline personality disorder (BPD) symptoms. The purpose of this study was to examine the characteristics of NSSI disorder and compare it to BPD and other DSM Axis I diagnoses commonly seen in clinical practice to aid in the determination of whether NSSI should be considered a separate, valid diagnostic entity. Chart data were analyzed from the screening, intake, and termination information of 571 treatment-seeking patients in a general practice clinic. Patients were classified into one of three groups: NSSI without BPD, BPD (with and without NSSI) or a comparison condition for those who did not meet criteria for the first 2 groups. Participants in these 3 groups were compared on functioning at intake, psychopathology, and diagnostic co-occurrence. Results indicated important group differences regarding diagnostic co-occurrence rates, patient history of associated features, and impairment at intake. The NSSI group displayed similar levels of functional impairment as the BPD group, including on indices of suicidality. The BPD group reported increased experiences with abuse and fewer men relative to the NSSI group. Most in the NSSI group did not exhibit subthreshold BPD symptoms or personality disorder not otherwise specified. In conclusion, a potential NSSI disorder may be characterized by high levels of depressive symptoms, anxiety, suicidality, and low functioning relative to other Axis I diagnoses.


MicroRNA and mRNA interactions coordinate the immune response in non-lethal heat stressed Litopenaeus vannamei against AHPND-causing Vibrio parahaemolyticus.
While Vibrio parahaemolyticus (VPAHPND) has been identified as the cause of early mortality syndrome (EMS) or acute hepatopancreatic necrosis disease (AHPND) in shrimp, mechanisms of host response remain unknown. Understanding these processes is important to improve farming practices because this understanding will help to develop methods to enhance shrimp immunity. Pre-treatment of shrimp with 5-minute chronic non-lethal heat stress (NLHS) for 7 days was found to significantly increase Litopenaeus vannamei survival against VPAHPND infection. To elucidate the mechanism involved, mRNA and miRNA expression profiles from the hemocyte of L. vannamei challenged with VPAHPND after NLHS with corresponding control conditions were determined by RNA-Seq. A total of 2,664 mRNAs and 41 miRNAs were differentially expressed after the NLHS treatment and VPAHPND challenge. A miRNA-mRNA regulatory network of differentially expressed miRNAs (DEMs) and differentially expressed genes (DEGs) was subsequently constructed and the interactions of DEMs in regulating the NLHS-induced immune-related pathways were identified. Transcriptomic data revealed that miRNA and mRNA interactions contribute to the modulation of NLHS-induced immune responses, such as the prophenoloxidase-activating system, hemocyte homeostasis, and antimicrobial peptide production, and these responses enhance VPAHPND resistance in L. vannamei.


Performance of Contactless Respiratory Rate Monitoring by Albus HomeTM, an Automated System for Nocturnal Monitoring at Home: A Validation Study.
Respiratory rate (RR) is a clinically important predictor of cardio-respiratory deteriorations. The mainstay of clinical measurement comprises the manual counting of chest movements, which is variable between clinicians and limited to sporadic readings. Emerging solutions are limited by poor adherence and acceptability or are not clinically validated. Albus HomeTM is a contactless and automated bedside system for nocturnal respiratory monitoring that overcomes these limitations. This study aimed to validate the accuracy of Albus Home compared to gold standards in real-world sleeping environments. Participants undertook overnight monitoring simultaneously using Albus Home and gold-standard polygraphy with thoraco-abdominal respiratory effort belts (SomnomedicsEU). Reference RR readings were obtained by clinician-count of polygraphy data. For both the Albus system and reference, RRs were measured in 30-s segments, reported as breaths/minute, and compared. Accuracy was defined as the percentage of RRs from the Albus system within ±2 breaths/minute of reference counts. Across a diverse validation set of 32 participants, the mean accuracy exceeded 98% and was maintained across different participant characteristics. In a Bland-Altman analysis, Albus RRs had strong agreement with reference mean differences and the limits of agreement of -0.4 and ±1.2 breaths/minute, respectively. Albus Home is a contactless yet accurate system for automated respiratory monitoring. Validated against gold -standard methods, it enables long-term, reliable nocturnal monitoring without patient burden.


Kinetic and thermodynamic analysis of processes relevant to initiation of olefin metathesis by ruthenium phosphonium alkylidene catalysts.
Initiation processes in a family of ruthenium phosphonium alkylidene catalysts, some of which are commercially available, are presented. Seven 16-electron zwitterionic catalyst precursors of general formula (H(2)IMes)(Cl)(3)Ru=C(H)P(R(1))(2)R(2) (R(1) = R(2) = C(6)H(11), C(5)H(9), i-C(3)H(7), 1-Cy(3)-Cl, 1-Cyp(3)-Cl, 1-(i)Pr(3)-Cl; R(1) = C(6)H(11), R(2) = CH(2)CH(3), 1-EtCy(2)-Cl; R(1) = C(6)H(11), R(2) = CH(3), 1-MeCy(2)-Cl; R(1) = i-C(3)H(7), R(2) = CH(2)CH(3), 1-Et(i)Pr(2)-Cl; R(1) = i-C(3)H(7), R(2) = CH(3), 1-Me(i)Pr(2)-Cl) were prepared. These compounds can be converted to the metathesis active 14-electron phosphonium alkylidenes by chloride abstraction with B(C(6)F(5))(3). The examples with symmetrically substituted phosphonium groups exist as monomers in solution and are rapid initiators of olefin metathesis reactions. The unsymmetrically substituted phosphonium alkylidenes are observed to undergo reversible dimerization, the extent of which is dependent on the steric bulk of the phosphonium group. Kinetic and thermodynamic parameters of these equilibria are presented, as well as experiments that show that metathesis is only initiated through the monomers; thus dedimerization is required for initiation. In another detailed study, the series of catalysts 1-R(3) were reacted with o-isopropoxystyrene under pseudo-first-order conditions to quantify second-order olefin binding rates. A more complex initiation process was observed in that the rates were accelerated by catalytic amounts of ethylene produced in the reaction with o-isopropoxystyrene. The ability of the catalyst to generate ethylene is related to the nature of the phosphonium group, and initiation rates can be dramatically increased by the intentional addition of a catalytic amount of ethylene.


Development & Deployment of a Real-time Healthcare Predictive Analytics Platform.
The deployment of predictive analytic algorithms that can safely and seamlessly integrate into existing healthcare workflows remains a significant challenge. Here, we present a scalable, cloud-based, fault-tolerant platform that is capable of extracting and processing electronic health record (EHR) data for any patient at any time following admission and transferring results back into the EHR. This platform has been successfully deployed within the UC San Diego Health system and utilizes interoperable data standards to enable portability.


Improving the temporal resolution of functional MR imaging using keyhole techniques.
Using a keyhole technique, it is shown that the data acquisition rate of gradient-echo imaging for functional MRI (fMRI) studies can be increased substantially. The resulting enhancement of the temporal resolution of fMRIs was accomplished without modifying the hardware of a conventional MRI system. High spatial resolution fMRI images were first collected with conventional full k-space acquisition and image reconstruction. Using the same data set, simulation reconstruction using the keyhole principle and zero-padding were performed for comparison with the full k-space reconstruction. No significant changes were found for fMRI images generated from the keyhole technique with a data sharing profile of 50% of the k-space. As k-space data sharing profiles increased to 75 and 87.5%, the keyhole fMRI images began to show only modest changes in activation intensity and area compared with the standard images. In contrast, zero-padding fMRI images produced a significant disparity both in activation intensity and area relative to the truly high-resolution fMRI images. The keyhole technique's ability to retain the intensity and area of fMRI information, while substantially reducing acquisition time, makes it a promising method for fMRI studies.


Why Do Patients with Mental Disorders Default Treatment? A Qualitative Enquiry in Rural Kwazulu-Natal, South Africa.
Although treatment default by psychiatric patients or mental health care users is a global challenge, this behavior is reported to be higher in South Africa. The Manguzi District Hospital in rural Kwa-Zulu Natal Province, South Africa, experiences high rates of treatment default by psychiatric patients. The objective of this study was to determine the reasons for treatment defaulting at Manguzi Hospital, KwaZulu-Natal Province, South Africa. An explorative qualitative design, using in-depth interviews, was conducted with mental health care users who had defaulted out-patient psychiatric treatment. Twenty-one mental health care users were interviewed before data saturation was reached. Nvivo version 11 was used to analyze the qualitative data. Major themes that emerged confirmed that social factors are key contributions to treatment defaulting, and these include denial of the mental disorders; belief that they are cured; lack of, or disintegration of social support; preference for traditional medicine; and flaws in the health care system. Social determinants of treatment outcomes for mental disorders require tailor-made support systems for patients in these rural communities, which include increase in health literacy and attention to the cultural understanding of mental disorders.


Serenoa repens associated with Urtica dioica (ProstaMEV) and curcumin and quercitin (FlogMEV) extracts are able to improve the efficacy of prulifloxacin in bacterial prostatitis patients: results from a prospective randomised study.
We report the results of a prospective randomised study to evaluate the therapeutic effect of Serenoa repens, Urtica dioica (ProstaMEV), quercitin and curcumin (FlogMEV) extracts associated with prulifloxacin in patients affected by chronic bacterial prostatitis (CBP). From a whole population of 284 patients, 143 patients affected by CBP [National Institutes of Health (NIH) class II prostatitis] were enrolled. All patients received prulifloxacin 600 mg daily for 14 days, in accordance with antibiogram results. Patients were split into two groups: Group A received prulifloxacin associated with ProstaMEV and FlogMEV; Group B received only antibiotic therapy. Microbiological and clinical efficacies were tested by two follow-up visits at 1 month and 6 months, respectively. Quality of life (QoL) was measured using the NIH Chronic Prostatitis Symptom Index (CPSI) and International Prostatic Symptom Score (IPSS) questionnaires. Group A comprised 106 patients and Group B comprised 37 patients. One month after treatment, 89.6% of patients who had received prulifloxacin associated with ProstaMEV and FlogMEV did not report any symptoms related to CBP, whilst only 27% of patients who received antibiotic therapy alone were recurrence-free (P < 0.0001). Significant differences were found between groups in terms of symptoms and QoL (P < 0.0001 for both). Six months after treatment, no patients in Group A had recurrence of disease whilst two patients in Group B did. Questionnaire results demonstrated statistically significant differences between groups (all P < 0.001). The association of S. repens, U. dioica (ProstaMEV), quercitin and curcumin (FlogMEV) extracts is able to improve the clinical efficacy of prulifloxacin in patients affected by CBP.


Multiomics Profiling Reveals Signatures of Dysmetabolism in Urban Populations in Central India.
Non-communicable diseases (NCDs) have become a major cause of morbidity and mortality in India. Perturbation of host-microbiome interactions may be a key mechanism by which lifestyle-related risk factors such as tobacco use, alcohol consumption, and physical inactivity may influence metabolic health. There is an urgent need to identify relevant dysmetabolic traits for predicting risk of metabolic disorders, such as diabetes, among susceptible Asian Indians where NCDs are a growing epidemic. Here, we report the first in-depth phenotypic study in which we prospectively enrolled 218 adults from urban and rural areas of Central India and used multiomic profiling to identify relationships between microbial taxa and circulating biomarkers of cardiometabolic risk. Assays included fecal microbiota analysis by 16S ribosomal RNA gene amplicon sequencing, quantification of serum short chain fatty acids by gas chromatography-mass spectrometry, and multiplex assaying of serum diabetic proteins, cytokines, chemokines, and multi-isotype antibodies. Sera was also analysed for N-glycans and immunoglobulin G Fc N-glycopeptides. Multiple hallmarks of dysmetabolism were identified in urbanites and young overweight adults, the majority of whom did not have a known diagnosis of diabetes. Association analyses revealed several host-microbe and metabolic associations. Host-microbe and metabolic interactions are differentially shaped by body weight and geographic status in Central Indians. Further exploration of these links may help create a molecular-level map for estimating risk of developing metabolic disorders and designing early interventions.


Anastral meiotic spindle morphogenesis: role of the non-claret disjunctional kinesin-like protein.
We have used time-lapse laser scanning confocal microscopy to directly examine microtubule reorganization during meiotic spindle assembly in living Drosophila oocytes. These studies indicate that the bipolarity of the meiosis I spindle is not the result of a duplication and separation of centrosomal microtubule organizing centers (MTOCs). Instead, microtubules first associate with a tight chromatin mass, and then bundle to form a bipolar spindle that lacks asters. Analysis of mutant oocytes indicates that the Non-Claret Disjunctional (NCD) kinesin-like protein is required for normal spindle assembly kinetics and stabilization of the spindle during metaphase arrest. Immunolocalization analyses demonstrate that NCD is associated with spindle microtubules, and that the centrosomal components gamma-tubulin, CP-190, and CP-60 are not concentrated at the meiotic spindle poles. Based on these observations, we propose that microtubule bundling by the NCD kinesin-like protein promotes assembly of a stable bipolar spindle in the absence of typical MTOCs.


Evaluation of preload reserve during isometric exercise testing in patients with old myocardial infarction: Doppler echocardiographic study.
To estimate the preload reserve in response to an increase in afterload in patients with old myocardial infarction, the relation between the Doppler echocardiographic inflow velocity pattern and left ventricular end-diastolic pressure was investigated during isometric handgrip exercise testing. The study population consisted of 16 normal subjects and 40 patients with old myocardial infarction. The 40 patients were subdivided into two groups according to left ventricular end-diastolic pressure at rest: group I (22 patients), less than 18 mm Hg; group II (18 patients), 18 mm Hg or more. At rest, the ratio of peak velocity in atrial contraction phase to peak velocity in early diastolic filling phase (A/E) was significantly higher in the patients with old myocardial infarction than in normal subjects; values in the two subgroups of myocardial infarction did not differ significantly. The A/E ratio and left ventricular end-diastolic pressure increased significantly during exercise in group I. Conversely, the change in left ventricular end-diastolic pressure during exercise in group II was significantly greater than that in group I, and was associated with a decrease in the A/E ratio. Thus, an atrial compensatory mechanism operated effectively in response to the increase in afterload in patients with a normal left ventricular filling pressure, whereas this compensatory mechanism deteriorated in patients with elevated left ventricular filling pressure due to a limited preload reserve.


The Genetic Modifiers of Motor OnsetAge (GeM MOA) Website: Genome-wide Association Analysis for Genetic Modifiers of Huntington's Disease.
Huntington's disease (HD) is a dominantly inherited disease caused by a CAG expansion mutation in HTT. The age at onset of clinical symptoms is determined primarily by the length of this CAG expansion but is also influenced by other genetic and/or environmental factors. Recently, through genome-wide association studies (GWAS) aimed at discovering genetic modifiers, we identified loci associated with age at onset of motor signs that are significant at the genome-wide level. However, many additional HD modifiers may exist but may not have achieved statistical significance due to limited power. In order to disseminate broadly the entire GWAS results and make them available to complement alternative approaches, we have developed the internet website "GeM MOA" where genetic association results can be searched by gene name, SNP ID, or genomic coordinates of a region of interest. Users of the Genetic Modifiers of Motor Onset Age (GeM MOA) site can therefore examine support for association between any gene region and age at onset of HD motor signs. GeM MOA's interactive interface also allows users to navigate the surrounding region and to obtain association p-values for individual SNPs. Our website conveys a comprehensive view of the genetic landscape of modifiers of HD from the existing GWAS, and will provide the means to evaluate the potential influence of genes of interest on the onset of HD. GeM MOA is freely available at https://www.hdinhd.org/.


Audio-visual feedback improves the BCI performance in the navigational control of a humanoid robot.
Advancement in brain computer interfaces (BCI) technology allows people to actively interact in the world through surrogates. Controlling real humanoid robots using BCI as intuitively as we control our body represents a challenge for current research in robotics and neuroscience. In order to successfully interact with the environment the brain integrates multiple sensory cues to form a coherent representation of the world. Cognitive neuroscience studies demonstrate that multisensory integration may imply a gain with respect to a single modality and ultimately improve the overall sensorimotor performance. For example, reactivity to simultaneous visual and auditory stimuli may be higher than to the sum of the same stimuli delivered in isolation or in temporal sequence. Yet, knowledge about whether audio-visual integration may improve the control of a surrogate is meager. To explore this issue, we provided human footstep sounds as audio feedback to BCI users while controlling a humanoid robot. Participants were asked to steer their robot surrogate and perform a pick-and-place task through BCI-SSVEPs. We found that audio-visual synchrony between footsteps sound and actual humanoid's walk reduces the time required for steering the robot. Thus, auditory feedback congruent with the humanoid actions may improve motor decisions of the BCI's user and help in the feeling of control over it. Our results shed light on the possibility to increase robot's control through the combination of multisensory feedback to a BCI user.