Setting up a pain management programme. The Ayrshire experience.
A controlled trial of an outpatient cognitive behavioural pain management programme for sufferers of non-cancer chronic pain is described. A multidisciplinary team set up a programme of ten half day sessions for groups of ten to fourteen patients aiming to improve activity levels and control over pain; to reduce maladaptive pain behaviours and drug intake; to mitigate negative mood; to modify unhelpful beliefs and to maintain treatment gains by operant and cognitive methods. Self report questionnaires were employed before and six weeks, six months and one year after the programme. Fifty-eight patients entered the study group and 39 patients completed the programme and initial follow up with further attrition in long term follow up. There were no changes in the waiting list control group of twelve subjects but the study group made significant short and long term improvements in pain severity, activity levels, mood, coping and experienced fewer catastrophizing thoughts.


56Fe irradiation-induced cognitive deficits through oxidative stress in mice.
The rapid growth of manned space flight results in more concerns about health risks and an urgent need for health assessment for space travel. The cosmic environment is complicated and full of radiation. Because of their strong biological effects, heavy ions such as 56Fe ions are considered to be an important component of these lethal galactic rays. Due to the importance of brain function to astronauts, we explored the long-term effects and potential mechanisms of 56Fe ion radiation on mice brains containing the hippocampus. In our study, radiation doses were carried out with 0.5 Gy, 1 Gy or 2 Gy. One month after whole-body 56Fe ion exposure, the Morris water maze test was performed to assess the ability of spatial learning and memory. A histological study was used for pathology analysis of the hippocampus. Alteration of oxidative stress was reflected by MDA and GSH and oxidative DNA damage marked by 8-OHdG was detected by biochemical and immunofluorescence methods. In our results, irradiated groups exhibited significant changes in behavioral performance and also showed loose and edematous arrangement in the pathological characteristics. Furthermore, whole brain levels of MDA, GSH and 8-OHdG increased in the irradiated groups. In addition, increased expression of 8-OHdG can also be detected by immunofluorescence in the hippocampus. Our findings revealed a linkage between radiation-induced oxidative stress and behavioral deficits. This may suggest an underlying mechanism of brain tissue protection and risk assessment in manned space flight.


Anxiety and depression among people living in quarantine centers during COVID-19 pandemic: A mixed method study from western Nepal.
In response to the COVID-19 pandemic, incoming travelers were quarantined at specific centers in Nepal and major checkpoints in Nepal-India border. Nepal adopted a generic public health approaches to control and quarantine returnee migrants, with little attention towards the quality of quarantine facilities and its aftermath, such as the poor mental health of the returnee migrants. The main objective of this study was to explore the status of anxiety and depression, and factors affecting them among returnee migrants living in institutional quarantine centers of western Nepal. A mixed method approach in this study included a quantitative survey and in-depth interviews (IDIs) among respondents in quarantine centers of Karnali province between 21st April and 15th May 2020. Survey questionnaire utilized Beck Depression Inventory (BDI) and Beck Anxiety Inventory (BAI) tools, which were administered among 441 quarantined returnee migrants. IDIs were conducted among 12 participants which included a mix of six quarantined migrants and healthcare workers each from the quarantine centres. Descriptive and inferential analyses were conducted on quantitative data; and thematic analysis was utilized for qualitative data. Mild depression (9.1%; 40/441) and anxiety (16.1%; 71/441) was common among respondents followed by moderate depression and anxiety {depression (3.4%; 15/441), anxiety (4.1%; 18/441)} and severe depression and anxiety {depression (1.1%; 5/441), anxiety (0.7%; 3/441)}. Anxiety and depression were independent of their socio-demographic characteristics. Perceived fear of contracting COVID-19, severity and death were prominent among the respondents. Respondents experienced stigma and discrimination in addition to being at the risk of disease and possible loss of employment and financial responsibilities. In addition, poor (quality and access to) health services, and poor living condition at the quarantine centres adversely affected respondents' mental health. Depression and anxiety were high among quarantined population and warrants more research. Institutional quarantine centers of Karnali province of Nepal were in poor conditions which adversely impacted mental health of the respondents. Poor resource allocation for health, hygiene and living conditions can be counterproductive to the population quarantined.


Polarimetric Balanced Detection: Background-Free Mid-IR Evanescent Field Laser Spectroscopy for Low-Noise, Long-term Stable Chemical Sensing.
In this work, we introduce polarimetric balanced detection as a new attenuated total reflection (ATR) infrared (IR) sensing scheme, leveraging unequal effective thicknesses achieved with laser light of different polarizations. We combined a monolithic widely tunable Vernier quantum cascade laser (QCL-XT) and a multibounce ATR IR spectroscopy setup for analysis of liquids in a process analytical setting. Polarimetric balanced detection enables simultaneous recording of background and sample spectra, significantly reducing long-term drifts. The root-mean-square noise could be improved by a factor of 10 in a long-term experiment, compared to conventional absorbance measurements obtained via the single-ended optical channel. The sensing performance of the device was further evaluated by on-site measurements of ethanol in water, leading to an improved limit of detection (LOD) achieved with polarimetric balanced detection. Sequential injection analysis was employed for automated injection of samples into a custom-built ATR flow cell mounted above a zinc sulfide multibounce ATR element. The QCL-XT posed to be suitable for mid-IR-based sensing in liquids due to its wide tunability. Polarimetric balanced detection proved to enhance the robustness and long-term stability of the sensing device, along with improving the LOD by a factor of 5. This demonstrates the potential for new polarimetric QCL-based ATR mid-IR sensing schemes for in-field measurements or process monitoring usually prone to a multitude of interferences.


Walnut diets up-regulate the decreased hippocampal neurogenesis and age-related cognitive dysfunction in d-galactose induced aged rats.
Recently, dietary intervention has been considered as a prospective strategy in delaying age-related cognitive dysfunction and brain plasticity degeneration. This study explored the effect of walnut diets (6% and 9%, 8 weeks) on cognitive behavior, hippocampal neurogenesis and the neurotrophic signaling pathway in d-galactose (d-gal) model rats. Behavioral tests showed that walnut diets significantly reversed spatial memory loss in the Morris water test, locomotor activity deficiency in an open field test, and a recognition behavior reduction in a novel object recognition task. Immunohistochemistry analysis demonstrated walnut diets significantly increased the hippocampal neurogenesis in d-gal model rats. Moreover, western blot results indicated that walnut diets reserved a d-gal induced decrease of hippocampal pCREB (Ser133) and BDNF expression, two crucial intracellular molecules involved in hippocampal neurogenesis. These findings confirmed that chronic walnut-rich diets could ameliorate cognitive dysfunction in d-gal model rats, and the up-regulation of neurogenesis, as well as the expression of pCREB and BDNF in hippocampus, may be one of the molecular and cellular mechanisms underlying these effects.


[Aids and tuberculosis: coinfection from the perspective of the quality of life of patients].
Tuberculosis (TB) and HIV coinfection adversely affects the lives of individuals in both the biological and psychosocial aspects. Aiming to describe the quality of life of individuals with HIV/TB coinfection, this descriptive cross-sectional study was conducted in Ribeirão Preto-SP. Participants were HIV-seropositive individuals with and without TB, using the WHOQOL HIV BREF. 115 individuals who were HIV-positive participated: 57 were coinfected and 58 were not; most were male heterosexuals, predominantly aged 40-49 years. Of those coinfected, most had lower education and income. In assessing the quality of life the coinfected individuals showed lower results in all areas, with significant differences in the Physical, Psychological, Level of Independence and Social Relations areas. TB and HIV / AIDS are stigmatized diseases, and overlap of the two may have severe consequences on the physical and psychosocial health of the individual.


Prevalence of pre-clinical autoimmunity in the normal adult population residing in a metropolitan city of India: A cross-sectional study.
A steep rise in the incidence of autoimmune diseases over the decades has been observed, which is simply not explainable with population-level genetic changes, indicating thereby that environmental factors play an important role in their causation. Then again, how air pollution affects the immune system is still not completely elucidated. This study intends to check the presence of autoantibodies and inflammatory markers in normal adults residing for more than 10 years in a highly polluted region. In this observational cross-sectional study design, 1,500 subjects residing in Delhi, India, for more than 10 years were screened, of whom 500 were recruited for the study. Distance from the main road to an individual's house was calculated, which was taken as a proxy for traffic pollution exposure. These subjects were analyzed for autoantibodies and inflammatory markers. The mean age of our cohort was 31.0±8.3 years. Autoantibody positivity was observed in 18% of the subjects, whereas inflammatory markers were elevated in 68% of the subjects. Subjects residing within 200 m of the main road had a higher prevalence of autoantibodies antinuclear antibody (12.5% vs 6.5% p=0.03) and rheumatoid factor (9.6% vs 4.5% p=0.02) than the subjects residing at or more than 250 m away from the main road. A total of 18% of normal subjects had autoantibody positivity. The odds of developing antinuclear antibodies were twice higher in subjects who resided within 200 m of the main road where the exposure to pollution was higher.


Reducing hospital-acquired infections and improving the rational use of antibiotics in a developing country: an effectiveness study.
Prevention of hospital-acquired infections (HAI) is central to providing safe and high quality healthcare. Transmission of infection between patients by health workers, and the irrational use of antibiotics have been identified as preventable aetiological factors for HAIs. Few studies have addressed this in developing countries. To implement a multifaceted infection control and antibiotic stewardship programme and evaluate its effectiveness on HAIs and antibiotic use. A before-and-after study was conducted over 27 months in a teaching hospital in Indonesia. All children admitted to the paediatric intensive care unit and paediatric wards were observed daily. Assessment of HAIs was made based on the criteria from the Centers for Disease Control and Prevention. The multifaceted intervention consisted of a hand hygiene campaign, antibiotic stewardship (using the WHO Pocket Book of Hospital Care for Children guidelines as standards of antibiotic prescribing for community-acquired infections), and other elementary infection control practices. Data were collected using an identical method in the preintervention and postintervention periods. We observed a major reduction in HAIs, from 22.6% (277/1227 patients) in the preintervention period to 8.6% (123/1419 patients) in the postintervention period (relative risk (RR) (95% CI) 0.38 (0.31 to 0.46)). Inappropriate antibiotic use declined from 43% (336 of 780 patients who were prescribed antibiotics) to 20.6% (182 of 882 patients) (RR 0.46 (0.40 to 0.55)). Hand hygiene compliance increased from 18.9% (319/1690) to 62.9% (1125/1789) (RR 3.33 (2.99 to 3.70)). In-hospital mortality decreased from 10.4% (127/1227) to 8% (114/1419) (RR 0.78 (0.61 to 0.97)). Multifaceted infection control interventions are effective in reducing HAI rates, improving the rational use of antibiotics, increasing hand hygiene compliance, and may reduce mortality in hospitalised children in developing countries.


Predictive Processing in Cognitive Robotics: A Review.
Predictive processing has become an influential framework in cognitive sciences. This framework turns the traditional view of perception upside down, claiming that the main flow of information processing is realized in a top-down, hierarchical manner. Furthermore, it aims at unifying perception, cognition, and action as a single inferential process. However, in the related literature, the predictive processing framework and its associated schemes, such as predictive coding, active inference, perceptual inference, and free-energy principle, tend to be used interchangeably. In the field of cognitive robotics, there is no clear-cut distinction on which schemes have been implemented and under which assumptions. In this letter, working definitions are set with the main aim of analyzing the state of the art in cognitive robotics research working under the predictive processing framework as well as some related nonrobotic models. The analysis suggests that, first, research in both cognitive robotics implementations and nonrobotic models needs to be extended to the study of how multiple exteroceptive modalities can be integrated into prediction error minimization schemes. Second, a relevant distinction found here is that cognitive robotics implementations tend to emphasize the learning of a generative model, while in nonrobotics models, it is almost absent. Third, despite the relevance for active inference, few cognitive robotics implementations examine the issues around control and whether it should result from the substitution of inverse models with proprioceptive predictions. Finally, limited attention has been placed on precision weighting and the tracking of prediction error dynamics. These mechanisms should help to explore more complex behaviors and tasks in cognitive robotics research under the predictive processing framework.


Hemangiomas versus arterio-venous malformations: role of elastic stains and mast cell density.
Vascular anomalies present diagnostic challenges to histopathologists. Mulliken and Glowacki's classification categorizes vascular lesions into hemangiomas and vascular malformations. This study explored diagnostic clues in the histomorphology of hemangiomas and vascular malformations. A total of 120 cases of benign vascular lesions were retrieved from 12 years period. A total of 94 cases, where complete clinical details and representative paraffin sections were available, were included in this study. Hematoxylin and eosin (H and E) stain and Verhoeff's stain for elastic tissue were done on all cases and lesions were classified into hemangiomas or arterio-venous malformations (AVM). Mast cell density in all lesions was calculated from toluidine blue stained sections. Ten cases of hemangiomas were reclassified as AVM on the basis of presence and absence of arteriovenous structures. Intra-lesional nerves were seen in significantly higher number of AVMs compared to hemangiomas. Medium and thick sized nerve bundles were seen in 56% of AVMs, while they were not seen in any of the hemangiomas. Mean mast cell density was significantly higher in proliferating hemangiomas (53.12 ± 27.83 cells/mm2) compared to involuting hemangiomas (11.43 ± 7.9 cells/mm2). Use of elastic tissue stains are useful ancillary tools to distinguish between AVMs and hemangiomas. The presence of arteries and arterioles are an integral part of AVMs. The presence of the intra-lesional nerves can be useful to distinguish between AVMs and hemangiomas even on H and E stained sections. The significantly higher mast cell density seen in proliferating hemangiomas compared with involuting ones, seem to suggest that mast cells play an important role in the natural history of these lesions.


Nurses as 'guests'--a study of a concept in light of Jacques Derrida's philosophy of hospitality.
As revealed in previous empirical research, nurses describe their position in home-based nursing care (HBNC) as that of 'guests' in the patient's home. Such a description is problematic as 'guests' might not be considered to belong to the realm of professionalism. As Jacques Derrida's work on hospitality has received wide publicity, sparking theoretical and philosophical discussion about host and guest, the aim of this study was to explore how the concept 'guests' can be understood in the light of Derrida's philosophy of hospitality. The study revealed that (a) guest must be considered a binary concept; and (b) hospitality should be regarded as an exchange of giving and receiving between a host and a guest. The present study demonstrated that it is important to reflect on the meaning of the concepts used by nurses in HBNC. Further theoretical and empirical exploration of the concept 'hospitality' would be fruitful, i.e. what is patients' understanding of 'hospitality' and 'hostility' related to nurses' descriptions of themselves as 'guests' in the patient's home.


Bed Rest Reduction Following Cardiac Catheterizations Using Vascular Closure Devices.
Bed rest duration following deployment of a vascular closure device after transfemoral left-sided cardiac catheterization is not standardized. Despite research supporting reduced bed rest, many hospitals require prolonged bed rest. Delayed ambulation is associated with back pain, urine retention, difficulty eating, and longer stay. To study length of stay, safety, and opportunity cost savings of reduced bed rest at a large urban hospital. A single-site 12-week study of 1-hour bed rest after transfemoral cardiac catheterizations using vascular closure devices. Results were compared with historical controls treated similarly. The standard bed rest group included 295 patients (207 male, 88 female; mean [SD] age, 64.4 [8.6] years). The early ambulation group included 260 patients (188 male, 72 female; mean [SD] age, 64 [9.3] years). The groups had no significant difference in age (t634 = 1.18, P = .21) or sex (χ12=0.2, P = .64). Three patients in the standard bed rest group and 1 in the early ambulation group had hematomas (P = .36). The stay for diagnostic cardiac catheterizations was longer in the standard bed rest group (mean [SD], 220.7 [55.2] minutes) than in the early ambulation group (mean [SD], 182.1 [78.5] minutes; t196 = 4.06; P < .001). Stay for percutaneous coronary interventions was longer in the standard bed rest group (mean [SD], 400.2 [50.8] minutes) than in the early ambulation group (mean [SD], 381.6 [54.7] minutes; t262 = 2.86; P = .005). Reduced bed rest was safe, shortened stays, and improved efficiency by creating opportunity cost savings.


The effects of environmental enrichment on nicotine condition place preference in male rats.
Environmental enrichment has previously been shown to alter sensitivity to psychostimulants and opiates in various preclinical models. However, little research has been conducted studying the effects of environmental enrichment on the more commonly abused drug, nicotine. The current study raised male rats in either enriched conditions (EC) or isolated conditions (IC) and tested the animals' sensitivity to acquisition, extinction and reinstatement of nicotine conditioned place preference (CPP). Using a 3-chamber CPP apparatus, male Sprague-Dawley rats were conditioned with 1 of 3 doses of nicotine (0.4, 0.6, and 0.8 mg/kg) or saline on alternating days across 8 conditioning trials, followed by a test day for a nicotine-induced CPP response. Next, the animals had 5 extinction sessions followed by a nicotine-primed reinstatement session. EC rats displayed nicotine CPP at all 3 doses, whereas IC rats failed to show significant nicotine CPP relative to saline controls. EC rats also showed extinction of the nicotine-induced CPP response by the fifth extinction session for all 3 nicotine doses tested. However, only the 2 highest doses of the nicotine prime reinstated a CPP response in EC rats relative to saline controls. Taken together, these findings suggest that environmental enrichment may increase sensitivity to the rewarding effects of nicotine.


The effect of vitamin D supplementation on inflammatory and hemostatic markers and disease activity in patients with systemic lupus erythematosus: a randomized placebo-controlled trial.
Systemic lupus erythematosus (SLE) is a chronic multisystem inflammatory autoimmune disease. Vitamin D has potent immunomodulatory properties that support its use in the treatment of autoimmune conditions, including SLE. We assessed vitamin D status in patients with SLE and determined alterations in inflammatory and hemostatic markers and disease activity before and after vitamin D supplementation. Patients with SLE (n = 267) were randomized 2:1 to receive either oral cholecalciferol 2000 IU/day or placebo for 12 months. Outcome measures included assessment of alterations in levels of proinflammatory cytokines and hemostatic markers, and improvement in disease activity before and after 12 months of supplementation. Disease activity was measured by the SLE Disease Activity Index. Vitamin D levels were measured by Liaison immunoassay (normal 30-100 ng/ml). Serum levels between 10 and 30 ng/ml were classified as vitamin D insufficiency and levels < 10 ng/ml as vitamin D deficiency. The mean 25(OH)D level at baseline was 19.8 ng/ml in patients compared to 28.7 ng/ml in controls. The overall prevalence of suboptimal and deficient 25(OH)D serum levels among patients with SLE at baseline was 69% and 39%, respectively. Lower 25(OH)D levels correlated significantly with higher SLE disease activity. At 12 months of therapy, there was a significant improvement in levels of inflammatory and hemostatic markers as well as disease activity in the treatment group compared to the placebo group. Vitamin D supplementation in patients with SLE is recommended because increased vitamin D levels seem to ameliorate inflammatory and hemostatic markers and show a tendency toward subsequent clinical improvement. Clinical Trial Registry NCT01425775.


An immediate-late gene expression module decodes ERK signal duration.
The RAF-MEK-ERK signalling pathway controls fundamental, often opposing cellular processes such as proliferation and apoptosis. Signal duration has been identified to play a decisive role in these cell fate decisions. However, it remains unclear how the different early and late responding gene expression modules can discriminate short and long signals. We obtained both protein phosphorylation and gene expression time course data from HEK293 cells carrying an inducible construct of the proto-oncogene RAF By mathematical modelling, we identified a new gene expression module of immediate-late genes (ILGs) distinct in gene expression dynamics and function. We find that mRNA longevity enables these ILGs to respond late and thus translate ERK signal duration into response amplitude. Despite their late response, their GC-rich promoter structure suggested and metabolic labelling with 4SU confirmed that transcription of ILGs is induced immediately. A comparative analysis shows that the principle of duration decoding is conserved in PC12 cells and MCF7 cells, two paradigm cell systems for ERK signal duration. Altogether, our findings suggest that ILGs function as a gene expression module to decode ERK signal duration.


A practical method to fabricate gold substrates for surface-enhanced Raman spectroscopy.
We describe a practical method of fabricating surface-enhanced Raman spectroscopy (SERS) substrates based on dip-coating poly-L-lysine derivatized microscope slides in a gold colloidal suspension. The use of only commercially available starting materials in this preparation is particularly advantageous, aimed at both reducing time and the inconsistency associated with surface modification of substrates. The success of colloid deposition has been demonstrated by scanning electron microscopy (SEM) and the corresponding SERS response (giving performance comparable to the corresponding traditional colloidal SERS substrates). Reproducibility was evaluated by conducting replicate measurements across six different locations on the substrate and assessing the extent of the variability (standard deviation values of spectral parameters: peak width and height), in response to either Rhodamine 6G or Isoniazid. Of particular interest is the observation of how some peaks in a given spectrum are more susceptible to data variability than others. For example, in a Rhodamine 6G SERS spectrum, spectral parameters of the peak at 775 cm(-1) were shown to have a relative standard deviation (RSD) % of <10%, while the peak at 1573 cm(-1) has a RSD of >or=10%. This observation is best explained by taking into account spectral variations that arise from the effect of a chemisorption process and the local nature of chemical enhancement mechanisms, which affects the enhancement of some spectral peaks but not others (analogous to resonant Raman phenomenon).


Impact of 2015 earthquakes on a local hospital in Nepal: A prospective hospital-based study.
Natural disasters pose a great challenge to the health systems and individual health facilities. In low-resource settings, disaster preparedness systems are often limited and not been well described. Two devastating earthquakes hit Nepal within a 17-days period in 2015. This study aims to describe the burden and distribution of emergency cases to a local hospital. This is a prospective observational study of patients presenting to a local hospital for a period of 21 days following the earthquake on April 25, 2015. Demographic and clinical information was prospectively registered for all patients in the systematic emergency registry. Systematic telephone interviews were conducted in a random sample of the patients 90 days after admission to the hospital. A total of 2,003 emergency patients were registered during the period. The average daily number of emergency patients during the first five days was almost five times higher (n = 150) than the pre-incident daily average (n = 35). The majority of injuries were fractures (58%), 348 (56%) in the lower extremities. A total of 345 surgical procedures were performed and the hospital treated 111 patients with severe injuries related to the earthquake (compartment syndrome, crush injury, and internal injury). Among those with follow-up interviews, over 90% reported that they had been severely affected by the earthquakes; complete house damage, living in temporary shelter, or loss of close family member. The hospital experienced a very high caseload during the first days, and the majority of patients needed orthopaedic services. The proportion of severely injured and in-hospital deaths were relatively low, probably indicating that the most severely injured did not reach the hospital in time. The experiences underline the need for robust and easily available local health services that can respond to disasters.


Comparative analysis of missing value imputation methods to improve clustering and interpretation of microarray experiments.
Microarray technologies produced large amount of data. In a previous study, we have shown the interest of k-Nearest Neighbour approach for restoring the missing gene expression values, and its positive impact of the gene clustering by hierarchical algorithm. Since, numerous replacement methods have been proposed to impute missing values (MVs) for microarray data. In this study, we have evaluated twelve different usable methods, and their influence on the quality of gene clustering. Interestingly we have used several datasets, both kinetic and non kinetic experiments from yeast and human. We underline the excellent efficiency of approaches proposed and implemented by Bo and co-workers and especially one based on expected maximization (EM_array). These improvements have been observed also on the imputation of extreme values, the most difficult predictable values. We showed that the imputed MVs have still important effects on the stability of the gene clusters. The improvement on the clustering obtained by hierarchical clustering remains limited and, not sufficient to restore completely the correct gene associations. However, a common tendency can be found between the quality of the imputation method and the gene cluster stability. Even if the comparison between clustering algorithms is a complex task, we observed that k-means approach is more efficient to conserve gene associations. More than 6.000.000 independent simulations have assessed the quality of 12 imputation methods on five very different biological datasets. Important improvements have so been done since our last study. The EM_array approach constitutes one efficient method for restoring the missing expression gene values, with a lower estimation error level. Nonetheless, the presence of MVs even at a low rate is a major factor of gene cluster instability. Our study highlights the need for a systematic assessment of imputation methods and so of dedicated benchmarks. A noticeable point is the specific influence of some biological dataset.


Structure, function, and evolution of adenovirus-associated RNA: a phylogenetic approach.
To explore the structure and function of a small regulatory RNA, we examined the virus-associated (VA) RNA species of all 47 known human adenovirus serotypes and of one simian virus, SA7. The VA RNA gene regions of 43 human adenoviruses were amplified and sequenced, and the structures of 10 representative VA RNAs were probed by nuclease sensitivity analysis. Most human viruses have two VA RNA species, VA RNA, and VA RNAII, but nine viruses (19%) have a single VA RNA gene. Sequence alignments classified the RNAs into eight families, corresponding broadly to the known virus groups, and three superfamilies. One superfamily contains the single VA RNAs of groups A and F and the VA RNAI species of group C; the second contains the VA RNAI species of groups B1, D, and E and the unclassified viruses (adenovirus types 42 to 47), as well as the single VA RNAs of group B2; and the third contains all VA RNAII species. Fourteen regions of homology occur throughout the molecule. The longest of these correspond to transcription signals; most of the others participate in RNA secondary structure. The previously identified tetranucleotide pair, GGGU:ACCC, is nearly invariant, diverging slightly (to GGGU:ACCU) only in the two group F viruses and forming a stem in the central domain that is critical for VA RNA structure and function. Secondary structure models which accommodate the nuclease sensitivity data and sequence variations within each family were generated. The major structural features-the terminal stem, apical stem-loop, and central domain-are conserved in all VA RNAs, but differences exist in the apical stem and central domains, especially of the VA RNAII species. Sequence analysis suggests that an ancestral VA RNA gene underwent duplication during the evolution of viruses containing two VA RNA genes. Although the VA RNAII gene seems to have been lost or inactivated by secondary deletion events in some viruses, the high degree of homology among the VA RNAII species implies that this RNA may play an undiscovered role in virus survival. We speculate that the VA RNA genes originated from cellular sequences containing multiple tRNA genes.


Somatostatin analog and pegvisomant combination therapy for acromegaly.
Optimal biochemical control cannot be attained by long-acting somatostatin analog monotherapy in a large proportion of patients with acromegaly. Such therapy might result in increased mortality, poor control of signs and symptoms of disease and decreased quality of life. Combination treatment with somatostatin analogs and pegvisomant (a growth-hormone-receptor antagonist) is, however, highly effective at normalizing the level of insulin-like growth factor I in over 90% of patients and might also have a favorable effect on quality of life in those with biochemically controlled acromegaly. Moreover, whereas pegvisomant monotherapy does not lead to a decrease in the size of the pituitary tumor, combination therapy with somatostatin analogs results in a clinically relevant decrease in tumor size in about 20% of patients. The main adverse effects of combination treatment are transient elevations in the levels of transaminases, which occur in about 15% of patients, especially in those with diabetes mellitus. In this Review, we discuss the available data on the long-term efficacy and safety of somatostatin analog-pegvisomant combination treatment and its potential use in patients with acromegaly.


Biological consequences of potential repair intermediates of clustered base damage site in Escherichia coli.
Clustered DNA damage induced by a single radiation track is a unique feature of ionizing radiation. Using a plasmid-based assay in Escherichia coli, we previously found significantly higher mutation frequencies for bistranded clusters containing 7,8-dihydro-8-oxoguanine (8-oxoG) and 5,6-dihydrothymine (DHT) than for either a single 8-oxoG or a single DHT in wild type and in glycosylase-deficient strains of E. coli. This indicates that the removal of an 8-oxoG from a clustered damage site is most likely retarded compared to the removal of a single 8-oxoG. To gain further insights into the processing of bistranded base lesions, several potential repair intermediates following 8-oxoG removal were assessed. Clusters, such as DHT+apurinic/apyrimidinic (AP) and DHT+GAP have relatively low mutation frequencies, whereas clusters, such as AP+AP or GAP+AP, significantly reduce the number of transformed colonies, most probably through formation of a lethal double strand break (DSB). Bistranded AP sites placed 3' to each other with various interlesion distances also blocked replication. These results suggest that bistranded base lesions, i.e., single base lesions on each strand, but not clusters containing only AP sites and strand breaks, are repaired in a coordinated manner so that the formation of DSBs is avoided. We propose that, when either base lesion is initially excised from a bistranded base damage site, the remaining base lesion will only rarely be converted into an AP site or a single strand break in vivo.


Boosting therapeutic potency of antibodies by taming Fc domain functions.
Monoclonal antibodies (mAbs) are one of the most widely used drug platforms for infectious diseases or cancer therapeutics because they selectively target pathogens, infectious cells, cancerous cells, and even immune cells. In this way, they mediate the elimination of target molecules and cells with fewer side effects than other therapeutic modalities. In particular, cancer therapeutic mAbs can recognize cell-surface proteins on target cells and then kill the targeted cells by multiple mechanisms that are dependent upon a fragment crystallizable (Fc) domain interacting with effector Fc gamma receptors, including antibody-dependent cell-mediated cytotoxicity and antibody-dependent cell-mediated phagocytosis. Extensive engineering efforts have been made toward tuning Fc functions by either reinforcing (e.g. for targeted therapy) or disabling (e.g. for immune checkpoint blockade therapy) effector functions and prolonging the serum half-lives of antibodies, as necessary. In this report, we review Fc engineering efforts to improve therapeutic potency, and propose future antibody engineering directions that can fulfill unmet medical needs.


Understanding trends in Australian alcohol consumption-an age-period-cohort model.
To decompose Australian trends in alcohol consumption into their age, period (survey year) and cohort (birth year/generation) components. In particular, we aimed to test whether recent declines in overall consumption have been influenced by reductions in drinking among recently born cohorts. Seven cross-sectional waves of the Australian National Drug Strategy Household Survey (1995-2013). Age, period and cohort effects were estimated using a linear and logistic cross-classified random-effects models (CCREMs). Australia A total of 124 440 Australians (69 193 females and 55 257 males), aged 14-79 years. Whether or not respondents consumed alcohol in the 12 months prior to the survey and, for those who did, the estimated volume of pure alcohol consumed, derived using standard quantity-frequency survey questions. Controlling for age and period effects, there was significant variation in drinking participation and drinking volume by birth cohort. In particular, male cohorts born between the 1965 and 1974 and female cohorts born between 1955 and 1974 reported higher rates of drinking participation (P < 0.05), while the most recent cohorts (born in the 1990s) had lower rates of participation (P < 0.01). Among drinkers, the most recently born cohort also had sharply lower average consumption volumes than older cohorts for both men and women (P < 0.01). Recent birth cohorts (born between 1995 and 1999) in Australia report significantly lower rates of both drinking participation and drinking volume than previous cohorts, controlling for their age distribution and overall changes in population drinking. These findings suggest that the recent decline in alcohol consumption in Australia has been driven by declines in drinking among these recently born cohorts. These trends are consistent with international shifts in youth drinking.


Nutrient and methyl mercury exposure from consuming fish.
There is controversy about the risks and benefits of consuming fish. Fish consumption provides nutrients, some of which are essential for brain growth and development. All fish, however, contain methyl mercury (MeHg), a known neurotoxicant. The toxic effect of MeHg seems most damaging during brain development, and thus, prenatal exposure is of greatest concern. At present the level of prenatal exposure associated with risk to a child's neurodevelopment is not known. Balancing the rewards and possible risks of fish consumption presents a dilemma to consumers and regulatory authorities. We review the nutrients in fish that are important in brain development and the current evidence of risk from MeHg at exposure levels achieved by consuming fish. We then review the findings from a large prospective cohort study of a population that consumes fish daily, the Seychelles Child Development Study. The MeHg content of the fish consumed in the Seychelles is similar to that of ocean fish available in industrialized countries, so they represent a sentinel population for any risk from fish consumption. In the Seychelles, evaluations of the children through 9 y of age show no consistent pattern of adverse associations with prenatal MeHg exposure. Recent studies in the Seychelles have focused on nutrients in fish that might influence a child's development, including long-chain polyunsaturated fatty acids, iodine, iron, and choline. Preliminary findings from this study suggest that the beneficial influence of nutrients from fish may counter any adverse effects of MeHg on the developing nervous system.


Meta-analysis of correlated traits via summary statistics from GWASs with an application in hypertension.
Genome-wide association studies (GWASs) have identified many genetic variants underlying complex traits. Many detected genetic loci harbor variants that associate with multiple-even distinct-traits. Most current analysis approaches focus on single traits, even though the final results from multiple traits are evaluated together. Such approaches miss the opportunity to systemically integrate the phenome-wide data available for genetic association analysis. In this study, we propose a general approach that can integrate association evidence from summary statistics of multiple traits, either correlated, independent, continuous, or binary traits, which might come from the same or different studies. We allow for trait heterogeneity effects. Population structure and cryptic relatedness can also be controlled. Our simulations suggest that the proposed method has improved statistical power over single-trait analysis in most of the cases we studied. We applied our method to the Continental Origins and Genetic Epidemiology Network (COGENT) African ancestry samples for three blood pressure traits and identified four loci (CHIC2, HOXA-EVX1, IGFBP1/IGFBP3, and CDH17; p < 5.0 × 10(-8)) associated with hypertension-related traits that were missed by a single-trait analysis in the original report. Six additional loci with suggestive association evidence (p < 5.0 × 10(-7)) were also observed, including CACNA1D and WNT3. Our study strongly suggests that analyzing multiple phenotypes can improve statistical power and that such analysis can be executed with the summary statistics from GWASs. Our method also provides a way to study a cross phenotype (CP) association by using summary statistics from GWASs of multiple phenotypes.


Stromal Vascular Fraction-enriched Fat Grafting for the Treatment of Symptomatic End-neuromata.
The purpose of this study was to methodically illustrate and highlight the crucial steps of stromal vascular fraction (SVF)-enriched fat grafting as a novel treatment of symptomatic end-neuromata of peripheral sensory nerves, and in this study, specifically of the superficial branch of the radial nerve (SBRN). Despite a multitude of existing treatments, persistent postoperative pain and common pain relapse are still very common, independent of the procedure assessed. The neuroma is microsurgically excised accordingly to standardized protocol. Instead of the relocation of the regenerating nerve stump in neighboring anatomical structures, such as muscle or bone, a fat graft is applied perifocally and acts as a mechanical barrier. In order to reduce the fat resorption rate and boost the regenerative potential of the graft, the highly concentrated SVF is integrated in the grafting. The SVF is isolated from subcutaneous fat by enzymatic and mechanic separation of the lipoaspirate by a specific commercial isolation system. The SVF-enriched fat graft provides both a mechanical barrier and various biological effects at the cellular level, including improving angiogenesis, inflammation, and fibrosis. Both mechanical and biologic effects help to reduce the disorganized axonal outgrowth of the nerve stump during nerve regeneration and hence prevent the recurrence of painful end-neuromata.


Development of a Novel Multi-Isoform ALDH Inhibitor Effective as an Antimelanoma Agent.
The aldehyde dehydrogenases (ALDH) are a major family of detoxifying enzymes that contribute to cancer progression and therapy resistance. ALDH overexpression is associated with a poor prognosis in many cancer types. The use of multi-ALDH isoform or isoform-specific ALDH inhibitors as anticancer agents is currently hindered by the lack of viable candidates. Most multi-ALDH isoform inhibitors lack bioavailability and are nonspecific or toxic, whereas most isoform-specific inhibitors are not effective as monotherapy due to the overlapping functions of ALDH family members. The present study details the development of a novel, potent, multi-isoform ALDH inhibitor, called KS100. The rationale for drug development was that inhibition of multiple ALDH isoforms might be more efficacious for cancer compared with isoform-specific inhibition. Enzymatic IC50s of KS100 were 207, 1,410, and 240 nmol/L toward ALDH1A1, 2, and 3A1, respectively. Toxicity of KS100 was mitigated by development of a nanoliposomal formulation, called NanoKS100. NanoKS100 had a loading efficiency of approximately 69% and was stable long-term. NanoKS100 was 5-fold more selective for killing melanoma cells compared with normal human fibroblasts. NanoKS100 administered intravenously at a submaximal dose (3-fold lower) was effective at inhibiting xenografted melanoma tumor growth by approximately 65% without organ-related toxicity. Mechanistically, inhibition by KS100 significantly reduced total cellular ALDH activity to increase reactive oxygen species generation, lipid peroxidation, and accumulation of toxic aldehydes leading to apoptosis and autophagy. Collectively, these data suggest the successful preclinical development of a nontoxic, bioavailable, nanoliposomal formulation containing a novel multi-ALDH isoform inhibitor effective in the treatment of cancer.


Reduction of the amplified spontaneous emission threshold in semiconducting polymer waveguides on porous silica.
Hybrid organic-inorganic monomode waveguides of conjugated polymers on porous silicon (PS) substrates have been fabricated. Different low refractive index PS substrates, varying from 1.46 down to 1.18 have been studied. Amplified spontaneous emission (ASE) has been observed for all the samples and the ASE threshold has been monitored as a function of the PS refractive index. A decrease in the ASE threshold is detected when the PS refractive index decreases. These results have been analysed in the frame of a four level waveguide amplifier model and the theoretical predictions are in agreement with the experimental data.


Association of hemolytic activity of Pseudomonas entomophila, a versatile soil bacterium, with cyclic lipopeptide production.
Pseudomonas entomophila is an entomopathogenic bacterium that is able to infect and kill Drosophila melanogaster upon ingestion. Its genome sequence suggests that it is a versatile soil bacterium closely related to Pseudomonas putida. The GacS/GacA two-component system plays a key role in P. entomophila pathogenicity, controlling many putative virulence factors and AprA, a secreted protease important to escape the fly immune response. P. entomophila secretes a strong diffusible hemolytic activity. Here, we showed that this activity is linked to the production of a new cyclic lipopeptide containing 14 amino acids and a 3-C(10)OH fatty acid that we called entolysin. Three nonribosomal peptide synthetases (EtlA, EtlB, EtlC) were identified as responsible for entolysin biosynthesis. Two additional components (EtlR, MacAB) are necessary for its production and secretion. The P. entomophila GacS/GacA two-component system regulates entolysin production, and we demonstrated that its functioning requires two small RNAs and two RsmA-like proteins. Finally, entolysin is required for swarming motility, as described for other lipopeptides, but it does not participate in the virulence of P. entomophila for Drosophila. While investigating the physiological role of entolysin, we also uncovered new phenotypes associated with P. entomophila, including strong biocontrol abilities.


The effect of "Jelly" CdTe QD uptake on RAW264.7 monocytes: immune responses and cell fate study.
Encapsulation of Quantum Dots (QDs) has become an essential factor which regulates particles cytotoxicity, as well as physical and chemical stability. Negatively charged cellular membranes have a great affinity to nanoparticles with surface molecules carrying positive charge, hence creating perfect conditions for fast and aggressive intracellular penetration. The preference for non-charged outer shells is topical in QD design and various applications. In the current paper we develop gelatination as a prominent coating approach to create neutrally passivated QDs with improved biocompatibility. We have revealed the trends in particle's uptake, accumulation, intracellular localisation and retaining time as well as RAW264.7 monocyte cell fate and immune responses. Also the difference in particle endocytosis kinetics and dynamics has been shown to depend on the QD core size. The intracellular QD content along with cell responses at the population level was quantified by flow cytometry.


Strategies to promote prudent antibiotic use: exploring the views of professionals who develop and implement guidelines and interventions.
A variety of interventions have been developed to promote prudent antibiotic use, especially for respiratory tract infections (RTIs); however, it is not yet clear which are most acceptable and feasible for implementation across a wide range of contexts. This study elicited the views of experts, professionals who develop and implement guidelines and interventions, from five countries, on the development of RTI guidelines and interventions for implementing them. The aim was to determine whether there are common features of interventions which experts consider useful in changing health professionals' behaviour, or whether there are important contextual differences in views. Fifty semi-structured interviews explored experts' views and experiences of strategies across five countries. Interviews were carried out in person or over the phone, transcribed verbatim and translated into English, if not already in English, for analysis. Themes were remarkably consistent across the countries, and these could be summarized as five sets of recommendations: guidelines should be developed by health care professionals to better fit GPs' needs; address GP concerns about recommendations and explain the need for guidelines; design flexible interventions to increase feasibility across primary care practice; provide interventions which engage GPs; and provide consistent messages about antibiotic use for patients, professionals and the public. Key features need to be addressed when developing future guidelines and interventions in order to improve their implementation. Consistency in experts' views across countries indicates the potential for the development of interventions which could be implemented on a multinational scale with widespread support from key opinion leaders.


The leukotriene B4 receptor (BLT1) is required for effector CD8+ T cell-mediated, mast cell-dependent airway hyperresponsiveness.
Studies in both humans and rodents have suggested that CD8+ T cells contribute to the development of airway hyperresponsiveness (AHR) and that leukotriene B4 (LTB4) is involved in the chemotaxis of effector CD8+ T cells (T(EFF)) to the lung by virtue of their expression of BLT1, the receptor for LTB4. In the present study, we used a mast cell-CD8-dependent model of AHR to further define the role of BLT1 in CD8+ T cell-mediated AHR. C57BL/6+/+ and CD8-deficient (CD8-/-) mice were passively sensitized with anti-OVA IgE and exposed to OVA via the airways. Following passive sensitization and allergen exposure, C57BL/6+/+ mice developed altered airway function, whereas passively sensitized and allergen-exposed CD8-/- mice failed to do so. CD8-/- mice reconstituted with CD8+ T(EFF) developed AHR in response to challenge. In contrast, CD8-/- mice reconstituted with BLT1-deficient effector CD8+ T cells did not develop AHR. The induction of increased airway responsiveness following transfer of CD8+ T(EFF) or in wild-type mice could be blocked by administration of an LTB4 receptor antagonist confirming the role of BLT1 in CD8+ T cell-mediated AHR. Together, these data define the important role for mast cells and the LTB4-BLT1 pathway in the development of CD8+ T cell-mediated allergic responses in the lung.


Traumatic fragmentation and concurrent infection of a palmar sesamoid in a cat.
A 9-year-old neutered male domestic shorthair cat was referred for assessment of a chronic non-weightbearing left forelimb lameness that had an acute onset following a suspected cat bite to the distal limb 4 weeks previously. There was minimal improvement following conservative management. On examination there was discomfort on palpation of the left palmar metacarpal region. An orthopaedic examination performed under sedation identified a moderate effusion of the left fourth metacarpophalangeal joint. A CT scan was performed, which identified fragmentation of the medial palmar sesamoid of the fourth digit (sesamoid V). Arthrocentesis of the fourth metacarpophalangeal joint identified septic inflammation. Surgical removal of the fragmented palmar sesamoid was performed and was submitted for histopathology and bacteriology analysis. Postoperative CT confirmed the removal of all fragments. Pasteurella species were isolated from the sesamoid fragments. Histopathology revealed osteomyelitis, neutrophilic inflammation and multifocal necrosis, with evidence of fibrosis present. The cat was re-examined 3 months postoperatively, at which point there was no evidence of lameness and orthopaedic examination of the limb was unremarkable. To our knowledge, this is the first reported case of fragmentation of a palmar sesamoid in a cat. This case study describes the diagnosis and the successful management of a cat with fragmentation of a palmar sesamoid, following an altercation with another cat.


Structure, mechanism, and inhibition of Hedgehog acyltransferase.
The Sonic Hedgehog (SHH) morphogen pathway is fundamental for embryonic development and stem cell maintenance and is implicated in various cancers. A key step in signaling is transfer of a palmitate group to the SHH N terminus, catalyzed by the multi-pass transmembrane enzyme Hedgehog acyltransferase (HHAT). We present the high-resolution cryo-EM structure of HHAT bound to substrate analog palmityl-coenzyme A and a SHH-mimetic megabody, revealing a heme group bound to HHAT that is essential for HHAT function. A structure of HHAT bound to potent small-molecule inhibitor IMP-1575 revealed conformational changes in the active site that occlude substrate binding. Our multidisciplinary analysis provides a detailed view of the mechanism by which HHAT adapts the membrane environment to transfer an acyl chain across the endoplasmic reticulum membrane. This structure of a membrane-bound O-acyltransferase (MBOAT) superfamily member provides a blueprint for other protein-substrate MBOATs and a template for future drug discovery.


Structure-activity relationships of new heterocycle-containing bisphosphonates as inhibitors of bone resorption and as inhibitors of growth of Dictyostelium discoideum amoebae.
The mechanisms by which bisphosphonate drugs inhibit osteoclast-mediated bone resorption are unclear. Effects of bisphosphonates on cellular enzymes, metabolic pathways, and osteoclast morphology have previously been described and could culminate in a generalized cytotoxic effect or a decreased capacity of osteoclasts to resorb bone. Recent studies of the structure-activity relationship for the bisphosphonate side chain indicate, however, that at least the newer generations of nitrogen-containing bisphosphonates probably act by binding to a specific target at a site that is complementary in structure to the bisphosphonate side chain. We have previously proposed that such a target for bisphosphonates is also present in amoebae of the cellular slime mold Dictyostelium discoideum, because growth of this microorganism is inhibited by a wide range of bisphosphonates in a manner that closely reflects the antiresorptive potencies of the bisphosphonates in vivo. We have added support for this view by examining the potency towards Dictyostelium of bisphosphonates in which slight changes in the structure of the side chain or conformational restrictions to the side chain have marked effects on antiresorptive potency. The changes in the side chain that affected the in vivo antiresorptive potency of the bisphosphonates consistently affected in a similar manner the potency of the bisphosphonates as inhibitors of the growth of Dictyostelium amoebae. These observations confirm that bisphosphonate drugs have a molecular target that is common to both Dictyostelium amoebae and osteoclasts.


McGrath MAC Videolaryngoscope Versus Optiscope Video Stylet for Tracheal Intubation in Patients With Manual Inline Cervical Stabilization: A Randomized Trial.
Manual inline stabilization of the head and neck is a recommended maneuver for tracheal intubation in patients with a suspected cervical injury. However, because applying this maneuver inevitably restricts neck flexion and head extension, indirect intubating devices such as a videolaryngoscope or a video stylet could be required for successful tracheal intubation. In this study, we compared the clinical performance of the McGrath MAC videolaryngoscope versus the Optiscope video stylet in patients with manual inline cervical stabilization during tracheal intubation. In 367 consecutive patients undergoing elective cervical spine surgery, tracheal intubation was randomly performed with manual inline stabilization using either the McGrath MAC videolaryngoscope (group M, n = 183) or the Optiscope video stylet (group O, n = 184) by 2 experienced anesthesiologists in a single institution. The primary outcome was the first-attempt success rate of tracheal intubation. Secondary outcomes were intubation time and the incidence of postoperative airway complications, such as sore throat, hoarseness, blood in the oral cavity, and blood staining on the endotracheal tube. The first-attempt success rate of tracheal intubation was significantly higher in group M compared with group O (92.3% vs 81.0%; risk difference [95% confidence interval], 0.11 [0.05-0.18]; P = .002). The intubation time was significantly shorter in group M than in group O (35.7 ± 27.8 vs 49.2 ± 43.8; mean difference [95% confidence interval], 13.5 [5.9-21.1]; P = .001). The incidence of postoperative airway complications was not significantly different between the 2 groups. The McGrath MAC videolaryngoscope showed a higher first-attempt success rate for tracheal intubation and a shorter intubation time than the Optiscope video stylet in cervical spine patients with manual inline stabilization during tracheal intubation. These results suggest that the McGrath MAC videolaryngoscope may be a better option for tracheal intubation in such patients.


Ecological and evolutionary determinants for the adaptive radiation of the Madagascan vangas.
Adaptive radiation is the rapid diversification of a single lineage into many species that inhabit a variety of environments or use a variety of resources and differ in traits required to exploit these. Why some lineages undergo adaptive radiation is not well-understood, but filling unoccupied ecological space appears to be a common feature. We construct a complete, dated, species-level phylogeny of the endemic Vangidae of Madagascar. This passerine bird radiation represents a classic, but poorly known, avian adaptive radiation. Our results reveal an initial rapid increase in evolutionary lineages and diversification in morphospace after colonizing Madagascar in the late Oligocene some 25 Mya. A subsequent key innovation involving unique bill morphology was associated with a second increase in diversification rates about 10 Mya. The volume of morphospace occupied by contemporary Madagascan vangas is in many aspects as large (shape variation)--or even larger (size variation)--as that of other better-known avian adaptive radiations, including the much younger Galapagos Darwin's finches and Hawaiian honeycreepers. Morphological space bears a close relationship to diet, substrate use, and foraging movements, and thus our results demonstrate the great extent of the evolutionary diversification of the Madagascan vangas.


Residual embryonic cells as precursors of a Barrett's-like metaplasia.
Barrett's esophagus is an intestine-like metaplasia and precursor of esophageal adenocarcinoma. Triggered by gastroesophageal reflux disease, the origin of this metaplasia remains unknown. p63-deficient mice, which lack squamous epithelia, may model acid-reflux damage. We show here that p63 null embryos rapidly develop intestine-like metaplasia with gene expression profiles similar to Barrett's metaplasia. We track its source to a unique embryonic epithelium that is normally undermined and replaced by p63-expressing cells. Significantly, we show that a discrete population of these embryonic cells persists in adult mice and humans at the squamocolumnar junction, the source of Barrett's metaplasia. We show that upon programmed damage to the squamous epithelium, these embryonic cells migrate toward adjacent, specialized squamous cells in a process that may recapitulate early Barrett's. Our findings suggest that certain precancerous lesions, such as Barrett's, initiate not from genetic alterations but from competitive interactions between cell lineages driven by opportunity.


Functional proteomics mapping of a human signaling pathway.
Access to the human genome facilitates extensive functional proteomics studies. Here, we present an integrated approach combining large-scale protein interaction mapping, exploration of the interaction network, and cellular functional assays performed on newly identified proteins involved in a human signaling pathway. As a proof of principle, we studied the Smad signaling system, which is regulated by members of the transforming growth factor beta (TGFbeta) superfamily. We used two-hybrid screening to map Smad signaling protein-protein interactions and to establish a network of 755 interactions, involving 591 proteins, 179 of which were poorly or not annotated. The exploration of such complex interaction databases is improved by the use of PIMRider, a dedicated navigation tool accessible through the Web. The biological meaning of this network is illustrated by the presence of 18 known Smad-associated proteins. Functional assays performed in mammalian cells including siRNA knock-down experiments identified eight novel proteins involved in Smad signaling, thus validating this integrated functional proteomics approach.


The role of intermediate filament proteins in the development of neurological disease.
Intermediate filaments (IFs), along with microfilaments and microtubules, comprise the three intracellular filaments identified in eukaryotic cells to date. Together, these three distinct filamentous networks act in a dynamic and tightly interconnected fashion to comprise the eukaryotic cytoskeleton. As such, they are involved in a number of essential and diverse cellular processes, including division, molecular transport, and the maintenance of structural integrity in the face of mechanical stress. Underscoring the ubiquitous importance of IF proteins to the normal function of cellular systems, mutations in IF-encoding genes that affect the structure, function, or regulation of these proteins are commonly found in association with a range of heritable genetic diseases. The diversity of IF-related disease is indeed as wide as the distribution of IF proteins themselves, effecting the development of a broad range of disease phenotypes. Here we review, with specific reference to recent developments in the correlation of genotype with phenotype, how the perturbation of IF networks can elicit the development of human neurological disease.


[Intraperitoneal administration of 50% enantiomeric excess (S75-R25) bupivacaine in postoperative analgesia of laparoscopic cholecystectomy].
The analgesic effect of intraperitoneal administration of local anesthetics after laparoscopic cholecystectomy is a controversial issue, and the results described vary from considerable pain relief to little reduction in pain. The objective of this study was to evaluate the efficacy of the intraperitoneal administration of 50% enantiomeric excess bupivacaine (S75-R25) for the postoperative pain relief of laparoscopic cholecystectomy. A randomized, double blind, placebo controlled study was conducted with 40 patients undergoing laparoscopic cholecystectomy, who were divided in two groups: GI (n = 20) received 80 mL of intraperitoneal 0,125% S75-R25 bupivacaine at the end of the procedure; and GII (n = 20) received 80 mL of intraperitoneal normal saline. Both groups received 40 mg of tenoxicam and 30 mg.kg-1 of intravenous dypirone shortly before the end of the surgery. Tramadol was used for postoperative analgesia (PO). Pain scores were evaluated at rest, sitting up, and during the Valsalva maneuver, according to a numeric scale upon waking up and 2, 4, 8, 12, and 24 hours postoperatively; the presence of shoulder pain was assessed, as well as the length of time until the first request of analgesic and its cumulative consumption. There was a statistically significant difference in resting pain scores at 12 hours PO (GI < GII). The length of time until the first request of tramadol was greater in GI and this group presented smaller consumption of this drug, but these differences were not statistically significant. The intraperitoneal instillation of 80 mL of 0.125% S75-R25 bupivacaine provided for lower resting pain scores, which was statistically significant only at the 12th postoperative hour.


The impact of obesity on laparoscopic appendectomy: Results from the ACS National Surgical Quality Improvement Program pediatric database.
Childhood obesity is a worsening epidemic. Little is known about the impact of elevated BMI on perioperative and postoperative complications in children who undergo laparoscopic surgery. The purpose of this study was to examine the effects of obesity on surgical outcomes in children using laparoscopic appendectomy as a model for the broader field of laparoscopic surgery. Using the Pediatric National Surgical Quality Improvement Program (NSQIP) data from 2012, patients aged 2-18years old with acute uncomplicated and complicated appendicitis who underwent laparoscopic appendectomy were identified. Children with a body mass index (BMI)≥95th percentile for their age and gender were considered obese. Primary outcomes, including overall morbidity and wound complications, were compared between nonobese and obese children. Multivariate regression analysis was conducted to identify the impact of obesity on outcome. A total of 2812 children with acute appendicitis who underwent appendectomy were included in the analysis; 22% were obese. Obese children had longer operative times but did not suffer increased postoperative complications when controlling for confounders (OR 1.3, 95% CI: 0.83-0.072 for overall complications, OR 1.3, 95% CI: 0.84-1.95 for wound complications). Obesity is not an independent risk factor for postoperative complications following laparoscopic appendectomy. Although operative times are increased in obese children, obesity does not increase the likelihood of 30-day postoperative complications.


Identification of vowel length, word stress, and compound words and phrases by postlingually deafened cochlear implant listeners.
The accurate perception of prosody assists a listener in deriving meaning from natural speech. Few studies have addressed the ability of cochlear implant (CI) listeners to perceive the brief duration prosodic cues involved in contrastive vowel length, word stress, and compound word and phrase identification. To compare performance in the perception of brief duration prosodic contrasts by CI participants and a control group of normal hearing participants. This study investigated the ability to perceive these cues in quiet and noise conditions, and to identify auditory perceptual factors that might predict prosodic perception in the CI group. Prosodic perception was studied both in noise and quiet because noise is a pervasive feature of everyday environments. A quasi-experimental correlation design was employed. Twenty-one CI recipients participated along with a control group of 10 normal hearing participants. All CI participants were unilaterally implanted adults who had considerable experience with oral language prior to implantation. Speech identification testing measured the participants' ability to identify word stress, vowel length, and compound words or phrases all of which were presented with minimal-pair response choices. Tests were performed in quiet and in speech-spectrum shaped noise at a 10 dB signal-to-noise ratio. Also, discrimination thresholds for four acoustic properties of a synthetic vowel were measured as possible predictors of prosodic perception. Testing was carried out during one session, and participants used their clinically assigned speech processors. The CI group could not identify brief prosodic cues as well as the control group, and their performance decreased significantly in the noise condition. Regression analysis showed that the discrimination of intensity predicted performance on the prosodic tasks. The performance decline measured with the older participants meant that age also emerged as a predictor. This study provides a portrayal of CI recipients' ability to perceive brief prosodic cues. This is of interest in the preparation of rehabilitation materials used in training and in developing realistic expectations for potential CI candidates.


Are women at higher risk than men? Gender differences among teenagers and adults in their response to threat of war and terror.
The present study examined whether women are at higher risk of developing stress reactions in situations of war and terror. The study looked at gender differences within two samples-teenagers (n = 353) and adults (n = 890)-regarding the impact of stress that developed in response to a situation of threat of war and terror as a result of Israel's withdrawal from Lebanon. The study tested: (1) gender differences regarding cognitive appraisal of the stressor, coping styles, psychological symptoms, and life satisfaction; (2) whether cognitive appraisal and coping styles mediated gender differences in psychological symptoms and life satisfaction; and (3) whether the two age groups differed regarding the contribution of gender to the studied variables. The results revealed that among the teenagers, gender differences were found only in cognitive appraisal and psychological symptoms, while among adults, gender differences were found in all the studied variables. The results support the mediating hypothesis with regard to psychological symptoms, but not with regard to life satisfaction. The results also show a different contribution of gender in each of the age groups regarding psychological symptoms, but not regarding life satisfaction, which leaves some doubt regarding the assumptions that women tend to be more affected by stress than men.


High-quality reduced graphene oxide-nanocrystalline platinum hybrid materials prepared by simultaneous co-reduction of graphene oxide and chloroplatinic acid.
Reduced graphene oxide-nanocrystalline platinum (RGO-Pt) hybrid materials were synthesized by simultaneous co-reduction of graphene oxide (GO) and chloroplatinic acid with sodium citrate in water at 80°C, of pH 7 and 10. The resultant RGO-Pt hybrid materials were characterized using transmission electron microscopy (TEM), powder X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), Fourier-transform infrared spectroscopy, and thermogravimetric analysis. Platinum (Pt) nanoparticles were anchored randomly onto the reduced GO (RGO) sheets with average mean diameters of 1.76 (pH 7) and 1.93 nm (pH 10). The significant Pt diffraction peaks and the decreased intensity of (002) peak in the XRD patterns of RGO-Pt hybrid materials confirmed that the Pt nanoparticles were anchored onto the RGO sheets and intercalated into the stacked RGO layers at these two pH values. The Pt loadings for the hybrid materials were determined as 36.83 (pH 7) and 49.18% (pH 10) by mass using XPS analysis. With the assistance of oleylamine, the resultant RGO-Pt hybrid materials were soluble in the nonpolar organic solvents, and the dispersion could remain stable for several months.


Biology of Thripinema nicklewoodi (Tylenchida), an Obligate Frankliniella occidentalis (Thysanoptera) Parasite.
Frankliniella occidentalis, a serious pest of agricultural crops, is difficult to manage because chemical and biological control measures frequently fail to affect F. occidentalis in their preferred microhabitats. Parasitism by the host-specific, entomopathogenic nematode Thripinema nicklewoodi may provide a much-needed alternative to current control strategies. Infection does not cause death of the host; rather, the result is sterilization that leads to suppression of F. occidentalis populations. We describe a simple rearing method and the results from studies aimed at providing details on its biology-both essential first steps to examining its biological control potential. All F. occidentalis life stages are susceptible to infection, but to varying degrees (most susceptible to least susceptible): female pupae, second instar larvae, first instar larvae, male pupae, adult females, adult males. Nematodes emerge from female and male F. occidentalis for approximately 15 and 9 days, with approximately 14 and 7 nematodes emerging per day, respectively. Females and males are short-lived outside of the host, with mean survival rates ranging between 7 and 86 hours. Transmission does not occur in the soil but rather on or within plant structures that are preferred microhabitats visited by F. occidentalis. Results from a dose-response study suggest that augmentative applications of T. nicklewoodi may be useful to generate increased infection rates and subsequent suppression of F. occidentalis populations.


Norms for mental health services in South Africa.
In the aftermath of apartheid, South Africa has inherited a fragmented, under-resourced and inequitable public sector mental health service. Attempts are being made to reform mental health services, in keeping with new health policy, which proposes the downscaling of psychiatric institutions and the development of community-based services. This study set out to develop a set of service norms for the care of people with severe psychiatric conditions (SPC) in South Africa, to assist the implementation of the new policy. A national situation analysis of current public sector mental health services was conducted. A model was developed for estimating the mental health service resource needs of people with SPC. Following consultation with provincial stakeholders, a set of service norms were developed taking into account national indicators from the situation analysis (as a baseline level) and proposals of the model (as a target level). The study recommends an increase in the number of acute psychiatric beds in general hospitals; development of community-based residential care; redistribution of staff from hospital to community services, particularly in rural areas; and the development of information systems to monitor the transitions to community-based care. The norms proposals presented in this study express mental health service needs in terms of quantifiable service resource and utilisation levels. In doing so, the study attempts to make explicit the assumptions and values on which planning is based.


Cognitive control involves theta power within trials and beta power across trials in the prefrontal-subthalamic network.
There is increasing evidence that the medial prefrontal cortex participates in conflict and feedback monitoring while the subthalamic nucleus adjusts actions. Yet how these two structures coordinate their activity during cognitive control remains poorly understood. We recorded from the human prefrontal cortex and the subthalamic nucleus simultaneously while participants (n = 22) performed a novel task involving high conflict trials, complete response inhibition trials, and trial-to-trial behavioural adaptations to conflict and errors. Overall, we found that within-trial adaptions to both conflict and complete response inhibition involved changes in the theta band while across-trial behavioural adaptations to both conflict and errors involved changes in the beta band (P < 0.05). Yet the role each region's theta and beta oscillations played during the task differed significantly between the two sites. Trials that involved either within-trial conflict or complete response inhibition were associated with increased theta phase synchrony between the medial prefrontal cortex and the subthalamic nucleus (P < 0.05). Despite increased synchrony, however, increases in prefrontal theta power were associated with response inhibition, while increases in subthalamic theta power were associated with response execution (P < 0.05). In the beta band, post-response increases in prefrontal beta power were suppressed when the completed trial contained either conflict or an erroneous response (P < 0.05). Subthalamic beta power, on the other hand, was only modified during the subsequent trial that followed a conflict or error trial. Notably, these adaptation trials exhibited slower response times (P < 0.05), suggesting that both brain regions contribute to across-trial adaptations but do so at different stages of the adaptation process. Taken together, our data shed light on the mechanisms underlying within-trial and across-trial cognitive control and how disruption of this network can negatively impact cognition. More broadly, however, our data also demonstrate that the specific role of a brain region, rather than the frequency being utilized, governs the behavioural correlates of oscillatory activity.


Mobile Messaging Support Versus Usual Care for People With Type 2 Diabetes on Glycemic Control: Protocol for a Multicenter Randomized Controlled Trial.
Health outcomes for people treated for type 2 diabetes could be substantially improved in sub-Saharan Africa. Failure to take medicine regularly to treat diabetes has been identified as a major problem. Resources to identify and support patients who are not making the best use of medicine in low- and middle-income settings are scarce. Mobile phones are widely available in these settings, including among people with diabetes; linked technologies, such as short message service (SMS) text messaging, have shown promise in delivering low-cost interventions efficiently. However, evidence showing that these interventions will work when carried out at a larger scale and measuring the extent to which they will improve health outcomes when added to usual care is limited. The objective of this trial is to test the effectiveness of sending brief, automated SMS text messages for improving health outcomes and medication adherence in patients with type 2 diabetes compared to an active control. We will carry out a randomized trial recruiting from clinics in two contrasting settings in sub-Saharan Africa: Cape Town, South Africa, and Lilongwe, Malawi. Intervention messages will advise people about the benefits of their diabetes treatment and offer motivation and encouragement around lifestyle and use of medication. We allocated patients, using randomization with a minimization algorithm, to receive either three to four intervention messages per week or non-health-related messages every 6 weeks. We will follow up with participants for 12 months, measuring important risk factors for poor health outcomes and complications in diabetes. This will enable us to estimate potential health benefits, including the primary outcome of hemoglobin A1c (HbA1c) levels as a marker for long-term blood glucose control and a secondary outcome of blood pressure control. We will record the costs of performing these activities and estimate cost-effectiveness. We will also use process evaluation to capture the collection of medication and assess the reception of the intervention by participants and health care workers. Recruitment to the trial began in September 2016 and follow-up of participants was completed in October 2018. Data collection from electronic health records and other routinely collected sources is continuing. The database lock is anticipated in June 2019, followed by analysis and disclosing of group allocation. The knowledge gained from this study will have wide applications and advance the evidence base for effectiveness of mobile phone-based, brief text messaging on clinical outcomes and in large-scale, operational settings. It will provide evidence for cost-effectiveness and acceptability that will further inform policy development and decision making. We will work with a wide network that includes patients, clinicians, academics, industry, and policy makers to help us identify opportunities for informing people about the work and raise awareness of what is being developed and studied. ISRCTN Registry ISRCTN70768808; http://www.isrctn.com/ISRCTN70768808 (Archived by WebCite at http://www.webcitation.org/786316Zqk). DERR1-10.2196/12377.


Inner ear drug delivery through a cochlear implant: Pharmacokinetics in a Macaque experimental model.
The method of drug delivery directly into the cochlea with an implantable pump connected to a CI electrode array ensures long-term delivery and effective dose control, and also provides the possibility to use different drugs. The objective is to develop a model of inner ear pharmacokinetics of an implanted cochlea, with the delivery of FITC-Dextran, in the non-human primate model. A preclinical cochlear electrode array (CI Electrode Array HL14DD, manufactured by Cochlear Ltd.) attached to an implantable peristaltic pump filled with FITC-Dextran was implanted unilaterally in a total of 15 Macaca fascicularis (Mf). Three groups were created (5 Mf in each group), according to three different drug delivery times: 2 hours, 24 hours and 7 days. Perilymph (10 samples, 1μL each) was sampled from the apex of the cochlea and measured immediately after extraction with a spectrofluorometer. After scarifying the specimens, x-Rays and histological analysis were performed. Surgery, sampling and histological analysis were performed successfully in all specimens. FITC-Dextran quantification showed different patterns, depending on the delivery group. In the 2 hours injection experiment, an increase in FITC-Dextran concentrations over the sample collection time was seen, reaching maximum concentration peaks (420-964µM) between samples 5 and 7, decreasing in successive samples, without returning to baseline. The 24-hours and 7-days injection experiments showed even behaviour throughout the 10 samples obtained, reaching a plateau with mean concentrations ranging from 2144 to 2564 µM and from 1409 to 2502µM, respectively. Statistically significant differences between the 2 hours and 24 hours groups (p = 0.001) and between the 2 hours and 7 days groups (p = 0.037) were observed, while between the 24 hours and 7 days groups no statistical differences were found. This experimental study shows that a model of drug delivery and pharmacokinetics using an active pump connected to an electrode array is feasible in Mf. An infusion time ranging from 2 to 24 hours is required to reach a maximum concentration peak at the apex. It establishes then an even concentration profile from base to apex that is maintained throughout the infusion time in Mf. Flow mechanisms during injection and during sampling that may explain such findings may involve cochlear aqueduct flow as well as the possible existence of substance exchange from scala tympani to extracellular spaces, such as the modiolar space or the endolymphatic sinus, acting as a substance reservoir to maintain a relatively flat concentration profile from base to apex during sampling. Leveraging the learnings achieved by experimentation in rodent models, we can move to experiment in non-human primate with the aim of achieving a useful model that provides transferrable data to human pharmacokinetics. Thus, it may broaden clinical and therapeutic approaches to inner ear diseases.


Effects of a Novel Mouthwash on Dental Remineralization.
The goal of this study was to evaluate the in vivo effects of a novel mouthwash on enamel remineralization. Ten healthy volunteers wore removable intra-oral appliances for three study arms with duration of 5 days each. In 1 study arm, subjects used Oral Essentials Sensitivity FormulaR mouthwash; in another arm they used SensodyneR mouthwash, and in the third arm they used no mouthwash at all. Sequence of mouthwash use was randomized, and study participants and researchers were blinded throughout the study. Subjects used Crest Total CareR toothpaste throughout the study. During a one week washout period before study begin and between each study arm, subjects also used Crest Total CareR toothpaste. A total of 300 enamel samples were included in this study, 150 served as baseline controls, and 150 as test samples subjected to demineralization prior to intra-oral wear. At the end of each study arm, enamel chips were removed from the appliance and underwent standard Microhardness (Knoop) measurements, as did the control samples. Enamel microhardness in the test vs the 2 control groups was compared using the Kruskal-Wallis one-way analysis of variance with post-hoc Tukey's test to test for differences in remineralization between the 3 treatments. Both mouthwashes demonstrated similar levels of recovery from demineralization as the "no mouthwash" arm of the study, with no significant differences for all groupings and comparisons (p>0.05). A novel mouthwash for sensitive teeth supports enamel recovery from demineralization.


Long-term exposure of proximal tubular epithelial cells to glucose induces transforming growth factor-beta 1 synthesis via an autocrine PDGF loop.
We have recently reported increased transforming growth factor (TGF)-beta1 gene transcription in proximal tubular cells within 12 hours of exposure to 25 mmol/L D-glucose, with a requirement for a second stimulus such as platelet-derived growth factor (PDGF) to increase its translation in short-term experiments. In the current study we investigated the effect on TGF-beta 1 production of prolonged exposure of proximal tubular cells to high glucose concentrations. Enzyme-linked immunosorbent assay of cell culture supernatant showed significant increase in latent TGF-beta 1 only after 7 days exposure to high glucose. Radiolabeling of glucose-stimulated cells with (3)H amino acids and subsequent immunoprecipitation of TGF-beta 1 demonstrated de novo synthesis from day 5 of high glucose exposure onwards. Similarly, polysome analysis showed enhanced translation of TGF-beta mRNA after 4 or more days of high glucose exposure. TGF-beta 1 synthesis, following addition of glucose, was inhibited by blockade of the PDGF-alpha receptor subunit. Glucose did not alter PDGF expression, nor expression of PDGF alpha-receptors. Activation of the receptor following addition of 25 mm D-glucose could be demonstrated suggesting increased sensitivity to endogenous PDGF. Exposure to glucose activated p38MAP kinase, and inhibition of this activation abrogated both glucose induced TGF-beta 1 transcriptional activation and TGF-beta 1 synthesis. Inhibition of p38MAP kinase did not influence the effect of exogenous PDGF when cells were stimulated sequentially by glucose and PDGF. We postulate that glucose induces an early increase in TGF-beta 1 transcription via activation of p38MAP kinase. In addition, glucose causes a late increase in PDGF-dependent TGF-beta 1 translation by enhancing cellular sensitivity to PDGF. This provides a potential explanation for the clinical observation that prolonged poor glycemic control may contribute to progression of diabetic nephropathy.


[11C]PK11195-PET Brain Imaging of the Mitochondrial Translocator Protein in Mitochondrial Disease.
To explore the possibilities of radioligands against the mitochondrial outer membrane protein TSPO as biomarkers for mitochondrial disease, we performed PET (PET)-MR brain imaging with [11C]PK11195 in 14 patients with genetically confirmed mitochondrial disease and 33 matched controls. A case-control study of PET-MR imaging with the TSPO radioligand [11C]PK11195. Forty-six percent of symptomatic patients had volumes of abnormal radiotracer binding greater than the 95th percentile in controls. [11C]PK11195 binding was generally greater in grey matter and significantly decreased in white matter. This was most striking in patients with nuclear TYMP or mitochondrial m.3243A>G MT-TL1 mutations, in keeping with differences in mitochondrial density seen post mortem. Some regional binding patterns corresponded to clinical presentation and underlying mutation, even in the absence of structural changes on MRI. This was most obvious for the cerebellum, where patients with ataxia had decreased binding in the cerebellar cortex, but not necessarily volume loss. Overall, there was a positive correlation between aberrant [11C]PK11195 binding and clinical severity. These findings endorse the use of PET imaging with TSPO radioligands as a non-invasive in vivo biomarker of mitochondrial pathology. This study provides Class III evidence that PET-MR brain imaging with TSPO radioligands identifies mitochondrial pathology.


Preoperative brain μ-opioid receptor availability predicts weight development following bariatric surgery in women.
Bariatric surgery is the most effective method for weight loss in morbid obesity. There is significant individual variability in the weight loss outcomes, yet factors leading to postoperative weight loss or weight regain remain elusive. Alterations in the μ-opioid receptor (MOR) and dopamine D2 receptor (D2R) systems are associated with obesity and appetite control, and the magnitude of initial brain receptor system perturbation may predict long-term surgical weight loss outcomes. We tested this hypothesis by studying 19 morbidly obese women (mean BMI 40) scheduled to undergo bariatric surgery. We measured their preoperative MOR and D2R availabilities using positron emission tomography with [11C]carfentanil and [11C]raclopride, respectively, and then assessed their weight development association with regional MOR and D2R availabilities at 24-month follow-up. MOR availability in the amygdala consistently predicted weight development throughout the follow-up period, but no associations were found for D2R. This is the first study to our knowledge to demonstrate that neuroreceptor markers prior to bariatric surgery are associated with postoperative weight development. Postoperative weight regain may derive from dysfunction in the opioid system, and weight loss outcomes after bariatric surgery may be partially predicted based on preoperative brain receptor availability, opening up new potential for treatment possibilities.


Distress and metacognition in psychosis prone individuals: comparing high schizotypy to the at-risk mental state.
Both schizotypy and at-risk mental states (ARMS: prodromal states) define individuals at risk for psychotic symptoms. However, the relationship between the 2 is unclear. ARMS individuals are, by definition, help-seeking and therefore at greater risk. We tested whether high schizotypes and ARMS exist along the same continuum by examining maladaptive metacognitions and distress. About 95 healthy volunteers (39% male; mean age, 22.8 years) completed the Schizotypal Personality Questionnaire, the Launay-Slade Hallucinations Scale, Metacognitions Questionnaire (MCQ), and the General Health Questionnaire, and 58 help seeking individuals with ARMS status (41% male; mean age, 22.2 years) completed the Metacognitions Questionnaire and General Health Questionnaire. With increasing expression of schizotypy and hallucinatory proneness healthy volunteers became difficult to differentiate from ARMS patients and showed similarities in distress and metacognitive abnormalities. Results suggest healthy volunteers who express both schizotypal trait and proneness to hallucinations have cognitive processes in common with ARMS patients.


Role of natural herbs in the treatment of hypertension.
Hypertension (HTN) is the medical term for high blood pressure. It is dangerous because it makes the heart work too hard and contributes to atherosclerosis (hardening of arteries), besides increasing the risk of heart disease and stroke. HTN can also lead to other conditions such as congestive heart failure, kidney disease, and blindness. Conventional antihypertensives are usually associated with many side effects. About 75 to 80% of the world population use herbal medicines, mainly in developing countries, for primary health care because of their better acceptability with human body and lesser side effects. In the last three decades, a lot of concerted efforts have been channeled into researching the local plants with hypotensive and antihypertensive therapeutic values. The hypotensive and antihypertensive effects of some of these medicinal plants have been validated and others disproved. However, ayurvedic knowledge needs to be coupled with modern medicine and more scientific research needs to be done to verify the effectiveness, and elucidate the safety profile of such herbal remedies for their antihypertensive potential.


Environmental change explains cichlid adaptive radiation at Lake Malawi over the past 1.2 million years.
Long paleoecological records are critical for understanding evolutionary responses to environmental forcing and unparalleled tools for elucidating the mechanisms that lead to the development of regions of high biodiversity. We use a 1.2-My record from Lake Malawi, a textbook example of biological diversification, to document how climate and tectonics have driven ecosystem and evolutionary dynamics. Before ∼800 ka, Lake Malawi was much shallower than today, with higher frequency but much lower amplitude water-level and oxygenation changes. Since ∼800 ka, the lake has experienced much larger environmental fluctuations, best explained by a punctuated, tectonically driven rise in its outlet location and level. Following the reorganization of the basin, a change in the pacing of hydroclimate variability associated with the Mid-Pleistocene Transition resulted in hydrologic change dominated by precession rather than the high-latitude teleconnections recorded elsewhere. During this time, extended, deep lake phases have abruptly alternated with times of extreme aridity and ecosystem variability. Repeated crossings of hydroclimatic thresholds within the lake system were critical for establishing the rhythm of diversification, hybridization, and extinction that dominate the modern system. The chronology of these changes closely matches both the timing and pattern of phylogenetic history inferred independently for the lake's extraordinary array of cichlid fish species, suggesting a direct link between environmental and evolutionary dynamics.


White matter microstructural abnormalities in euthymic bipolar disorder.
Abnormal diffusion parameters are reported in specific brain regions and white matter tracts in bipolar disorder. To investigate whether these abnormalities are generalised, and thus evident in large regions of white matter. Diffusion parameters were measured at several regions in the corpus callosum and in deep/periventricular white matter in 28 currently euthymic patients with bipolar disorder and controls. White matter hyperintensity loads were assessed. Comparing the whole data-sets using the sign test, in the group with bipolar disorder, mean diffusivity was greater at all 15 sites (P<0.001) and fractional anisotropy was reduced at 13 (P<0.01). The effect of diagnosis was significant for callosal mean diffusivity and fractional anisotropy and for deep/periventricular mean diffusivity (MANCOVA). Comparing individual regions (Mann-Whitney U-test), prefrontal and periventricular mean diffusivity were significantly increased; callosal and occipital fractional anisotropy were significantly reduced. Former substance use and lithium were possible confounding factors. Periventricular white matter hyperintensities were associated with significantly increased periventricular mean diffusivity in individuals with bipolar disorder. Generalised white matter microstructural abnormalities may exist in bipolar disorder, possibly exacerbated by past substance use and ameliorated by lithium.


Real-time intraoperative 4D full-range FD-OCT based on the dual graphics processing units architecture for microsurgery guidance.
Real-time 4D full-range complex-conjugate-free Fourier-domain optical coherence tomography (FD-OCT) is implemented using a dual graphics processing units (dual-GPUs) architecture. One GPU is dedicated to the FD-OCT data processing while the second one is used for the volume rendering and display. GPU accelerated non-uniform fast Fourier transform (NUFFT) is also implemented to suppress the side lobes of the point spread function to improve the image quality. Using a 128,000 A-scan/second OCT spectrometer, we obtained 5 volumes/second real-time full-range 3D OCT imaging. A complete micro-manipulation of a phantom using a microsurgical tool is monitored by multiple volume renderings of the same 3D date set with different view angles. Compared to the conventional surgical microscope, this technology would provide the surgeons a more comprehensive spatial view of the microsurgical site and could serve as an effective intraoperative guidance tool.


Disruption of Higher Order DNA Structures in Friedreich's Ataxia (GAA)n Repeats by PNA or LNA Targeting.
Expansion of (GAA)n repeats in the first intron of the Frataxin gene is associated with reduced mRNA and protein levels and the development of Friedreich's ataxia. (GAA)n expansions form non-canonical structures, including intramolecular triplex (H-DNA), and R-loops and are associated with epigenetic modifications. With the aim of interfering with higher order H-DNA (like) DNA structures within pathological (GAA)n expansions, we examined sequence-specific interaction of peptide nucleic acid (PNA) with (GAA)n repeats of different lengths (short: n=9, medium: n=75 or long: n=115) by chemical probing of triple helical and single stranded regions. We found that a triplex structure (H-DNA) forms at GAA repeats of different lengths; however, single stranded regions were not detected within the medium size pathological repeat, suggesting the presence of a more complex structure. Furthermore, (GAA)4-PNA binding of the repeat abolished all detectable triplex DNA structures, whereas (CTT)5-PNA did not. We present evidence that (GAA)4-PNA can invade the DNA at the repeat region by binding the DNA CTT strand, thereby preventing non-canonical-DNA formation, and that triplex invasion complexes by (CTT)5-PNA form at the GAA repeats. Locked nucleic acid (LNA) oligonucleotides also inhibited triplex formation at GAA repeat expansions, and atomic force microscopy analysis showed significant relaxation of plasmid morphology in the presence of GAA-LNA. Thus, by inhibiting disease related higher order DNA structures in the Frataxin gene, such PNA and LNA oligomers may have potential for discovery of drugs aiming at recovering Frataxin expression.