A systematic review of interventions to improve uptake of pertussis vaccination in pregnancy.
Maternal pertussis vaccination has been introduced in several countries to prevent pertussis morbidity and mortality in infants too young to be vaccinated. Our review aimed to systematically collect and summarize the available evidence on the effectiveness of interventions used to improve pertussis vaccination uptake in pregnant women. We conducted a systematic search of MEDLINE/PubMed, PMC and CINAHL. Before and after studies and those with a concurrent control group were considered for inclusion. Standardized effect sizes were described as the ratio of the odds to be vaccinated in the intervention group compared with the standard care group and absolute benefit increase (ABI) were calculated. Six studies were included in the review, of which three were randomized controlled trials (RCTs). Strategies to improve uptake were focused on healthcare providers, pregnant women, or enhancing vaccine access. Healthcare provider interventions included provider reminder, education, feedback and standing orders. Interventions directed at pregnant women focused solely on education. Observational studies showed: (1) the provision of maternal pertussis vaccination by midwives at the place of antenatal care has improved uptake of pertussis vaccine during pregnancy from 20% to 90%; (2) introduction of an automated reminder within the electronic medical record was associated with an improvement in the pertussis immunization rate from 48% to 97%; (3) an increase in prenatal pertussis vaccine uptake from 36% to 61% after strategies to increase provider awareness of recommendations were introduced. In contrast to these findings, interventions in all three RCTs (2 involved education of pregnant women, 1 had multi-component interventions) did not demonstrate improved vaccination uptake. Based on the existing research, we recommend incorporating midwife delivered maternal immunization programs at antenatal clinics, use of a provider reminder system to target unvaccinated pregnant women and include maternal pertussis immunization as part of standard antenatal care.


Stable hovering of a jellyfish-like flying machine.
Ornithopters, or flapping-wing aircraft, offer an alternative to helicopters in achieving manoeuvrability at small scales, although stabilizing such aerial vehicles remains a key challenge. Here, we present a hovering machine that achieves self-righting flight using flapping wings alone, without relying on additional aerodynamic surfaces and without feedback control. We design, construct and test-fly a prototype that opens and closes four wings, resembling the motions of swimming jellyfish more so than any insect or bird. Measurements of lift show the benefits of wing flexing and the importance of selecting a wing size appropriate to the motor. Furthermore, we use high-speed video and motion tracking to show that the body orientation is stable during ascending, forward and hovering flight modes. Our experimental measurements are used to inform an aerodynamic model of stability that reveals the importance of centre-of-mass location and the coupling of body translation and rotation. These results show the promise of flapping-flight strategies beyond those that directly mimic the wing motions of flying animals.


Physician-administered clinical score of vulvar lichen sclerosus: A study of 36 cases.
Vulvar lichen sclerosus (VLS) often remains undetected for years due to lack of awareness, as well as private nature of the disease. Advanced disease severely affects the quality of life and is associated with increased risk of vulvar squamous cell carcinoma (SCC). The aim of this study was to assess the usefulness of a physician-administered clinical scoring system for the clinical diagnosis and evaluation of VLS. To the best of our knowledge, this is the first study using the clinical score developed by Günthert et al on the VLS patients. The study conducted was an observational cross-sectional study of 36 cases attending Dermatology OPD of Government Medical College with clinically proven and previously untreated VLS enrolled over a 1 year period. Cases were retrospectively subjected to evaluation by physician-administered clinical score based on 6 clinical features, viz. erosions, agglutination, hyperkeratosis, stenosis, fissures, and atrophy. The average age of 36 clinically diagnosed VLS cases was 56.4 years. Most common clinical features were hyperkeratosis and atrophy found in 86.11% cases followed by erosions (75%) with one-third cases having grade 2 (severe) changes. One case had well-differentiated SCC clitoris at presentation. The mean physician-administered clinical score was 5.583, and 80.56% cases had clinical score ≥4 validating the clinical diagnosis. Early diagnosis and prompt treatment is the key to prevent sequelae and complications of VLS. The physician-administered clinical score can be a useful tool to diagnose and later evaluate the response of treatment and prognosis of VLS cases.


An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management.
This document is an international evidence-based guideline on the diagnosis and management of idiopathic pulmonary fibrosis, and is a collaborative effort of the American Thoracic Society, the European Respiratory Society, the Japanese Respiratory Society, and the Latin American Thoracic Association. It represents the current state of knowledge regarding idiopathic pulmonary fibrosis (IPF), and contains sections on definition and epidemiology, risk factors, diagnosis, natural history, staging and prognosis, treatment, and monitoring disease course. For the diagnosis and treatment sections, pragmatic GRADE evidence-based methodology was applied in a question-based format. For each diagnosis and treatment question, the committee graded the quality of the evidence available (high, moderate, low, or very low), and made a recommendation (yes or no, strong or weak). Recommendations were based on majority vote. It is emphasized that clinicians must spend adequate time with patients to discuss patients' values and preferences and decide on the appropriate course of action.


Two functional copies of the DGCR6 gene are present on human chromosome 22q11 due to a duplication of an ancestral locus.
The DGCR6 (DiGeorge critical region) gene encodes a putative protein with sequence similarity to gonadal (gdl), a Drosophila melanogaster gene of unknown function. We mapped the DGCR6 gene to chromosome 22q11 within a low copy repeat, termed sc11.1a, and identified a second copy of the gene, DGCR6L, within the duplicate locus, termed sc11.1b. Both sc11.1 repeats are deleted in most persons with velo-cardio-facial syndrome/DiGeorge syndrome (VCFS/DGS), and they map immediately adjacent and internal to the low copy repeats, termed LCR22, that mediate the deletions associated with VCFS/DGS. We sequenced genomic clones from both loci and determined that the putative initiator methionine is located further upstream than originally described, but in a position similar to the mouse and chicken orthologs. DGCR6L encodes a highly homologous, functional copy of DGCR6, with some base changes rendering amino acid differences. Expression studies of the two genes indicate that both genes are widely expressed in fetal and adult tissues. Evolutionary studies using FISH mapping in several different species of ape combined with sequence analysis of DGCR6 in a number of different primate species indicate that the duplication is at least 12 million years old and may date back to before the divergence of Catarrhines from Platyrrhines, 35 mya. These data suggest that there has been selective evolutionary pressure toward the functional maintenance of both paralogs. Interestingly, a full-length HERV-K provirus integrated into the sc11.1a locus after the divergence of chimpanzees and humans.


Mono-allelic POLG expression resulting from nonsense-mediated decay and alternative splicing in a patient with Alpers syndrome.
Alpers syndrome is an autosomal recessive mitochondrial DNA depletion disorder that affects children and young adults. It is characterized by a progressive, fatal brain and liver disease. This syndrome has been associated with mutations in POLG, the gene encoding the mitochondrial DNA polymerase (pol gamma). Most patients with Alpers syndrome have been found to be compound heterozygotes, carrying two pathogenic mutations in trans at the POLG locus. POLG is a nuclear-encoded gene whose protein product is imported into mitochondria, where it is essential for mtDNA replication and repair. We studied the skin fibroblasts of a patient with Alpers syndrome having the genotype E873stop/A467T. The E873stop mutation produces a premature termination codon (TAG) in exon 17. The A467T mutation produces a threonine to alanine substitution at a highly conserved site in exon 7. The allele bearing the stop codon (E873-TAG) is predicted to produce a truncated, catalytically inactive polymerase. However, only full-length pol gamma protein was detected by Western blot analysis. Here, we show that transcripts containing this stop codon undergo nonsense-associated alternative splicing and nonsense-mediated decay. More than 95% of the functional POLG mRNA was derived from the allele bearing the A467T mutation and less than 5% contained the E873stop mutation. These events ensured that virtually all POLG protein in the cell was expressed from the A467T allele. Therefore, the Alpers phenotype in this patient was a consequence of a single-copy gene dose of the A467T allele, and selective elimination of transcripts bearing the E873stop mutation.


Pairwise Heuristic Sequence Alignment Algorithm Based on Deep Reinforcement Learning.
Goal: Various methods have been developed to analyze the association between organisms and their genomic sequences. Among them, sequence alignment is the most frequently used method for comparative analysis of biological genomes. We intend to propose a novel pairwise sequence alignment method using deep reinforcement learning to break out the old pairwise alignment algorithms. Methods: We defined the environment and agent to enable reinforcement learning in the sequence alignment system. This novel method, named DQNalign, can immediately determine the next direction by observing the subsequences within the moving window. Results: DQNalign shows superiority in the dissimilar sequence pairs that have low identity values. And theoretically, we confirm that DQNalign has a low dimension for the sequence length in view of the complexity. Conclusions: This research shows the application method of deep reinforcement learning to the sequence alignment system and how deep reinforcement learning can improve the conventional sequence alignment method.


Initial eye movements during face identification are optimal and similar across cultures.
Culture influences not only human high-level cognitive processes but also low-level perceptual operations. Some perceptual operations, such as initial eye movements to faces, are critical for extraction of information supporting evolutionarily important tasks such as face identification. The extent of cultural effects on these crucial perceptual processes is unknown. Here, we report that the first gaze location for face identification was similar across East Asian and Western Caucasian cultural groups: Both fixated a featureless point between the eyes and the nose, with smaller between-group than within-group differences and with a small horizontal difference across cultures (8% of the interocular distance). We also show that individuals of both cultural groups initially fixated at a slightly higher point on Asian faces than on Caucasian faces. The initial fixations were found to be both fundamental in acquiring the majority of information for face identification and optimal, as accuracy deteriorated when observers held their gaze away from their preferred fixations. An ideal observer that integrated facial information with the human visual system's varying spatial resolution across the visual field showed a similar information distribution across faces of both races and predicted initial human fixations. The model consistently replicated the small vertical difference between human fixations to Asian and Caucasian faces but did not predict the small horizontal leftward bias of Caucasian observers. Together, the results suggest that initial eye movements during face identification may be driven by brain mechanisms aimed at maximizing accuracy, and less influenced by culture. The findings increase our understanding of the interplay between the brain's aims to optimally accomplish basic perceptual functions and to respond to sociocultural influences.


Immunoepidemiology of Wuchereria bancrofti infection: parasite transmission intensity, filaria-specific antibodies, and host immunity in two East African communities.
We compared the age profiles of infection and specific antibody intensities in two communities with different transmission levels in East Africa to examine the contribution of humoral responses to human immunity to the vector-borne helminth Wuchereria bancrofti. The worm intensities were higher and exhibited a nonlinear age pattern in a high-transmission community, Masaika, in contrast to the low but linearly increasing age infection profile observed for a low-transmission community, Kingwede. The mean levels of specific immunoglobulin G1 (IgG1), IgG2, IgG4, and IgE were also higher in Masaika, but intriguingly, the IgG3 response was higher in Kingwede. The age-antibody patterns differed in the two communities but in a manner apparently contrary to a role in acquired immunity when the data were assessed using simple correlation methods. By contrast, multivariate analyses showed that the antibody response to infection may be classified into three types and that two of these types, a IgG3-type response and a response measuring a trade-off in host production of IgG4 and IgG3 versus production of IgG1, IgG2, and IgE, had a negative effect on Wuchereria circulating antigen levels in a manner that supported a role for these responses in the generation of acquired immunity to infection. Mathematical modeling supported the conclusions drawn from empirical data analyses that variations in both transmission and worm intensity can explain community differences in the age profiles and impacts of these antibody response types. This study showed that parasite-specific antibody responses may be associated with the generation of acquired immunity to human filarial infection but in a form which is dependent on worm transmission intensity and interactions between immune components.


Valbenazine for tardive dyskinesia: A systematic review of the efficacy and safety profile for this newly approved novel medication-What is the number needed to treat, number needed to harm and likelihood to be helped or harmed?
The objective of this systematic review was to describe the efficacy, tolerability, and safety of valbenazine for the treatment of tardive dyskinesia (TD). The pivotal registration trials were accessed by querying http://www.ncbi.nlm.nih.gov/pubmed/ and http://www.clinicaltrials.gov, for the search terms 'valbenazine' OR 'NBI-98854', and by also querying the EMBASE (Elsevier) commercial database for clinical poster abstracts, and by asking the manufacturer for copies of posters presented at congresses. Product labeling provided additional information. All available clinical reports of studies were identified. Descriptions of the principal results and calculation of number needed to treat (NNT) and number needed to harm (NNH) for relevant dichotomous outcomes were extracted from the available study reports and other sources of information. Valbenazine, a reversible inhibitor of Vesicular Monoamine Transporter Type 2 (VMAT2), received approval for the treatment of TD in adults based on a clinical trial development programme that included three 6-week parallel group, randomised, placebo-controlled studies, including one Phase III trial described in product labeling. The recommended dose for valbenazine is 80 mg/d. The percentage of responders in the Phase III acute study, as defined by ≥50% reduction from baseline in the Abnormal Involuntary Movement Scale dyskinesia score was 40.0% for valbenazine 80 mg/d vs 8.7% for placebo, yielding a NNT of 4 (95% CI 3-6). As pooled from available data, discontinuation rates because of an adverse event were 2.9% for valbenazine-treated patients vs 1.6% for placebo-treated patients, resulting in a NNH of 76 (ns). The only adverse event that met the threshold of incidence ≥5% for valbenazine and a rate of ≥2 times than that observed with placebo was somnolence (somnolence, fatigue, sedation), with rates of 10.9% for valbenazine (all doses) vs 4.2% for placebo, resulting in a NNH of 15 (95% CI 9-52). An additional warning and precaution is that valbenazine can prolong the ECG QT interval, however, the valbenazine product label does not contain any bolded boxed warnings or contraindications. Valbenazine is presently the only US Food and Drug Administration-approved agent specifically indicated for the treatment of TD. Valbenazine is about 15 times more likely to result in a response than in a discontinuation because of an adverse event. Head-to-head comparisons with other VMAT2 inhibitors among patients with TD in the 'real world' are needed.


Comparison of Limulus assay, standard plate count, and total coliform count for microbiological assessment of renovated wastewater.
The Limulus endotoxin assay was compared to the standard plate count and total coliform count for assessment of the bacteriological quality of reclaimed wastewater. A total of 48 water samples from an advanced waste treatment plant in Dallas, Tex. were examined by the three techniques. Limulus assays were technically simpler to perform and provided results much sooner than conventional culture methods. However, the endotoxin values did not correlate extremely well with determinations of viable bacterial numbers. This lack of correlation may have been due to alterations in the normal ratio of viable gram-negative cells to endotoxin caused by water reclamation procedures.


A supraphysiological dose of testosterone induces nitric oxide production and oxidative stress.
Accumulating evidence indicates that abuse of anabolic androgenic steroids may cause cardiovascular adverse side-effects, including endothelial dysfunction. The aim of the present study was to investigate the effects of supra-physiological doses of testosterone on the endothelial production of nitric oxide (NO) and oxidative stress in vitro and in vivo. Testosterone enanthate was administrated as of a single 500 mg dose to healthy volunteers (N = 27). Gene expression was studied in human vascular endothelial cells exposed to testosterone. The in vivo results show that the urinary NO level and the antioxidative capacity were significantly decreased two days after testosterone administration. In agreement, our in vitro studies show that testosterone inhibits the gene expression of endothelial NO synthase (eNOS) after 48 hours. When the antioxidant seleno-L-methionine was added, the down-regulation of mRNA specific eNOS was partly abrogated. The mRNA expression of antioxidizing enzyme genes was significantly inhibited after eight hours and recovered 48 hours after testosterone treatment of endothelial cells. These results show that a supraphysiological dose of testosterone decreases the expression of eNOS and consequently the formation of NO, which could partly be explained by oxidative stress. These results indicate that supraphysiological doses of testosterone may induce endothelial dysfunction, which is of interest in relation to the cardiovascular adverse side-effects observed in anabolic androgenic steroid abusers.


Diminished brain resilience syndrome: A modern day neurological pathology of increased susceptibility to mild brain trauma, concussion, and downstream neurodegeneration.
The number of sports-related concussions has been steadily rising in recent years. Diminished brain resilience syndrome is a term coined by the lead author to describe a particular physiological state of nutrient functional deficiency and disrupted homeostatic mechanisms leading to increased susceptibility to previously considered innocuous concussion. We discuss how modern day environmental toxicant exposure, along with major changes in our food supply and lifestyle practices, profoundly reduce the bioavailability of neuro-critical nutrients such that the normal processes of homeostatic balance and resilience are no longer functional. Their diminished capacity triggers physiological and biochemical 'work around' processes that result in undesirable downstream consequences. Exposure to certain environmental chemicals, particularly glyphosate, the active ingredient in the herbicide, Roundup(®), may disrupt the body's innate switching mechanism, which normally turns off the immune response to brain injury once danger has been removed. Deficiencies in serotonin, due to disruption of the shikimate pathway, may lead to impaired melatonin supply, which reduces the resiliency of the brain through reduced antioxidant capacity and alterations in the cerebrospinal fluid, reducing critical protective buffering mechanisms in impact trauma. Depletion of certain rare minerals, overuse of sunscreen and/or overprotection from sun exposure, as well as overindulgence in heavily processed, nutrient deficient foods, further compromise the brain's resilience. Modifications to lifestyle practices, if widely implemented, could significantly reduce this trend of neurological damage.


CIC-DUX4 oncoprotein drives sarcoma metastasis and tumorigenesis via distinct regulatory programs.
Transcription factor fusion genes create oncoproteins that drive oncogenesis and represent challenging therapeutic targets. Understanding the molecular targets by which such fusion oncoproteins promote malignancy offers an approach to develop rational treatment strategies to improve clinical outcomes. Capicua-double homeobox 4 (CIC-DUX4) is a transcription factor fusion oncoprotein that defines certain undifferentiated round cell sarcomas with high metastatic propensity and poor clinical outcomes. The molecular targets regulated by the CIC-DUX4 oncoprotein that promote this aggressive malignancy remain largely unknown. We demonstrated that increased expression of ETS variant 4 (ETV4) and cyclin E1 (CCNE1) occurs via neomorphic, direct effects of CIC-DUX4 and drives tumor metastasis and survival, respectively. We uncovered a molecular dependence on the CCNE-CDK2 cell cycle complex that renders CIC-DUX4-expressing tumors sensitive to inhibition of the CCNE-CDK2 complex, suggesting a therapeutic strategy for CIC-DUX4-expressing tumors. Our findings highlight a paradigm of functional diversification of transcriptional repertoires controlled by a genetically aberrant transcriptional regulator, with therapeutic implications.


Observation of Electroweak Production of Same-Sign W Boson Pairs in the Two Jet and Two Same-Sign Lepton Final State in Proton-Proton Collisions at sqrt[s]=13 TeV.
The first observation of electroweak production of same-sign W boson pairs in proton-proton collisions is reported. The data sample corresponds to an integrated luminosity of 35.9 fb^{-1} collected at a center-of-mass energy of 13 TeV with the CMS detector at the LHC. Events are selected by requiring exactly two leptons (electrons or muons) of the same charge, moderate missing transverse momentum, and two jets with a large rapidity separation and a large dijet mass. The observed significance of the signal is 5.5 standard deviations, where a significance of 5.7 standard deviations is expected based on the standard model. The ratio of measured event yields to that expected from the standard model at leading order is 0.90±0.22. A cross section measurement in a fiducial region is reported. Bounds are given on the structure of quartic vector boson interactions in the framework of dimension-8 effective field theory operators and on the production of doubly charged Higgs bosons.


Deficiency of mitochondrial fumarase activity in tomato plants impairs photosynthesis via an effect on stomatal function.
Transgenic tomato (Solanum lycopersicum) plants expressing a fragment of a fumarate hydratase (fumarase) gene in the antisense orientation and exhibiting considerable reductions in the mitochondrial activity of this enzyme show impaired photosynthesis. The rate of the tricarboxylic acid cycle was reduced in the transformants relative to the other major pathways of carbohydrate oxidation and the plants were characterized by a restricted rate of dark respiration. However, biochemical analyses revealed relatively little alteration in leaf metabolism as a consequence of reducing the fumarase activity. That said, in comparison to wild-type plants, CO(2) assimilation was reduced by up to 50% under atmospheric conditions and plants were characterized by a reduced biomass on a whole plant basis. Analysis of further photosynthetic parameters revealed that there was little difference in pigment content in the transformants but that the rate of transpiration and stomatal conductance was markedly reduced. Analysis of the response of the rate of photosynthesis to variation in the concentration of CO(2) confirmed that this restriction was due to a deficiency in stomatal function.


Stretching and injury prevention: an obscure relationship.
It is generally accepted that increasing the flexibility of a muscle-tendon unit promotes better performances and decreases the number of injuries. Stretching exercises are regularly included in warm-up and cooling-down exercises; however, contradictory findings have been reported in the literature. Several authors have suggested that stretching has a beneficial effect on injury prevention. In contrast, clinical evidence suggesting that stretching before exercise does not prevent injuries has also been reported. Apparently, no scientifically based prescription for stretching exercises exists and no conclusive statements can be made about the relationship of stretching and athletic injuries. Stretching recommendations are clouded by misconceptions and conflicting research reports. We believe that part of these contradictions can be explained by considering the type of sports activity in which an individual is participating. Sports involving bouncing and jumping activities with a high intensity of stretch-shortening cycles (SSCs) [e.g. soccer and football] require a muscle-tendon unit that is compliant enough to store and release the high amount of elastic energy that benefits performance in such sports. If the participants of these sports have an insufficient compliant muscle-tendon unit, the demands in energy absorption and release may rapidly exceed the capacity of the muscle-tendon unit. This may lead to an increased risk for injury of this structure. Consequently, the rationale for injury prevention in these sports is to increase the compliance of the muscle-tendon unit. Recent studies have shown that stretching programmes can significantly influence the viscosity of the tendon and make it significantly more compliant, and when a sport demands SSCs of high intensity, stretching may be important for injury prevention. This conjecture is in agreement with the available scientific clinical evidence from these types of sports activities. In contrast, when the type of sports activity contains low-intensity, or limited SSCs (e.g. jogging, cycling and swimming) there is no need for a very compliant muscle-tendon unit since most of its power generation is a consequence of active (contractile) muscle work that needs to be directly transferred (by the tendon) to the articular system to generate motion. Therefore, stretching (and thus making the tendon more compliant) may not be advantageous. This conjecture is supported by the literature, where strong evidence exists that stretching has no beneficial effect on injury prevention in these sports. If this point of view is used when examining research findings concerning stretching and injuries, the reasons for the contrasting findings in the literature are in many instances resolved.


Survival after stroke and transient ischemic attacks during the 1970s and 1980s.
Survival after stroke and transient ischemic attack was studied in Söderhamn, Sweden, during the periods 1975-1979 and 1983-1987; 640 patients with first-ever stroke and 97 with first-ever transient ischemic attack were registered and followed for 1-3 years. Approximately 90% of the patients were treated in the Department of Internal Medicine of Söderhamn Hospital. The protocols for physical rehabilitation and antithrombotic treatment changed between study periods. Between periods, 3-year survival after stroke increased by 16% (p less than 0.003). The 95% confidence intervals of the relative survival rates were 0.524-0.648, 0.435-0.567, and 0.337-0.475 at 1, 2, and 3 years, respectively, during the first period and 0.616-0.728, 0.600-0.732, and 0.576-0.748 during the second period. Fewer patients suffered fatal complications of stroke during the second period. The rate of stroke recurrence was approximately 10%/year during both study periods. Four patients suffered fatal hemorrhage during the first period, but no patient did so during the second period. Observed survival after transient ischemic attack did not differ from that expected in the first 2 years of follow-up during either study period. The risk for stroke after transient ischemic attack was approximately 5%/year during both periods. The higher survival rates after stroke during the second period seems to be the result of fewer fatal complications rather than of a reduced risk for recurrent stroke.


Perceived importance of AAC messages to support communication in rehabilitation settings.
Permanent or temporary speech loss can occur due to a variety of medical conditions and often requires individuals to use augmentative and alternative communication (AAC) strategies and technologies to support communication. The use of AAC in medical and rehabilitation settings is critical to ensure the health, safety and psychological well-being of communicatively vulnerable individuals. This study surveyed the perceived importance of communication messages within five categories (Basic Needs, Patient-Provider Specific Communication, Social, Feelings, and Messages for Young Children) by individuals with disability who have undergone recent medical care as well as by rehabilitation care providers. Results indicated that, with only a few exceptions, participants with disability more frequently selected all of the messages listed under the Patient-Provider Specific, Social, and Feelings categories compared to rehabilitation care providers' responses. Additionally, the individuals with disabilities selected messages that were more personalised to their specific care needs under Basic Needs. Both participant groups were asked to also suggest other messages that they perceived as important under each category. The other suggested messages demonstrated the potential need to provide personalisation to AAC displays to best meet the communication needs of individuals with disability.Implications for RehabilitationThere is a critical need for individuals who find themselves in medical settings (ICU, acute care hospital, rehabilitation hospital, etc.) to be able to communicate. This study provides preliminary information on the breadth of communication content that is perceived as relevant by individuals with disability and rehabilitation care providers. The need to provide personalized as well as a wide range of communication content options was of particular importance to individuals with disability. This information may provide specific guidance on how to best develop augmentative and alternative communication options for individuals in medical settings.


Pyrimidine Pool Disequilibrium Induced by a Cytidine Deaminase Deficiency Inhibits PARP-1 Activity, Leading to the Under Replication of DNA.
Genome stability is jeopardized by imbalances of the dNTP pool; such imbalances affect the rate of fork progression. For example, cytidine deaminase (CDA) deficiency leads to an excess of dCTP, slowing the replication fork. We describe here a novel mechanism by which pyrimidine pool disequilibrium compromises the completion of replication and chromosome segregation: the intracellular accumulation of dCTP inhibits PARP-1 activity. CDA deficiency results in incomplete DNA replication when cells enter mitosis, leading to the formation of ultrafine anaphase bridges between sister-chromatids at "difficult-to-replicate" sites such as centromeres and fragile sites. Using molecular combing, electron microscopy and a sensitive assay involving cell imaging to quantify steady-state PAR levels, we found that DNA replication was unsuccessful due to the partial inhibition of basal PARP-1 activity, rather than slower fork speed. The stimulation of PARP-1 activity in CDA-deficient cells restores replication and, thus, chromosome segregation. Moreover, increasing intracellular dCTP levels generates under-replication-induced sister-chromatid bridges as efficiently as PARP-1 knockdown. These results have direct implications for Bloom syndrome (BS), a rare genetic disease combining susceptibility to cancer and genomic instability. BS results from mutation of the BLM gene, encoding BLM, a RecQ 3'-5' DNA helicase, a deficiency of which leads to CDA downregulation. BS cells thus have a CDA defect, resulting in a high frequency of ultrafine anaphase bridges due entirely to dCTP-dependent PARP-1 inhibition and independent of BLM status. Our study describes previously unknown pathological consequences of the distortion of dNTP pools and reveals an unexpected role for PARP-1 in preventing DNA under-replication and chromosome segregation defects.


Sexual Partners of Street-Based Female Sex Workers in St. Petersburg, Russia: A Model of Partnership Characteristics as a Basis for Further Research.
Street-based sex work in Russia, as in many countries, carries with it a high risk for violence and the transmission of infectious diseases. The male partners of female sex workers are both cause and recipient of such risks. Because little is known about the men, we undertook a preliminary study to determine the feasibility of recruiting and interviewing them, develop typologies that describe partners, and derive hypotheses for further study and risk reduction intervention projects. We were able to conduct open-ended, qualitative interviews with street-based sex workers and, largely through these contacts, their male partners. To these data, we added interviews with social work and medical experts who engage with the sex workers. The text of interviews from 37 respondents were analyzed to identify commonly mentioned partner characteristics in five distinct domains: sociodemographics, behavioral patterns of the partners, motivations in seeking sex services, levels of partner engagement with the sex workers, and the social circumstances that moderate the engagement. Four of the five domains (all but sociodemographics) proved useful in identifying typologies that were best described as populated points in a matrix generated from the intersection of the four domains. The data were too limited to specify which of the points in the matrix are most common, but the points populated are useful in generating hypotheses for further study and in identifying potential avenues for risk reduction interventions.


Enterotoxigenicity of Salmonellae isolated from dogs in Nigeria.
Salmonella dublin, S agama and S typhimurium isolated from local dogs were tested for enterotoxigenic activity using Guinea-Pig Ligated Ileal Loop Technique. One millilitre each of whole-cell culture (WCC) and cell-free filtrate (CFF) of each isolate was injected into replicates of ligated loops. Enterotoxigenic activity, measured as mean dilatation index (DI) was determined for WCC and CFF of each isolate. Both WCC and unheated CFF of all the serotypes induced considerable fluid accumulation in the loops. The mean DI produced by WCC and unheated CFF varied significantly among the three serotypes. This variation seems to support the concept of multiple mechanisms for salmonella-induced diarrhoea.


What is the effect of prolonged sitting and physical activity on thoracic spine mobility? An observational study of young adults in a UK university setting.
Sedentary behaviour has long been associated with neck and low back pain, although relatively little is known about the thoracic spine. Contributing around 33% of functional neck movement, understanding the effect of sedentary behaviour and physical activity on thoracic spinal mobility may guide clinical practice and inform research of novel interventions. An assessor-blinded prospective observational study designed and reported in accordance with Strengthening the Reporting of Observational Studies in Epidemiology. UK university (June-September 2016). A convenience sample (18-30 years) was recruited and based on self-report behaviours, the participants were assigned to one of three groups: group 1, sitters-sitting >7 hours/day+physical activity<150 min/week; group 2, physically active-moderate exercise >150 min/week+sitting <4 hours/day and group 3, low activity-sitting 2-7 hours/day+physical activity <150 min/week. Thoracic spine mobility was assessed in the heel-sit position using Acumar digital goniometer; a validated measure. Descriptive and inferential analyses included analysis of variance and analysis of covariance for between group differences and Spearman's rank correlation for post hoc analysis of associations. The sample (n=92) comprised: sitters n=30, physically active n=32 and low activity n=30. Groups were comparable with respect to age and body mass index.Thoracic spine mobility (mean (SD)) was: group 1 sitters 64.75 (1.20), group 2 physically active 74.96 (1.18) and group 3 low activity 68.44 (1.22). Significant differences were detected between (1) sitters and low activity, (2) sitters and physically active (p<0.001). There was an overall effect size of 0.31. Correlations between thoracic rotation and exercise duration (r=0.67, p<0.001), sitting duration (r=-0.29, p<0.001) and days exercised (r=0.45, p<0.001) were observed. Findings evidence reduced thoracic mobility in individuals who spend >7 hours/day sitting and <150 min/week of physical activity. Further research is required to explore possible causal relationships between activity behaviours and spinal musculoskeletal health.


Uncommon pathways of immune escape attenuate HIV-1 integrase replication capacity.
An attenuation of the HIV-1 replication capacity (RC) has been observed for immune-mediated escape mutations in Gag restricted by protective HLA alleles. However, the extent to which escape mutations affect other viral proteins during natural infection is not well understood. We generated recombinant viruses encoding plasma HIV-1 RNA integrase sequences from antiretroviral-naïve individuals with early (n = 88) and chronic (n = 304) infections and measured the in vitro RC of each. In contrast to data from previous studies of Gag, we observed little evidence that host HLA allele expression was associated with integrase RC. A modest negative correlation was observed between the number of HLA-B-associated integrase polymorphisms and RC in chronic infection (R = -0.2; P = 0.003); however, this effect was not driven by mutations restricted by protective HLA alleles. Notably, the integrase variants S119R, G163E, and I220L, which represent uncommon polymorphisms associated with HLA-C*05, -A*33, and -B*52, respectively, correlated with lower RC (all q < 0.2). We identified a novel C*05-restricted epitope (HTDNGSNF(114-121)) that likely contributes to the selection of the S119R variant, the polymorphism most significantly associated with lower RC in patient sequences. An NL4-3 mutant encoding the S119R polymorphism displayed a ~35%-reduced function that was rescued by a single compensatory mutation of A91E. Together, these data indicate that substantial HLA-driven attenuation of integrase is not a general phenomenon during HIV-1 adaptation to host immunity. However, uncommon polymorphisms selected by HLA alleles that are not conventionally regarded to be protective may be associated with impaired protein function. Vulnerable epitopes in integrase might therefore be considered for future vaccine strategies.


[Impulsivity as an immediate factor between addictive disorders and Attention Deficit-Hyperactivity Disorder].
Impulsivity is a behavior in everyday life of mentally healthy individuals. But in some cases the degree of impulsivity begins to create negative effects on one's life and acquires pathological connotation. Two clinical entities in which can be observed a high degree of impulsivity is Attention Deficit Hyperactivity Disorder (ADHD) and Addictive disorders. In these disorders, both impulsive act and impulsive choice are observed. According to some researchers, genetic factors are involved in the control of impulsivity. The impulsive choice, in the sense of delay discounting, may be an intermediate phenotype or endophenotype that contributes to vulnerability with respect to specific disorders in which impulsivity plays a central and decisive role. Another group of researchers argue that ADHD is one of the expressions of a more generalized disorder, known as reward-deficiency syndrome. In this syndrome, it is included increased frequency of addictive disorders. On the other hand, some researchers argue that ADHD in adolescence does not increase the likelihood of developing dependencies, when it is not accompanied by comorbidity of conduct disorders. Regarding the use of substances, there have been conflicting views in relation to etiopathogenesis of impulsivity observed in the addicted patients and whether this impulsivity precedes or follows the onset of substance use. The element that links ADHD with impaired preoccupation with gambling and has been studied most is also impulsivity. Some researchers theorize that ADHD mediates with the element of impulsivity in the development of disordered involvement with gambling in some patients. The positive correlation between impulsivity and addiction to gambling arises, whether behavioral scales or questionnaires about personality have been used. Moreover the higher measured impulsivity of the patient, the more serious are the symptoms of dependence. Abnormalities in neurotransmitter systems have been found both in patients with dependence on gambling, as well as in patients with impulsive behavior. It seems that impulsivity in these players is part of their personality and not a transient behavior. The variety of views that exists and the debate surrounding this issue reflects the multidisciplinary nature of the phenomenon of impulsivity, when found in dual diagnosis of Attention Deficit/Hyperactivity Disorder and Addictive Disorder. It is important for patients with ADHD or any form of addictive disorder, presenting for treatment, to assess the degree of their impulsivity and to investigate the possible comorbidity with other mental health problems, in which impulsivity plays a central role.


Transcriptional and Post-transcriptional Mechanisms Limit Heading Date 1 (Hd1) Function to Adapt Rice to High Latitudes.
Rice flowering is controlled by changes in the photoperiod that promote the transition to the reproductive phase as days become shorter. Natural genetic variation for flowering time has been largely documented and has been instrumental to define the genetics of the photoperiodic pathway, as well as providing valuable material for artificial selection of varieties better adapted to local environments. We mined genetic variation in a collection of rice varieties highly adapted to European regions and isolated distinct variants of the long day repressor HEADING DATE 1 (Hd1) that perturb its expression or protein function. Specific variants allowed us to define novel features of the photoperiodic flowering pathway. We demonstrate that a histone fold domain scaffold formed by GRAIN YIELD, PLANT HEIGHT AND HEADING DATE 8 (Ghd8) and several NF-YC subunits can accommodate distinct proteins, including Hd1 and PSEUDO RESPONSE REGULATOR 37 (PRR37), and that the resulting OsNF-Y complex containing Hd1 can bind a specific sequence in the promoter of HEADING DATE 3A (Hd3a). Artificial selection has locally favored an Hd1 variant unable to assemble in such heterotrimeric complex. The causal polymorphism was defined as a single conserved lysine in the CCT domain of the Hd1 protein. Our results indicate how genetic variation can be stratified and explored at multiple levels, and how its description can contribute to the molecular understanding of basic developmental processes.


Autoradiographic demonstration of peripheral adenosine binding sites using [3H]NECA.
Autoradiographic localization of 5'-N-ethylcarboxamido[3H]adenosine ([3H]NECA) binding sites revealed a heterogeneous labeling of guinea-pig intestine with heavy labeling over the enteric ganglia and in clusters over the mucosa; a low level of label was homogeneously distributed over the muscularis externa. Under the conditions employed, no binding sites were revealed using [3H]-N6-cyclohexyladenosine ([3H]CHA), although both [3H]CHA and [3H]NECA binding sites were localized over comparable areas of rat brain. The relationship of the [3H]NECA binding sites to extracellular adenosine receptors is discussed.


A common scheme for cross-sensory correspondences across stimulus domains.
Following Karwoski, Odbert, and Osgood (1942, Journal of General Psychology 26 199-222), it is proposed that cross-sensory correspondences can arise from extensive, bi-directional cross-activation between dimensions of connotative meaning. If this account is correct, the same set of cross-sensory correspondences (eg brightness with high pitch, high pitch with sharpness, smallness with brightness) should emerge regardless of the sensory channel (auditory, visual, or tactile) that is probed. To test this prediction, participants rated a range of auditory, visual, and tactile stimuli on a series of rating scales relating to different dimensions of connotative meaning. With only a few minor exceptions, the same set of cross-sensory correspondences emerged from all types of stimulus variation. This supports the suggestion that cross-sensory correspondences can reflect reciprocal interactions between dimensions of connotative meaning, and indicates that Spence's (2011, Attention, Perception, & Psychophysics 73 971-995) theoretical framework might be usefully extended to include semantically-based correspondences.


Physical Disability and Increased Loneliness among Married Older Adults: The Role of Changing Social Relations.
Examining the social context of disablement, we investigated how changes in social relations affect loneliness among married older men and women. With longitudinal data on 914 married persons from the National Social Life, Health, and Aging Project (NSHAP), we found that changes in the quality of marital and nonmarital relations moderate the effect of disability on loneliness in unexpected ways. Increases in negative marital quality buffer the effect of physical disability, while increases in nonmarital support exacerbate it. Although not predicted by existing theory, these findings are consistent with some prior work suggesting that health-related stressors, like physical disability, condition the meaning of changes in social relations. We find, however, that negative social relations ameliorate loneliness only among disabled married men; disabled married women experience increased loneliness under similar circumstances. These differences have not been previously identified. We conclude by discussing the gendered nature of the social context of disablement.


Early results of extracardiac fontan procedure with autologous pericardial tube conduit.
Different types of conduits are used for extracardiac Fontan procedure. The use of autologous pericardial tube as an alternative conduit for connecting the inferior vena cava to the pulmonary artery is investigated. We performed 25 extracardiac Fontan procedures by using pericardial tube between June 2000 and October 2003. Fifteen patients were male. Mean age and weight were 7.6 +/- 4.9 years (range 3 to 24 years) and 22.8 +/- 10.4 kg (range 12 - 50 kg), respectively. All patients survived after extracardiac Fontan procedure. Prolonged chest tube drainage (> 7 days) was required in 9 (36 %) patients. Follow-up was complete and mean follow-up was 24.6 +/- 11.5 months (1 - 39 months). One patient died 3 months postoperatively. Routine serial postoperative echocardiographic examinations in all patients and magnetic resonance angiography in 6 patients with suspect flow patterns in echocardiography did not reveal any problems with the Fontan circuit. Fresh autologous pericardial tube conduit is a suitable and safe alternative for extracardiac Fontan procedures. Major advantages are availability, no cost, easy handling and hemostasis, low risk of thrombosis and emboli, and growth potential.


Immunogenicity of the meningococcal polysaccharide conjugate vaccine in pediatric kidney transplant patients.
Immunosuppressed kidney transplant patients may have suboptimal response to vaccinations. The aim of this study was to determine antibody response to a quadrivalent meningococcal conjugate vaccine (MenACWY-D) in adolescents with a kidney transplant. This was a prospective, single-center, cohort study. Adolescent patients (11-22 years old) with a functioning kidney transplant for at least 3 months and no previous meningococcal vaccination were eligible for enrollment. Antibody levels to all serogroups were measured before vaccination (baseline) and at 4 weeks and 1, 2 and 3 years after vaccination. Seropositivity was defined as a titer ≥ 1:8 at baseline, and seroconversion as a fourfold or greater increase in antibody titer from baseline at 4 weeks post-vaccination. Geometric mean titers (GMTs) were calculated at each time point and compared to published GMTs from vaccinated healthy adolescents. Nineteen patients were enrolled. No patient had seroprotective titers against all four serogroups at baseline. At 4 weeks post-vaccination 41% of patients seroconverted to all four serogroups, with seroconversion rates of 88, 53, 71 and 94% for serogroups A, C, W and Y, respectively. GMTs were significantly lower in adolescents with a kidney transplant than in healthy adolescents at 1 month (p = 0.02) and 3 years (p = 0.04) post-vaccination. There were no significant adverse events, episodes of rejection or death in any patient. Adolescents with a kidney transplant may not respond adequately to MenACWY-D and may experience more rapid declines in antibody titers than healthy adolescents. Further study is needed to determine if alternative dosing schedules can improve antibody response in this population.


Role of immunolglobulin-like transcript family receptors and their ligands in suppressor T-cell-induced dendritic cell tolerization.
The immunolglobulin-like transcript (ILT) family of proteins are surface receptors expressed by antigen-presenting cells capable of modulating host cell functions through intracellular signaling. Here we discuss the recent studies regarding the role of dendritic cell (DC)-expressed ILT receptors in suppressor T (Ts) cells induced DC tolerization. DC-expressed ILT3 and ILT4 are stimulated by their cognate ligands such as major histocompatibility complex class I (MHC-I), HLA-G, and CD1d, and this stimulation is a prerequisite for DC tolerization. The molecular interaction between ILT and ligands seems to create a tri-molecule complex at the interface between Ts cell and DC, which consists of DC-expressed ILT receptor and MHC-I, as well as T-cell-expressed T cell receptor (TCR). Furthermore, ILT4 recognition of MHC-I and CD1d is shown to be antigen dependent, suggesting that T-cell antigen specificity possibly affects the outcome of DC tolerization. Therefore the ILT-MHC interface could be a potential novel target for improving vaccine efficiency and allograft survival, or for devising new treatments for autoimmune diseases.


Alu RNA Modulates the Expression of Cell Cycle Genes in Human Fibroblasts.
Alu retroelements, whose retrotransposition requires prior transcription by RNA polymerase III to generate Alu RNAs, represent the most numerous non-coding RNA (ncRNA) gene family in the human genome. Alu transcription is generally kept to extremely low levels by tight epigenetic silencing, but it has been reported to increase under different types of cell perturbation, such as viral infection and cancer. Alu RNAs, being able to act as gene expression modulators, may be directly involved in the mechanisms determining cellular behavior in such perturbed states. To directly address the regulatory potential of Alu RNAs, we generated IMR90 fibroblasts and HeLa cell lines stably overexpressing two slightly different Alu RNAs, and analyzed genome-wide the expression changes of protein-coding genes through RNA-sequencing. Among the genes that were upregulated or downregulated in response to Alu overexpression in IMR90, but not in HeLa cells, we found a highly significant enrichment of pathways involved in cell cycle progression and mitotic entry. Accordingly, Alu overexpression was found to promote transition from G1 to S phase, as revealed by flow cytometry. Therefore, increased Alu RNA may contribute to sustained cell proliferation, which is an important factor of cancer development and progression.


Low Prevalence of Ocular Chlamydia trachomatis Infection and Active Trachoma in the Western Division of Fiji.
Trachoma is the leading infectious cause of blindness and is caused by ocular infection with the bacterium Chlamydia trachomatis (Ct). While the majority of the global disease burden is found in sub-Saharan Africa, the Western Pacific Region has been identified as trachoma endemic. Population surveys carried out throughout Fiji have shown an abundance of both clinically active trachoma and trachomatous trichiasis in all divisions. This finding is at odds with the clinical experience of local healthcare workers who do not consider trachoma to be highly prevalent. We aimed to determine whether conjunctival infection with Ct could be detected in one administrative division of Fiji. A population-based survey of 2306 individuals was conducted using the Global Trachoma Mapping Project methodology. Population prevalence of active trachoma in children and trichiasis in adults was estimated using the World Health Organization simplified grading system. Conjunctival swabs were collected from 1009 children aged 1-9 years. DNA from swabs was tested for the presence of the Ct plasmid and human endogenous control. The prevalence of active trachoma in 1-9 year olds was 3.4%. The age-adjusted prevalence was 2.8% (95% CI: 1.4-4.3%). The unadjusted prevalence of ocular Ct infection in 1-9 year-olds was 1.9% (19/1009), and the age-adjusted infection prevalence was 2.3% (95% CI: 0.4-2.5%). The median DNA load was 41 Ct plasmid copies per swab (min 20, first quartile 32, mean 6665, third quartile 161, max 86354). There was no association between current infection and follicular trachoma. No cases of trachomatous trichiasis were identified. The Western Division of Fiji has a low prevalence of clinical trachoma. Ocular Ct infections were observed, but they were predominantly low load infections and were not correlated with clinical signs. Our study data suggest that trachoma does not meet the WHO definition of a public health problem in this Division of Fiji, but the inconsistency with previous studies warrants further investigation.


Drug users attending general practice in Eastern Regional Health Authority (ERHA) area.
Dublin has an estimated 13,460 opiate drug users. The role of general practice in providing care for this group has increased over the last four years. A Central Methadone Treatment List (CMTL) registers all clients currently on treatment. To obtain a social, demographic and drug using profile of opiate users attending general practitioners (GPs) for methadone maintenance. A cross sectional survey of opiate users attending general practice for methadone maintenance in the Dublin area in early 1999. Data was collected on 571 clients (62% of total number attending general practice), of whom 97% had used heroin in the past and 12% had never injected. Although clients had been receiving methadone maintenance in general practice for a mean of 14 months, 16% were still using heroin, of whom 31% were still injecting. The mean age of first drug use was 15.5 years and of first injecting was 19.4 years. Younger clients are starting both to use drugs and inject drugs at an earlier age. Record keeping was good, with most items of information present in over 70% of the charts surveyed. A total of 17% of clients recorded on the CMTL could not be traced to the GP recorded as providing care. Despite treatment with methadone maintenance, there is a high level of continued risk activity in this group. Furthermore, a trend towards earlier initiation to drug use is apparent. The CMTL registration process requires further exploration.


Family-based association study on functional α-synuclein polymorphisms in attention-deficit/hyperactivity disorder.
Studies have strongly suggested a disturbed regulation of dopaminergic neurotransmission in attention-deficit/hyperactivity disorder (ADHD) and Parkinson's disease (PD). A genetic and phenotypic overlap between both disorders is discussed. A well-studied risk gene for PD is the gene coding for α-synuclein (SNCA). α-Synuclein, a protein located primarily in the presynaptic vesicles, has been suggested to play a role in the modulation of dopamine transporter (DAT) function. DAT is the target of psychostimulants for the treatment of ADHD and plays a key role in regulating the dopamine concentrations in the synaptic cleft. In our sample consisting of German families with children affected by ADHD, we tested for association of allelic variants of two functionally relevant polymorphisms of the α-synuclein gene (NACP-Rep1: 156 families, 232 children; rs356219: 195 families, 284 children) with ADHD. Transmission disequilibrium test analysis revealed no over-transmission for NACP-Rep1 (OR 1, pnom = 1 padj = 1) and rs356219 (OR 1.28; pnom = 0288) in affected siblings. However, a subanalysis on trios with index children showed a nominal association of rs356219 with ADHD (OR 1.43, pnom = 0.020), which survived Bonferroni correction (padj = 0.039); again, no association for NACP-Rep1 (OR 0.8, p = 0.317, padj = 0.634) was found. In conclusion, we found in our pilot study a trend for an association of the rs356219 genotype in SNCA that may affect α-synuclein function and contribute to the aetiology of ADHD. In light of the small sample size of our study, the link between PD and ADHD through dopamine-related neurobiology warrants further investigations. Future studies on SNCA in large ADHD samples should focus on specified symptoms and traits, e.g. attentional capacities or emotional dysregulation.


Acupuncture for some common disorders: a review of evaluative research.
This paper reviews the use of acupuncture to treat several disorders where pain is not the primary symptom. Studies on asthma have shown a small but consistent short-term therapeutic effect of acupuncture. One study of long-term effects found no improvement in asthma after acupuncture while the other reported a modest effect on symptom relief but with a greater impact on medication reduction. Further studies of the long-term effects of acupuncture on asthma would seem desirable even though the currently available findings are equivocal. Sufficient work has now been carried out on sensorineural deafness to conclude that acupuncture has no worthwhile effects on this condition. Only two studies have been carried out on tinnitus; they indicate that the effects of short courses of acupuncture are at best slight. There are some encouraging findings for acupuncture treatment of hypertension, although the study was seriously flawed by the lack of a no treatment control group. With regard to giving up smoking it seems that acupuncture may assist during the withdrawal period and that it compares favourably with other forms of treatment; whether there is any specific effect of the acupuncture is not yet clear. As with other attempts to stop people smoking, however, there is a high relapse rate. The trials of acupuncture on psychiatric disorders have suffered from the lack of detailed assessment and control groups; no conclusions can be drawn without further studies. The studies on weight loss similarly do not permit any firm conclusions about the usefulness of acupuncture.


Acute oral toxicity and brine shrimp lethality of Elaeis guineensis Jacq., (oil palm leaf) methanol extract.
Elaeis guineensis (Arecaceae) is widely used in West African traditional medicine for treating various ailments. An evaluation on the toxicity of extracts of this plant is crucial to support the therapeutic claims. The acute oral toxicity and brine shrimp lethality of a methanolic extract of this plant was tested. Oral administration of crude extract at the highest dose of 5,000 mg/kg resulted in no mortalities or evidence of adverse effects, implying that E. guineensis is nontoxic. Normal behavioral pattern, clinical signs and histology of vital organs confirm this evidence. The E. guineensis extracts screened for toxicity against brine shrimp had 50% lethal concentration (LC₅₀) values of more than 1.0 mg/mL (9.00 and 3.87 mg/mL, at 6 and 24 h, respectively), confirming that the extract was not toxic. Maximum mortalities occurred at 100 mg/mL concentration while the least mortalities happened to be at 0.195 mg/mL concentration. The results of both tests confirm that E. guineensis is nontoxic and hence safe for commercial utilization.


Assessment of regularization techniques for electrocardiographic imaging.
A widely used approach to solving the inverse problem in electrocardiography involves computing potentials on the epicardium from measured electrocardiograms (ECGs) on the torso surface. The main challenge of solving this electrocardiographic imaging (ECGI) problem lies in its intrinsic ill-posedness. While many regularization techniques have been developed to control wild oscillations of the solution, the choice of proper regularization methods for obtaining clinically acceptable solutions is still a subject of ongoing research. However there has been little rigorous comparison across methods proposed by different groups. This study systematically compared various regularization techniques for solving the ECGI problem under a unified simulation framework, consisting of both 1) progressively more complex idealized source models (from single dipole to triplet of dipoles), and 2) an electrolytic human torso tank containing a live canine heart, with the cardiac source being modeled by potentials measured on a cylindrical cage placed around the heart. We tested 13 different regularization techniques to solve the inverse problem of recovering epicardial potentials, and found that non-quadratic methods (total variation algorithms) and first-order and second-order Tikhonov regularizations outperformed other methodologies and resulted in similar average reconstruction errors.


Posterior mitral leaflet extension: an adjunctive repair option for ischemic mitral regurgitation?
Residual or recurrent mitral regurgitation frequently occurs after mitral valve repair for ischemic mitral regurgitation with an annuloplasty ring. Because annuloplasty primarily addresses annular dilatation, we studied an adjunctive technique that might correct restricted leaflet (Carpentier type IIIb) systolic closing motion, which often accompanies annular dilatation in patients with ischemic mitral regurgitation. Six sheep had radiopaque markers placed on the left ventricle, mitral leaflets and annulus, and mitral subvalvular apparatus. A pericardial patch was sutured into the middle scallop of the posterior mitral valve leaflet and furled in with a reefing stitch placed in the radial axis. Posterolateral left ventricular myocardial ischemia was created by using proximal circumflex occlusion to induce acute ischemic mitral regurgitation. Under open-chest conditions, 3-dimensional marker coordinates were measured by using biplane videofluoroscopy at baseline and during acute ischemia both before and after release of the reefing stitch (leaflet extension); transesophageal echocardiography was used to grade ischemic mitral regurgitation. Leaflet apical systolic tethering was not improved by leaflet extension, but ischemic mitral regurgitation decreased (control, 0.9 +/- 0.3*; ischemia, 2.4 +/- 0.3; leaflet extension, 1.5 +/- 0.3; *P < 0.002). Posterior mitral valve leaflet midline length (control, 1.45 +/- 0.09*; ischemia, 1.53 +/- 0.10; leaflet extension, 1.83 +/- 0.13*; *P < 0.001) and posterior mitral valve leaflet middle scallop area (control, 1.66 +/- 0.20 cm2*; ischemia, 1.91 +/- 0.22 cm2; leaflet extension, 2.36 +/- 0.22 cm2*; *P < 0.006) increased with leaflet extension because of patch unfurling (mean +/- 1 standard error of the mean; repeated-measures analysis of variance, Dunnet post-hoc test vs ischemia). Posterior mitral valve leaflet extension ameliorated acute ischemic mitral regurgitation but did not correct the abnormal apically restricted systolic posterior mitral valve leaflet closing motion. This technique might be a useful adjunct repair in combination with ring annuloplasty for ischemic mitral regurgitation, but the clinical role of this adjunct remains to be defined in patients.


First Report of Aecidium magnatum Anamorph of Uromyces acuminatus Causing Rust on Viburnum sargentii in Korea.
Viburnum sargentii Koehne belongs to the family Caprifoliaceae. It is a deciduous shrub that grows in wet mountainous area in Korea, Japan, and China. On July 2011, rust symptoms were observed on V. sargentii Koehne in Balwang mountain, Gangwon Province, Korea, at an altitude of 1,450 meters. The specimen was coded as DUCC506 and used to study in detail. Rust symptoms were present on leaves, floral axes, and petioles. The infected lesions slightly swelled and leaflets and leaves were distorted. These caused sharp bends in the petioles and wart-like galls on twigs. Defoliation and deflowering could result when infection was severe. The first symptom was small and pale yellow spots on the upper surfaces of the leaves. As the spots increased in size, they turned brown and tanned. Bright orange or yellow powdery masses of spores were produced in tiny cup-like structures that appeared on the undersurfaces of leaves and the surface of floral axes and petioles. Aecia were gregarious, cupulate, yellowish, and erumpent with a peridium having a lacerate, somewhat recurved margin. Peridial cells were hyaline to whitish, rhomboidal, 18 to 25 (avg. 21.5) × 15 to 20 (avg. 18) μm, smooth to finely verrucose, and not observed in aecial stage on floral axes and petioles. Aeciospores were globose to ellipsoid, 14 to 16 (avg. 15.4) × 15 to 16.5 (avg. 16) μm, hyaline to yellowish, with many verrucose surface and hyaline walls. These morphological properties correspond to the aecial stage of Uromyces acuminatus (1,4). From extracted genomic DNA, the D1 and D2 region of 28S ribosomal DNA was amplified with LROR (5'- ACCCGCTGAACTTAAGC-3') and LR4 (5'-ACCAGAGTTTCCTCTGG- 3') primer set. The 28S rDNA sequence of DUCC506 was deposited in GenBank DNA database under accession number KC570451. A nucleotide sequence similarity search through BLAST in the GenBank database revealed that the DUCC506's 28S rDNA shared 98% (607/622) similarity with that of U. acuminatus LD1005 (GU058004). Aecidium magnatum Arthur is the anamorph of U. acuminatus (2). Aecial and telial hosts of U. acuminatus belong to several families of Angiosperms and Spartina spp., respectively. No telial host was found near the infected aecial host V. sargentii. These morphological and molecular results support the morphological data to identify DUCC506 specimen is A. magnatum. To our knowledge, this is the first report of rust caused by A. magnatum on V. sargentii in Korea or elsewhere in the world. Rust caused by A. viburni was reported on V. sargentii in Korea without any morphological description (3). Peoples in Asia are interested in this host plant as it is used for ornamental and medicinal purpose. Therefore, our report would be useful information for the management of V. sargentii. References: (1) G. B. Cummins. The Rust Fungi of Cereals, Grasses and Bamboos. Springer-Verlag, New York, 1971. (2) D. F. Farr et al. Fungi on Plants and Plant Products in the United States. Page 1009. American Phytopathological Society Press, St. Paul, MN, 1989. (3) C. J. Kim. Kor. J. Micorbiol. 1:51, 1963. (4) H. Y. Yun et al. Plant Dis. 94:279, 2010.


Transmembrane helices of membrane proteins may flex to satisfy hydrophobic mismatch.
A novel mechanism for membrane modulation of transmembrane protein structure, and consequently function, is suggested in which mismatch between the hydrophobic surface of the protein and the hydrophobic interior of the lipid bilayer induces a flexing or bending of a transmembrane segment of the protein. Studies on model hydrophobic transmembrane peptides predict that helices tilt to submerge the hydrophobic surface within the lipid bilayer to satisfy the hydrophobic effect if the helix length exceeds the bilayer width. The hydrophobic surface of transmembrane helix 1 (TM1) of lactose permease, LacY, is accessible to the bilayer, and too long to be accommodated in the hydrophobic portion of a typical lipid bilayer if oriented perpendicular to the membrane surface. Hence, nuclear magnetic resonance (NMR) data and molecular dynamics simulations show that TM1 from LacY may flex as well as tilt to satisfy the hydrophobic mismatch with the bilayer. In an analogous study of the hydrophobic mismatch of TM7 of bovine rhodopsin, similar flexing of the transmembrane segment near the conserved NPxxY sequence is observed. As a control, NMR data on TM5 of lacY, which is much shorter than TM1, show that TM5 is likely to tilt, but not flex, consistent with the close match between the extent of hydrophobic surface of the peptide and the hydrophobic thickness of the bilayer. These data suggest mechanisms by which the lipid bilayer in which the protein is embedded modulates conformation, and thus function, of integral membrane proteins through interactions with the hydrophobic transmembrane helices.


Classification of the presynaptic muscarinic receptor subtype that regulates 3H-acetylcholine secretion in the guinea pig urinary bladder in vitro.
The experiments were done to investigate the presence and subtype of functionally presynaptic muscarinic receptors in cholinergic nerves of the guinea pig urinary bladder. Bladder strips were incubated with 3H-choline and superfused with Tyrode's solution containing eserine. Secreted 3H-acetylcholine was separated from 3H-choline. The electrically evoked 3H-acetylcholine secretion increased with the stimulation frequency. 3H-Acetylcholine secretion was enhanced by muscarinic antagonists, was depressed by carbachol and by alpha adrenoceptor agonists but was not influenced by drugs acting at beta adrenoceptors or purinoceptors. The rank order for the enhancing effect of muscarinic antagonist EC50 values was propantheline < atropine < methylatropine < N-desethyloxybutynin < UH-AH 37 < benzhexol < AQ-RA 741 < 4-DAMP < procyclidine < emepronium < secoverine < oxybutynin < tropicamide < promethazine < himbacine < hexahydrosiladifenidol < methoctramine = pirenzepine < dicyclomine < AF-DX 116, and the EC50 values correlated best with constants for the M4/m4 muscarinic receptor subtype. The enhancing effect of atropine was counteracted by carbachol; the effects of atropine and emepronium were not additive. The 3H-acetylcholine secretion was also enhanced by forskolin, 3-isobutyl-1-methylxanthine, 8-bromo cyclic AMP and dibutyryl cyclic AMP. The combined effects of atropine and forskolin were additive. These results suggest that the 3H-acetylcholine secretion in the guinea pig urinary bladder is regulated by a presynaptic muscarinic autoreceptor of the M4 subtype that is not coupled to adenylate cyclase.


Potential Adverse Drug Events with Tetrahydrocannabinol (THC) Due to Drug-Drug Interactions.
Tetrahydrocannabinol (THC) is the primary psychoactive ingredient in cannabis. While the safety of THC and cannabis has been extrapolated from millennia of recreational use, medical marijuana programs have increased exposure among medically complex individuals with comorbid conditions and many co-prescribed medications. Thus, THC should be recognized as a pharmacologically complex compound with potential for drug-drug interactions and adverse drug events. This review summarizes potential adverse drug events related to THC when combined with other medications. Metabolic drug-drug interactions are primarily due to THC conversion by CYP3A4 and CYP2C9, which can be impacted by several common medications. Further, CYP2C9 polymorphisms are highly prevalent in certain racial groups (up to 35% in Caucasians) and increase the bioavailability of THC. THC also has broad interactions with drug-metabolizing enzymes and can enhance adverse effects of other medications. Pharmacodynamic interactions include neurological effects, impact on the cardiovascular system, and risk of infection. General clinical recommendations for THC use include starting with low doses and titrating to desired effects. However, many interactions may be unavoidable, dose-limiting, or a barrier to THC-based therapy. Future work and research must establish sufficient data resources to capture medical marijuana use for such studies. Meanwhile, clinicians should balance the potential risks of THC and cannabis and the lack of strong evidence of efficacy in many conditions with patient desires for alternative therapy.


Past and present progress in the pharmacologic treatment of schizophrenia.
Despite treatment advances over the past decades, schizophrenia remains one of the most severe psychiatric disorders that is associated with a chronic relapsing course and marked functional impairment in a substantial proportion of patients. In this article, a historical overview of the pharmacologic advances in the treatment of schizophrenia over the past 50 years is presented. This is followed by a review of the current developments in optimizing the treatment and outcomes in patients with schizophrenia. Methodological challenges, potential solutions, and areas of particular need for further research are highlighted. Although treatment goals of response, remission, and recovery have been defined more uniformly, a good "effectiveness" measure mapping onto functional outcomes is still lacking. Moreover, the field must advance in transferring measurement-based approaches from research to clinical practice. There is an ongoing debate regarding whether and which first- or second-generation antipsychotics should be used. However, especially when considering individual adverse effect profiles, the differentiation into first- and second-generation antipsychotics as unified classes cannot be upheld, and a more differentiated view and treatment selection are required. The desired, individualized treatment approach needs to consider current symptoms, comorbid conditions, past therapeutic response, and adverse effects, as well as patient choice and expectations. Acute and long-term goals and effects of medication treatment should be balanced. To date, clozapine is the only evidence-based treatment for refractory patients, and the role of antipsychotic polypharmacy and other augmentation strategies remains unclear, at best. To discover novel treatments with enhanced/broader efficacy and improved tolerability, and to enable personalized treatment, the mechanisms underlying illness development and progression, symptomatic improvement, and side effect development need to be elucidated.


Rapid and reproducible characterization of sickling during automated deoxygenation in sickle cell disease patients.
In sickle cell disease (SCD), sickle hemoglobin (HbS) polymerizes upon deoxygenation, resulting in sickling of red blood cells (RBCs). These sickled RBCs have strongly reduced deformability, leading to vaso-occlusive crises and chronic hemolytic anemia. To date, there are no reliable laboratory parameters or assays capable of predicting disease severity or monitoring treatment effects. We here report on the oxygenscan, a newly developed method to measure RBC deformability (expressed as Elongation Index - EI) as a function of pO2 . Upon a standardized, 22 minute, automated cycle of deoxygenation (pO2 median 16 mmHg ± 0.17) and reoxygenation, a number of clinically relevant parameters are produced in a highly reproducible manner (coefficients of variation <5%). In particular, physiological modulators of oxygen affinity, such as, pH and 2,3-diphosphoglycerate showed a significant correlation (respectively R = -0.993 and R = 0.980) with Point of Sickling (PoS5% ), which is defined as the pO2 where a 5% decrease in EI is observed during deoxygenation. Furthermore, in vitro treatment with antisickling agents, including GBT440, which alter the oxygen affinity of hemoglobin, caused a reproducible left-shift of the PoS, indicating improved deformability at lower oxygen tensions. When RBCs from 21 SCD patients were analyzed, we observed a significantly higher PoS in untreated homozygous SCD patients compared to treated patients and other genotypes. We conclude that the oxygenscan is a state-of-the-art technique that allows for rapid analysis of sickling behavior in SCD patients. The method is promising for personalized treatment, development of new treatment strategies and could have potential in prediction of complications.


The structural and energetic basis for high selectivity in a high-affinity protein-protein interaction.
High-affinity, high-selectivity protein-protein interactions that are critical for cell survival present an evolutionary paradox: How does selectivity evolve when acquired mutations risk a lethal loss of high-affinity binding? A detailed understanding of selectivity in such complexes requires structural information on weak, noncognate complexes which can be difficult to obtain due to their transient and dynamic nature. Using NMR-based docking as a guide, we deployed a disulfide-trapping strategy on a noncognate complex between the colicin E9 endonuclease (E9 DNase) and immunity protein 2 (Im2), which is seven orders of magnitude weaker binding than the cognate femtomolar E9 DNase-Im9 interaction. The 1.77 A crystal structure of the E9 DNase-Im2 complex reveals an entirely noncovalent interface where the intersubunit disulfide merely supports the crystal lattice. In combination with computational alanine scanning of interfacial residues, the structure reveals that the driving force for binding is so strong that a severely unfavorable specificity contact is tolerated at the interface and as a result the complex becomes weakened through "frustration." As well as rationalizing past mutational and thermodynamic data, comparing our noncognate structure with previous cognate complexes highlights the importance of loop regions in developing selectivity and accentuates the multiple roles of buried water molecules that stabilize, ameliorate, or aggravate interfacial contacts. The study provides direct support for dual-recognition in colicin DNase-Im protein complexes and shows that weakened noncognate complexes are primed for high-affinity binding, which can be achieved by economical mutation of a limited number of residues at the interface.


Relaxing effect of rose oil on humans.
One increasingly popular type of alternative therapy is aromatherapy, but scientific validation in this field is still rare. The aim of this study was to investigate the effect of rose oil (Rosa damascena Mill, Rosaceae) on human autonomic parameters and emotional responses in healthy subjects after transdermal absorption. In order to exclude any olfactory stimulation the inhalation of the fragrances was prevented by breathing masks. Forty healthy volunteers participated in the experiments. Five autonomic parameters, i.e. blood pressure, breathing rate, blood oxygen saturation, pulse rate, and skin temperature, were recorded. Emotional responses were assessed by means of rating scales. Compared to placebo, rose oil caused significant decreases of breathing rate, blood oxygen saturation and systolic blood pressure, which indicate a decrease of autonomic arousal. At the emotional level, subjects in the rose oil group rated themselves as more calm, more relaxed and less alert than subjects in the control group. These findings are likely to represent a relaxing effect of the rose oil and provide some evidence for the use of rose oil in aromatherapy, such as causing relief of depression and stress in humans.


Optical detection of liquid-state NMR.
Nuclear magnetic resonance (NMR) in liquids and solids is primarily detected by recording the net dipolar magnetic field outside the spin-polarized sample. But the recorded bulk magnetic field itself provides only limited spatial or structural information about the sample. Most NMR applications rely therefore on more elaborate techniques such as magnetic field gradient encoding or spin correlation spectroscopy, which enable spatially resolved imaging and molecular structure analysis, respectively. Here we demonstrate a fundamentally different and intrinsically information-richer modality of detecting NMR, based on the rotation of the polarization of a laser beam by the nuclear spins in a liquid sample. Optical NMR detection has in fact a long history in atomic vapours with narrow resonance lines, but has so far only been applied to highly specialized condensed matter systems such as quantum dots. It has been predicted that laser illumination can shift NMR frequencies and thus aid detection, but the effect is very small and has never been observed. In contrast, our measurements on water and liquid 129Xe show that the complementary effect-the rotation of light polarization by nuclear spins-is readily measurable, and that it is enhanced dramatically in samples containing heavy nuclei. This approach to optical NMR detection should allow correlated optical and NMR spectroscopy on complex molecules, and continuous two-dimensional imaging of nuclear magnetization with spatial resolution limited only by light diffraction.


Female Service Members and Symptom Reporting after Combat and Non-Combat-Related Mild Traumatic Brain Injury.
Females are often excluded from military-related mild traumatic brain injury (mTBI) research because of its relatively low prevalence in this population. The purpose of this study was to focus on outcome from mTBI in female service members, compared with males. Participants were 172 United States military service members selected from a larger sample that had sustained an mTBI, and were evaluated within 24 months of injury (Age: mean = 28.9, SD = 8.1) at one of six military medical centers. Eighty-six women were matched to 86 men on nine key variables: TBI severity, mechanism of injury, bodily injury severity, days post-injury, age, number of deployments, theater where wounded, branch of service, and rank. Participants completed the Neurobehavioral Symptom Inventory (NSI) and the Posttraumatic Stress Disorder Checklist (PCL-C). There were no meaningful gender differences across all demographic and injury-related variables (p > 0.05). There were significant group differences and medium effect sizes for the NSI total score and all four NSI cluster scores. Symptoms most affected related to nausea, sensitivity to light, change in taste/smell, change in appetite, fatigue, and poor sleep. There were significant group differences and small-medium effect sizes for the PCL-C total score and two of the three PCL-C cluster scores. Symptoms most affected related to poor concentration, trouble remembering a stressful event, and disturbing memories/thoughts/images. Females consistently experienced more symptoms than males. As females become more active in combat-related deployments, it is critical that future studies place more emphasis on this important military population.


A comparison of 4- and 24-hour urine samples for the diagnosis of proteinuria in pregnancy.
Preeclampsia is a serious complication of pregnancy, and it is vital to diagnosis the condition as early as possible. Proteinuria is an important symptom of preeclampsia, and repeated urine analysis to screen for the condition is part of the standard antenatal care. The purpose of this study was to determine the correlation between 4- and 24-hour urine total protein values to examine whether the 4-hour urine samples could be used for the diagnosis of proteinuria in hypertensive disorders of pregnancy. A cross-sectional study was performed on 110 pregnant (after gestational week 20 of pregnancy) patients who were hypertensive (blood pressure ≥140/90 mmHg) and had proteinuria as defined by positive urinary protein of at least 1+ in dipstick. Patients' urine samples were collected over 24 hours; the first 4 hours were collected separately from the next 20-hours. Patients, who did not collect the 24-hour urine, were excluded from the study. One hundred patients met the criteria, and were included in the study. The urine volume, total protein and creatinine levels of 4- and 24-hours samples were measured. The correlation between 4-hour and 24-hour samples was examined using Pearson correlation test. Of the 100 patients, 42 had no proteinuria, 44 had mild proteinuria, and 14 had severe proteinuria. The urine protein values of 4-hour samples correlated with those of the 24-hours samples for patients with mild and severe forms of the disease (P<0.001, r=0.86). This study showed there was a correlation between 4-hour and 24-hour urine proteins. The finding indicates that a random 4-hour sample might be used for the initial assessment of proteinuria.


The putative lithium-mimetic ebselen reduces impulsivity in rodent models.
Deficits in impulse control feature in many psychiatric conditions including bipolar disorder, suicidality and addictions. Lithium lowers impulsivity in clinical populations and decreases pathological gambling in experimental medicine studies, but suffers from adverse effects, poor compliance and a low therapeutic index. Recently we identified that the neuroprotective agent ebselen, which is reportedly safe in humans, inhibited inositol monophosphatase (IMPase), a candidate lithium mechanism. Ebselen also reduced 5-HT receptor (5-HT2A) function which predicts impulsivity lowering properties. Here we investigated the effect of ebselen in rat models of impulsive behaviour. Ebselen was tested in two models of impulsivity with human analogues: the five-choice serial reaction time task (5-CSRTT) and rodent gambling task (rGT). The main outcome measures were premature responses (5-CSRTT and rGT) and choice behaviour (rGT), which model motor impulsivity and choice impulsivity, respectively. At doses that decreased 5-HT2A receptor function (DOI-induced wet dog shakes), ebselen decreased premature responding in the 5-CSRTT both in the absence and presence of cocaine. The 5-HT2A receptor antagonist MDL 100,907 also reduced premature responding in the 5-CSRTT although not in the presence of cocaine. In the rGT ebselen showed a tendency to reduce premature responding but had no effect on choice behaviour. These findings suggest that ebselen preferentially reduces motor impulsivity over choice impulsivity, and that inhibition of 5-HT2A receptor function is a contributing mechanism. Collectively, these data support the repurposing of ebselen as an anti-impulsive treatment and fast-tracking to clinical trials in patient groups characterised by poor impulse control.


A follow-up study for biomass yield QTLs in rice.
The biomass yield (plant weight) of rice fluctuates from year to year. In a previous study, we demonstrated that six quantitative trait loci (QTLs) contribute to the variation in the plant weight of recombinant inbred lines (RILs) of high-yielding Japanese rice cultivars. However, it remains unclear whether the effects of those QTLs are stable over multiple years. Therefore, we evaluated the effect of the alleles on the plant weight of RILs over multiple years, including a change of fertilization level (i.e., in different environments). Even though the biomass yields of all RILs fluctuated among environments, RILs that were selected on the basis of the genotypes of the detected QTLs had a stable rank order of plant weight that corresponded to their genotypes. This multiple-environment experiment reveals the highly significant contribution of both genotypic and environmental variances to the observed variance in plant weight. A marginally significant QTL-environment interaction was detected at only one of the six QTLs, with a subtle contribution. These results support the idea that the biomass yield of rice can be improved through QTL-based allele selection.


Polarization properties of a corner-cube retroreflector with three-dimensional polarization ray-tracing calculus.
The output polarization states of corner cubes (for both uncoated and metal-coated surfaces) with an input beam of arbitrary polarization state and of arbitrary tilt angle to the cube have been analyzed by using the three-dimensional polarization ray-tracing matrix method. The diattenuation and retardance of the corner-cube retroreflector (CCR) for all six different ray paths are calculated, and the relationships to the tilt angle and the tilt orientation angle are shown. When the tilt angle is large, hollow metal-coated CCR is more appropriate than solid metal-coated CCR for the case that the polarization states of output beam should be controlled.


Ripples on spikes show increased phase-amplitude coupling in mesial temporal lobe epilepsy seizure-onset zones.
Ripples (80-150 Hz) recorded from clinical macroelectrodes have been shown to be an accurate biomarker of epileptogenic brain tissue. We investigated coupling between epileptiform spike phase and ripple amplitude to better understand the mechanisms that generate this type of pathologic ripple (pRipple) event. We quantified phase amplitude coupling (PAC) between epileptiform electroencephalography (EEG) spike phase and ripple amplitude recorded from intracranial depth macroelectrodes during episodes of sleep in 12 patients with mesial temporal lobe epilepsy. PAC was determined by (1) a phasor transform that corresponds to the strength and rate of ripples coupled with spikes, and a (2) ripple-triggered average to measure the strength, morphology, and spectral frequency of the modulating and modulated signals. Coupling strength was evaluated in relation to recording sites within and outside the seizure-onset zone (SOZ). Both the phasor transform and ripple-triggered averaging methods showed that ripple amplitude was often robustly coupled with epileptiform EEG spike phase. Coupling was found more regularly inside than outside the SOZ, and coupling strength correlated with the likelihood a macroelectrode's location was within the SOZ (p < 0.01). The ratio of the rate of ripples coupled with EEG spikes inside the SOZ to rates of coupled ripples in non-SOZ was greater than the ratio of rates of ripples on spikes detected irrespective of coupling (p < 0.05). Coupling strength correlated with an increase in mean normalized ripple amplitude (p < 0.01), and a decrease in mean ripple spectral frequency (p < 0.05). Generation of low-frequency (80-150 Hz) pRipples in the SOZ involves coupling between epileptiform spike phase and ripple amplitude. The changes in excitability reflected as epileptiform spikes may also cause clusters of pathologically interconnected bursting neurons to grow and synchronize into aberrantly large neuronal assemblies.


Association of Kv1.5 and Kv1.3 contributes to the major voltage-dependent K+ channel in macrophages.
Voltage-dependent K(+) (Kv) currents in macrophages are mainly mediated by Kv1.3, but biophysical properties indicate that the channel composition could be different from that of T-lymphocytes. K(+) currents in mouse bone marrow-derived and Raw-264.7 macrophages are sensitive to Kv1.3 blockers, but unlike T-cells, macrophages express Kv1.5. Because Shaker subunits (Kv1) may form heterotetrameric complexes, we investigated whether Kv1.5 has a function in Kv currents in macrophages. Kv1.3 and Kv1.5 co-localize at the membrane, and half-activation voltages and pharmacology indicate that K(+) currents may be accounted for by various Kv complexes in macrophages. Co-expression of Kv1.3 and Kv1.5 in human embryonic kidney 293 cells showed that the presence of Kv1.5 leads to a positive shift in K(+) current half-activation voltages and that, like Kv1.3, Kv1.3/Kv1.5 heteromers are sensitive to r-margatoxin. In addition, both proteins co-immunoprecipitate and co-localize. Fluorescence resonance energy transfer studies further demonstrated that Kv1.5 and Kv1.3 form heterotetramers. Electrophysiological and pharmacological studies of different ratios of Kv1.3 and Kv1.5 co-expressed in Xenopus oocytes suggest that various hybrids might be responsible for K(+) currents in macrophages. Tumor necrosis factor-alpha-induced activation of macrophages increased Kv1.3 with no changes in Kv.1.5, which is consistent with a hyperpolarized shift in half-activation voltage and a lower IC(50) for margatoxin. Taken together, our results demonstrate that Kv1.5 co-associates with Kv1.3, generating functional heterotetramers in macrophages. Changes in the oligomeric composition of functional Kv channels would give rise to different biophysical and pharmacological properties, which could determine specific cellular responses.


Vaccine Hesitancy in Pediatric Primary Care Practices.
Understanding how pediatric practices handle parental vaccine hesitancy is important as it impacts the efficiency and effectiveness of pediatric practices. In total, 21 semi-structured interviews with pediatric practice staff within a primary care network were conducted between May 2012 and March 2013. Thematic analysis focused on the barriers and challenges of vaccine hesitancy and strategies to reduce the burden at the practice level. Barriers and challenges of vaccine hesitancy included time constraints, administrative challenges, financial challenges and strained patient-provider relationships. Strategies to minimize the burden of vaccine hesitancy included training for vaccine counseling, screening for vaccine hesitancy prior to immunization visits, tailored vaccine counseling, and primary care provider visits for follow-up immunization. Pediatric practices reported many challenges when caring for vaccine-hesitant families. Multiple strategies were identified to reduce the burden of vaccine hesitancy, which future studies should explore to determine how effective they are in increasing vaccine acceptance in pediatric practices.


The economic burden of HIV/AIDS on individuals and households in Nepal: a quantitative study.
There have been only limited studies assessing the economic burden of HIV/AIDS in terms of direct costs, and there has been no published study related to productivity costs in Nepal. Therefore, this study explores in detail the economic burden of HIV/AIDS, including direct costs and productivity costs. This paper focuses on the direct costs of seeking treatment, productivity costs, and related factors affecting direct costs, and productivity costs. This study was a cross-sectional, quantitative study. The primary data were collected through a structured face-to-face survey from 415 people living with HIV/AIDS (PLHIV). The study was conducted in six representative treatment centres of six districts of Nepal. The data analysis regarding the economic burden (direct costs and productivity costs) was performed from the household's perspective. Descriptive statistics have been used, and regression analyses were applied to examine the extent, nature and determinants of the burden of the disease, and its correlations. Average total costs due to HIV/AIDS (the sum of average total direct and average productivity costs before adjustment for coping strategies) were Nepalese Rupees (NRs) 2233 per month (US$ 30.2/month), which was 28.5% of the sample households' average monthly income. The average total direct costs for seeking HIV/AIDS treatment were NRs 1512 (US$ 20.4), and average productivity costs (before adjustment for coping strategies) were NRs 721 (US$ 9.7). The average monthly productivity losses (before adjustment for coping strategies) were 5.05 days per person. The major determinants for the direct costs were household income, occupation, health status of respondents, respondents accompanied or not, and study district. Health status of respondents, ethnicity, sexual orientation and study district were important determinants for productivity costs. The study concluded that HIV/AIDS has caused a significant economic burden for PLHIV and their families in Nepal. The study has a number of policy implications for different stakeholders. Provision of social support and income generating programmes to HIV-affected individuals and their families, and decentralising treatment services in each district seem to be viable solutions to reduce the economic burden of HIV-affected individuals and households.