Axonal Channel Capacity in Neuro-Spike Communication.
Novel nano-scale communication techniques are inspired by biological systems. Neuro-spike communication is an example of this communication paradigm which transfers vital information about external and internal conditions of the body through the nervous system. The analysis of this communication paradigm is beneficial to exploit in the artificial neural systems where nano-machines are linked to neurons to treat the neurodegenerative diseases. In these networks, nano-machines are used to replace the damaged segments of the nervous system and they exactly behave like biological entities. In neuro-spike communication, neurons / nano-machines exploit the electro-chemical spikes and molecular communication to transfer information. This communication paradigm can be divided into three main parts, namely the axonal pathway, the synaptic transmission, and the spike generation. In this paper, we focus on the axonal transmission part as a separate channel since the capacity of the axonal pathway has a significant effect on the capacity of neuro-spike communication channel. In thinner axons, the capacity of this part is the bottleneck of the neuro-spike communication channel capacity. Hence, we investigate the restricting factors of the axonal transmission which limit its capacity. We derive the capacity of single-input single-output and multiple-input single-output (MISO) axonal channels. In the MISO case, we investigate the effect of the correlation among inputs on the channel capacity. Moreover, we derive a closed form description for the optimum value of the input spike rate to maximize the capacity of the axonal channel when the information is encoded by firing rate of neurons / nano-machines.


Are men testing? Sex differentials in HIV testing in Mpumalanga Province, South Africa.
HIV testing is the centerpiece of the national AIDS program in South Africa and many HIV-endemic countries, yet there is surprisingly little published data on who uses testing services. In 2006, we conducted a census of HIV-testing records in all 282 public and non-governmental voluntary counseling and testing (VCT) sites in Mpumalanga (MP), South Africa, the province with the highest HIV prevalence in the country. We secured data on the age and sex of all those tested in 260 sites since the year testing was initiated, as far back as 1998 in some sites. For the year 2006, we also secured data on whether a client came to VCT through self-referral, antenatal services (prevent mother-to-child transmission (PMTCT)), or medical referral. The results characterize the rapid uptake of testing as facilities increased, with the number of people testing in MP more than doubling each year between 2002 and 2006. However, there is a persistent 3:1 differential of females:males testing, with 72.7% of all testing among females. When pregnancy-related testing (via PMTCT) is excluded, females still account for 65.1% of all testing in MP. The data also suggest men are more likely to test at older ages and as a result of medical referral. In summary, females in MP are far more likely to use HIV testing than males, even after accounting for increased access to testing during pregnancy. Sex differentials in HIV testing warrant closer policy attention.


Reliability of physical examination items used for classification of patients with low back pain.
The purpose of this study was to examine the interrater reliability of measurements obtained by examiners administering tests proposed to be important for classifying low back pain (LBP) problems. Ninety-five subjects with LBP (41 men, 54 women) and 43 subjects without LBP (17 men, 26 women) were examined by 5 therapists trained in the techniques used. A manual was developed by the first author that described the clinical examination procedures. The therapists were trained by the first author in the test procedures and definitions. The training included instruction through videotapes, practice and a written examination. Each examination was conducted by a pair of therapists. Within a pair, a therapist was the primary examiner for half of the subjects and an observer was the primary examiner for half of the subjects. Examination findings were recorded independently, without discussion. Percentage of agreement and generalized kappa coefficients were used to analyzed the data. Kappa values were > or = .75 for all 28 items related to the symptoms elicited and > or = .40 for 72% of the 25 items related to alignment and movement. The results suggest that experienced therapist who had trained together were able to agree on the results of examinations and obtain an acceptable level of reliability. Future work should focus on testing of reliability when more than one therapist performs the examination and when therapist not trained by the test developer to administer the examination perform the tests. [Van Dillen LR, Sahrmann SA, Norton BJ, et al. Reliability of physical examination items used for classification of patients with low back pain.


Prevalence and pattern of occupational exposure to hand transmitted vibration in Great Britain: findings from a national survey.
To estimate the number of workers in Great Britain with significant occupational exposure to hand transmitted vibration (HTV). Also, to identify the occupations and industries where such exposures arise, and the main sources of exposure. A questionnaire was posted to 22,194 men and women aged 16-64, comprising 21,201 subjects selected at random from the age-sex registers of 34 general practices in England, Scotland, and Wales, and a further 993 subjects selected at random from the central pay registers of the three armed services. Among other things, the questionnaire asked about exposure to sources of HTV in current and earlier employment. Responses were assessed by occupation and industry, and prevalence estimates for the country as a whole were derived from census information on occupational and industrial populations nationally. Estimates were also made in exposed workers of the average daily dose of vibration (A(8) root mean squared (rms) for the past week, based on their reported sources and durations of exposure. Usable questionnaires were returned by 12,907 subjects (overall response rate 58%). From these it was estimated that some 4.2 million men and 667 000 women in Great Britain are exposed to HTV at work in a 1 week period, and that personal daily exposures to vibration exceed a suggested action level equivalent to 2.8 ms(-2) for 8 hours (A(8) >2.8 ms(-2) rms) in at least 1.2 million men and 44,000 women. High estimated doses (A(8) >5 ms(-2) rms) arose most often in bricklayers and masons, gardeners and groundsmen, carpenters and joiners, electricians and electrical maintenance fitters, and builders and building contractors. The industries where high A(8) values most often arose were construction, motor vehicle repair and maintenance, manufacture of basic metals, and agriculture. The most common sources of exposure were hammer drills, hand held portable grinders, and jigsaws. Exposure to HTV is surprisingly prevalent, and preventive measures and health surveillance may be warranted for many men in Britain. Control strategies should focus on prevention at source, with priority accorded to the common sources of exposure and the occupations in which significant exposures tend to arise. Many vibratory tools that are common in Britain have been overlooked in previous surveys, highlighting an important focus for future research.


Two molecular pathways to transitional cell carcinoma of the bladder.
Noninvasive transitional cell carcinomas of the bladder can have two distinct morphologies suggesting they contain different genetic alterations. Papillary transitional cell carcinomas (T(a) tumors) are often multifocal and only occasionally progress, whereas flat tumors (carcinomas in situ, CIS), frequently progress to invasive disease. We examined 216 bladder tumors of various stages and histopathologies for two genetic alterations previously described to be of importance in bladder tumorigenesis. Loss of heterozygosity of chromosome 9 was observed in 24 of 70 (34%) T(a) tumors but was present in only 3 of 24 (12%) CIS and dysplasia lesions (P = 0.04). In contrast, only 1 of 36 (3%) T(a) tumors contained a p53 gene mutation compared to 15 of 23 (65%) CIS and dysplasias (P < 0.001), a frequency comparable to that observed in muscle invasive tumors (25 of 49; 51%). The presence of p53 mutations in CIS and dysplasia could explain their propensities to progress since these mutations are known to destabilize the genome. Analysis of several tumor pairs involving a CIS and an invasive cancer provided evidence that the chromosome 9 alteration may in some cases be involved in the progression of CIS to more invasive tumors, in addition to its role in the initiation of T(a) tumors. However, the CIS and secondary tumor were found to contain different genetic alterations in some patients suggesting divergent progression pathways. Bladder carcinogenesis may therefore proceed through two distinct genetic alteration pathways responsible for generating superficial tumors with differing morphologies and pathologies.


Predicting risk decisions in a modified Balloon Analogue Risk Task: Conventional and single-trial ERP analyses.
Event-related potential (ERP) has the potential to reveal the temporal neurophysiological dynamics of risk decision-making, but this potential has not been fully explored in previous studies. When predicting risk decision with ERPs, most studies focus on between-trial analysis that reflects feedback learning, while within-trial analysis that could directly link option assessment with behavioral output has been largely ignored. Suitable task design is crucial for applying within-trial prediction. In this study, we used a modified version of the classic Balloon Analogue Risk Task (BART). In each trial of the task, participants made multiple rounds of decisions between a risky option (pump up the balloon) and a safe option (cash out). Behavioral results show that as the level of economic risk increased, participants were less willing to make a risky decision and also needed a longer response time to do so. In general, the ERP results showed distinct characteristics compared with previous findings based on between-trial prediction, particularly about the role of the P1 component. Specifically, both the P1 (amplitude and latency) and P3 (amplitude) components evoked by current outcomes predicted subsequent decisions. We suggest that these findings indicate the importance of selective attention (indexed by the P1) and motivational functions (indexed by the P3), which may help clarify the cognitive mechanism of risk decision-making. The theoretical significance of these findings is discussed.


HR23B pathology preferentially co-localizes with p62, pTDP-43 and poly-GA in C9ORF72-linked frontotemporal dementia and amyotrophic lateral sclerosis.
Human homologue of yeast UV excision repair protein Rad23b (HR23B) inclusions are found in a number of neurodegenerative diseases, including frontotemporal dementia (FTD), Huntington's disease (HD), spinocerebellar ataxia type 3 and 7 (SCA3/7), fragile X associated tremor/ataxia syndrome (FXTAS) and Parkinson's disease (PD). Here, we describe HR23B pathology in C9ORF72 linked FTD and amyotrophic lateral sclerosis (ALS) cases. HR23B presented in neuropils, intranuclear inclusions and cytoplasmic and perinuclear inclusions and was predominantly found in cortices (frontal, temporal and motor), spinal cord and hippocampal dentate gyrus. HR23B co-localized with poly-GA-, pTDP-43- and p62-positive inclusions in frontal cortex and in hippocampal dentate gyrus, the latter showing higher co-localization percentages. HR23B binding partners XPC, 20S and ataxin-3, which are involved in nucleotide excision repair (NER) and the ubiquitin-proteasome system (UPS), did not show an aberrant distribution. However, C9ORF72 fibroblasts were more sensitive for UV-C damage than healthy control fibroblasts, even though all factors involved in NER localized normally to DNA damage and the efficiency of DNA repair was not reduced. HR23Bs other binding partner NGly1/PNGase, involved in ER-associated degradation (ERAD) of misfolded proteins, was not expressed in the majority of neurons in C9FTD/ALS brain sections compared to non-demented controls. Our results suggest a difference in HR23B aggregation and co-localization pattern with DPRs, pTDP-43 and p62 between different brain areas from C9FTD/ALS cases. We hypothesize that HR23B may play a role in C9ORF72 pathogenesis, possibly by aberrant ERAD functioning.


How often do they meet? Genetic similarity between European populations of a potential disease vector Culex pipiens.
Species in the Culex pipiens complex are common almost all over the world and represent important vectors for many serious zoonotic diseases. Even if, at the moment, many of the pathogens potentially transmitted by Cx. pipiens are not a problem in northern Europe, they may, with increasing temperatures and changing ecosystems caused by climate change, move northward in the future. Therefore, the question whether or not the Cx. pipiens populations in northern Europe will be competent vectors for them is of high importance. One way to estimate the similarity and the rate of contact between European Cx. pipiens populations is to look at the gene exchange between these populations. To test the genetic diversity and degree of differentiation between European Cx. pipiens populations, we used eight microsatellite markers in 10 mosquito populations originating from northern, central, and southern Europe. We found that three of the analyzed populations were very different from the rest of the populations and they also greatly differed from each other. When these three populations were removed, the variance among the rest of the populations was low, suggesting an extensive historic gene flow between many European Cx. pipiens populations. This suggests that infectious diseases spread by this species may not be associated with a certain vector genotype but rather with suitable environmental conditions. Consequently, we would expect these pathogens to disperse northward with favorable climatic parameters.


Sp1 and Sp3 Are the Transcription Activators of Human ek1 Promoter in TSA-Treated Human Colon Carcinoma Cells.
Ethanolamine kinase (EK) catalyzes the phosphorylation of ethanolamine, the first step in the CDP-ethanolamine pathway for the biosynthesis of phosphatidylethanolamine (PE). Human EK exists as EK1, EK2α and EK2β isoforms, encoded by two separate genes, named ek1 and ek2. EK activity is stimulated by carcinogens and oncogenes, suggesting the involvement of EK in carcinogenesis. Currently, little is known about EK transcriptional regulation by endogenous or exogenous signals, and the ek gene promoter has never been studied. In this report, we mapped the important regulatory regions in the human ek1 promoter. 5' deletion analysis and site-directed mutagenesis identified a Sp site at position (-40/-31) that was essential for the basal transcription of this gene. Treatment of HCT116 cells with trichostatin A (TSA), a histone deacetylase inhibitor, significantly upregulated the ek1 promoter activity through the Sp(-40/-31) site and increased the endogenous expression of ek1. Chromatin immunoprecipitation assay revealed that TSA increased the binding of Sp1, Sp3 and RNA polymerase II to the ek1 promoter in HCT116 cells. The effect of TSA on ek1 promoter activity was cell-line specific as TSA treatment did not affect ek1 promoter activity in HepG2 cells. In conclusion, we showed that Sp1 and Sp3 are not only essential for the basal transcription of the ek1 gene, their accessibility to the target site on the ek1 promoter is regulated by histone protein modification in a cell line dependent manner.


Monocyte subsets involved in the development of systemic lupus erythematosus and rheumatoid arthritis.
AbstractMonocytes are evolutionally conserved innate immune cells that play essential roles for the protection of the host against pathogens and also produce several inflammatory cytokines. Thus, the aberrant functioning of monocytes may affect not only host defense but also the development of inflammatory diseases. Monocytes are a heterogeneous population with phenotypical and functional differences. Most recent studies have shown that monocytes are divided into three subsets, namely classical, intermediate and non-classical subsets, both in humans and mice. Accumulating evidence showed that monocyte activation is associated with the disease progression in autoimmune diseases, such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). However, it remains to be determined how monocytes contribute to the disease process and which subset is involved. In this review, we discuss the pathogenic role of monocyte subsets in SLE and RA on the basis of current studies by ourselves and others to shed light on the suitability of monocyte-targeted therapies in these diseases.


Shifting gradients of macroscale cortical organization mark the transition from childhood to adolescence.
The transition from childhood to adolescence is marked by pronounced shifts in brain structure and function that coincide with the development of physical, cognitive, and social abilities. Prior work in adult populations has characterized the topographical organization of the cortex, revealing macroscale functional gradients that extend from unimodal (somatosensory/motor and visual) regions through the cortical association areas that underpin complex cognition in humans. However, the presence of these core functional gradients across development as well as their maturational course have yet to be established. Here, leveraging 378 resting-state functional MRI scans from 190 healthy individuals aged 6 to 17 y old, we demonstrate that the transition from childhood to adolescence is reflected in the gradual maturation of gradient patterns across the cortical sheet. In children, the overarching organizational gradient is anchored within the unimodal cortex, between somatosensory/motor and visual territories. Conversely, in adolescence, the principal gradient of connectivity transitions into an adult-like spatial framework, with the default network at the opposite end of a spectrum from primary sensory and motor regions. The observed gradient transitions are gradually refined with age, reaching a sharp inflection point in 13 and 14 y olds. Functional maturation was nonuniformly distributed across cortical networks. Unimodal networks reached their mature positions early in development, while association regions, in particular the medial prefrontal cortex, reached a later peak during adolescence. These data reveal age-dependent changes in the macroscale organization of the cortex and suggest the scheduled maturation of functional gradient patterns may be critically important for understanding how cognitive and behavioral capabilities are refined across development.


Cardiovascular imaging in Turner syndrome: state-of-the-art practice across the lifespan.
Cardiovascular imaging is essential to providing excellent clinical care for girls and women with Turner syndrome (TS). Congenital and acquired cardiovascular diseases are leading causes of the lifelong increased risk of premature death in TS. Non-invasive cardiovascular imaging is crucial for timely diagnosis and treatment planning, and a systematic and targeted imaging approach should combine echocardiography, cardiovascular magnetic resonance and, in select cases, cardiac CT. In recent decades, evidence has mounted for the need to perform cardiovascular imaging in all females with TS irrespective of karyotype and phenotype. This is due to the high incidence of outcome-determining lesions that often remain subclinical and occur in patterns specific to TS. This review provides an overview of state-of-the-art cardiovascular imaging practice in TS, by means of a review of the most recent literature, in the context of a recent consensus statement that has highlighted the role of cardiovascular diseases in these females.


Dietary sugars intake and cardiovascular health: a scientific statement from the American Heart Association.
High intakes of dietary sugars in the setting of a worldwide pandemic of obesity and cardiovascular disease have heightened concerns about the adverse effects of excessive consumption of sugars. In 2001 to 2004, the usual intake of added sugars for Americans was 22.2 teaspoons per day (355 calories per day). Between 1970 and 2005, average annual availability of sugars/added sugars increased by 19%, which added 76 calories to Americans' average daily energy intake. Soft drinks and other sugar-sweetened beverages are the primary source of added sugars in Americans' diets. Excessive consumption of sugars has been linked with several metabolic abnormalities and adverse health conditions, as well as shortfalls of essential nutrients. Although trial data are limited, evidence from observational studies indicates that a higher intake of soft drinks is associated with greater energy intake, higher body weight, and lower intake of essential nutrients. National survey data also indicate that excessive consumption of added sugars is contributing to overconsumption of discretionary calories by Americans. On the basis of the 2005 US Dietary Guidelines, intake of added sugars greatly exceeds discretionary calorie allowances, regardless of energy needs. In view of these considerations, the American Heart Association recommends reductions in the intake of added sugars. A prudent upper limit of intake is half of the discretionary calorie allowance, which for most American women is no more than 100 calories per day and for most American men is no more than 150 calories per day from added sugars.


Isolation and characterization of a cold-sensitive strain of coxsackievirus A10.
A coxsackievirus A10 strain, isolated from a clinical specimen from a patient with pharyngitis, was characterized with respect to its growth properties in different cultured cells and at different incubation temperatures. This virus multiplied within cultured cells and produced cytopathogenic effects, whereas a prototype strain of coxsackievirus A10 did not. The isolate multiplied efficiently in cultured cells at 37 degrees C but its replication was markedly restricted at 32 degrees C. Temperature shift experiments indicated that the cold-sensitive event affected the late function(s) of the virus.


Cognitive therapy vs medications in the treatment of moderate to severe depression.
There is substantial evidence that antidepressant medications treat moderate to severe depression effectively, but there is less data on cognitive therapy's effects in this population. To compare the efficacy in moderate to severe depression of antidepressant medications with cognitive therapy in a placebo-controlled trial. Random assignment to one of the following: 16 weeks of medications (n = 120), 16 weeks of cognitive therapy (n = 60), or 8 weeks of pill placebo (n = 60). Research clinics at the University of Pennsylvania, Philadelphia, and Vanderbilt University, Nashville, Tenn. Two hundred forty outpatients, aged 18 to 70 years, with moderate to severe major depressive disorder. Some study subjects received paroxetine, up to 50 mg daily, augmented by lithium carbonate or desipramine hydrochloride if necessary; others received individual cognitive therapy. The Hamilton Depression Rating Scale provided continuous severity scores and allowed for designations of response and remission. At 8 weeks, response rates in medications (50%) and cognitive therapy (43%) groups were both superior to the placebo (25%) group. Analyses based on continuous scores at 8 weeks indicated an advantage for each of the active treatments over placebo, each with a medium effect size. The advantage was significant for medication relative to placebo, and at the level of a nonsignificant trend for cognitive therapy relative to placebo. At 16 weeks, response rates were 58% in each of the active conditions; remission rates were 46% for medication, 40% for cognitive therapy. Follow-up tests of a site x treatment interaction indicated a significant difference only at Vanderbilt University, where medications were superior to cognitive therapy. Site differences in patient characteristics and in the relative experience levels of the cognitive therapists each appear to have contributed to this interaction. Cognitive therapy can be as effective as medications for the initial treatment of moderate to severe major depression, but this degree of effectiveness may depend on a high level of therapist experience or expertise.


Hiding and unveiling trans-chalcone in a constrained derivative of 4',7-dihydroxyflavylium in water: a versatile photochromic system.
A structurally constrained derivative of 4',7-dihydroxyflavylium was studied in aqueous solution and in CTAB micelles by pH jumps, flash photolysis and continuous irradiation with spectroscopic details assessed as well by theoretical calculations. In water, up to pH = 8, the compound shows only acid base chemistry with deprotonation of the flavylium cation to form a quinoidal base that further deprotonates with pKas of 4.8 and 7.4. In the basic region, unprotonated trans-chalcones are formed. No neutral trans-chalcone (Ct) is formed in water preventing the establishment of the well-known photochromism involving photoisomerization of this species with subsequent formation of the flavylium cation. Addition of 0.02 M CTAB drastically changes the mole fraction distribution of species, leading to the formation of Ct (χCt = 1 at pH = 5) and unveiling a photochromic behavior with a pH-tunable colour contrast in a large pH range (2 < pH < 8). The Ct species can be hidden again (irreversibly) upon addition of α-cyclodextrin that disrupts the CTAB micelles, reverting the system to its initial mole fraction distribution of species. These supramolecular inputs work atop the molecular reaction networks by modifying their species' mole fraction distribution.


Hypoxia-Activated Prodrug TH-302 Targets Hypoxic Bone Marrow Niches in Preclinical Leukemia Models.
To characterize the prevalence of hypoxia in the leukemic bone marrow, its association with metabolic and transcriptional changes in the leukemic blasts and the utility of hypoxia-activated prodrug TH-302 in leukemia models. Hyperpolarized magnetic resonance spectroscopy was utilized to interrogate the pyruvate metabolism of the bone marrow in the murine acute myeloid leukemia (AML) model. Nanostring technology was used to evaluate a gene set defining a hypoxia signature in leukemic blasts and normal donors. The efficacy of the hypoxia-activated prodrug TH-302 was examined in the in vitro and in vivo leukemia models. Metabolic imaging has demonstrated increased glycolysis in the femur of leukemic mice compared with healthy control mice, suggesting metabolic reprogramming of hypoxic bone marrow niches. Primary leukemic blasts in samples from AML patients overexpressed genes defining a "hypoxia index" compared with samples from normal donors. TH-302 depleted hypoxic cells, prolonged survival of xenograft leukemia models, and reduced the leukemia stem cell pool in vivo In the aggressive FLT3/ITD MOLM-13 model, combination of TH-302 with tyrosine kinase inhibitor sorafenib had greater antileukemia effects than either drug alone. Importantly, residual leukemic bone marrow cells in a syngeneic AML model remain hypoxic after chemotherapy. In turn, administration of TH-302 following chemotherapy treatment to mice with residual disease prolonged survival, suggesting that this approach may be suitable for eliminating chemotherapy-resistant leukemia cells. These findings implicate a pathogenic role of hypoxia in leukemia maintenance and chemoresistance and demonstrate the feasibility of targeting hypoxic cells by hypoxia cytotoxins.


Individual, facility and policy level influences on national coverage estimates for intermittent preventive treatment of malaria in pregnancy in Tanzania.
Delivery of two doses of intermittent preventive treatment of malaria during pregnancy (IPTp) is a key strategy to reduce the burden of malaria in pregnancy in sub-Saharan Africa. However, different settings have reported coverage levels well below the target 80%. Antenatal implementation guidelines in Tanzania recommend IPTp first dose to be given at the second antenatal visit, and second dose at the third visit. This investigation measured coverage of IPTp at national level in Tanzania and examined the role of individual, facility, and policy level influences on achieved coverage. Three national household and linked reproductive and child health (RCH) facility surveys were conducted July-August 2005, 2006, and 2007 in 210 clusters sampled using two-stage cluster sampling from 21 randomly selected districts. Female residents who reported a livebirth in the previous year were asked questions about malaria prevention during that pregnancy and individual characteristics including education, pregnancy history, and marital status. The RCH facility serving each cluster was also surveyed, and information collected about drug stocks, health education delivery, and the timing of antenatal care delivery by clinic users. The national IPTp coverage had declined over the survey period being 71% for first dose in 2005 falling to 65% in 2007 (chi2 2.9, p = 0.05), and 38% for second dose in 2005 but 30% in 2007 (chi2 4.4, p = 0.01). There was no evidence of any individual factors being associated with second dose coverage beyond living in an urban area. Availability of sulphadoxine-pyrimethamine at RCH had decreased year on year from 85% of clinics in stock in 2005 to 60% in 2007 (chi2 20.6, p < 0.001). This reduction was evident in rural but not urban clinics. If safety recommendations and national antenatal care guidelines for IPTp delivery were followed, in 2007 only 76% of pregnant women could have received IPTp first dose and only 46% could have received second dose. There is scope to improve IPTp first and second dose coverage at national scale within existing systems by improving stock at RCH, and by revising the existing guidelines to recommend delivery of IPTp after quickening, rather than at a pre-defined antenatal visit.


Direct observation of backbone planarization via side-chain alignment in single bulky-substituted polythiophenes.
The backbone conformation of conjugated polymers affects, to a large extent, their optical and electronic properties. The usually flexible substituents provide solubility and influence the packing behavior of conjugated polymers in films or in bad solvents. However, the role of the side chains in determining and potentially controlling the backbone conformation, and thus the optical and electronic properties on the single polymer level, is currently under debate. Here, we investigate directly the impact of the side chains by studying the bulky-substituted poly(3-(2,5-dioctylphenyl)thiophene) (PDOPT) and the common poly(3-hexylthiophene) (P3HT), both with a defined molecular weight and high regioregularity, using low-temperature single-chain photoluminescence (PL) spectroscopy and quantum-classical simulations. Surprisingly, the optical transition energy of PDOPT is significantly (∼2,000 cm-1 or 0.25 eV) red-shifted relative to P3HT despite a higher static and dynamic disorder in the former. We ascribe this red shift to a side-chain induced backbone planarization in PDOPT, supported by temperature-dependent ensemble PL spectroscopy. Our atomistic simulations reveal that the bulkier 2,5-dioctylphenyl side chains of PDOPT adopt a clear secondary helical structural motif and thus protect conjugation, i.e., enforce backbone planarity, whereas, for P3HT, this is not the case. These different degrees of planarity in both thiophenes do not result in different conjugation lengths, which we found to be similar. It is rather the stronger electronic coupling between the repeating units in the more planar PDOPT which gives rise to the observed spectral red shift as well as to a reduced calculated electron-hole polarization.


"It's sort of like being a detective": understanding how Australian men self-monitor their health prior to seeking help.
It is commonly held that men delay help seeking because they are ignorant about and disinterested in their health. However, this discussion has not been informed by men's lay perspectives, which have remained almost entirely absent from scholarship relating to men's help seeking practices. In this qualitative paper, we draw on semi-structured interviews with 36 South Australian men to examine their understandings of help seeking and health service use. We use participants' talk about self-monitoring to challenge the assumption that men are disinterested in their health, arguing instead that the men in our study monitored their health status and made conscious decisions about when and how to seek help. Using an inductive approach during the thematic analysis we were able to identify four key factors that influenced how men monitored their health and explain how these intersect with the way men sought help and used health services. We show that the men in our study were actively engaged in the self-monitoring of their health. We suggest that these findings offer an alternative approach for understanding how we can promote men's interaction with health services.


Physical linkage of the Vibrio cholerae mannose-sensitive hemagglutinin secretory and structural subunit gene loci: identification of the mshG coding sequence.
Vibrio cholerae O1 expresses a variety of cell surface factors which mediate bacterial adherence and colonization at the intestinal epithelium. The mannose-sensitive hemagglutinin (MSHA), a type IV pilus, is a potential attachment factor of the V. cholerae El Tor biotype. We describe a TnphoA mutant that is defective in its ability to hemagglutinate mouse erythrocytes. The TnphoA insertion maps to a recently identified genetic locus that encodes products that are predicted to be essential for assembly and export of the MSHA pilus. Insertional disruption at this locus in a mshA-phoA reporter strain provides evidence for a role of this locus in the latter stages of pilus assembly and/or export. These constructs have provided physical markers by which we have established close physical linkage of this secretion locus to a set of genes that includes the mshA structural gene. Sequence analysis of the intervening region between these two loci has revealed the presence of an open reading frame with homology to pilus biogenesis genes of several gram-negative bacteria. This genetic organization suggests an entire operon encoding the MSHA pilus and the components necessary for its assembly and secretion to the bacterial cell surface. The nomenclature of the MSHA structural and secretory locus has been redefined accordingly.


Evolution of neuroblast identity: seven-up and prospero expression reveal homologous and divergent neuroblast fates in Drosophila and Schistocerca.
In the Drosophila CNS, early neuroblast formation and fate are controlled by the pair-rule class of segmentation genes. The distantly related Schistocerca (grasshopper) embryo has a similar arrangement of neuroblasts, despite lack of known pair-rule gene function. Does divergent pair-rule gene function lead to different neuroblast identities, or can different patterning mechanisms produce homologous neuroblasts? We use four molecular markers to compare Drosophila and Schistocerca neuroblast identity: seven-up, prospero, engrailed, and fushi-tarazu/Dax. In both insects some early-forming neuroblasts share key features of neuroblast identity (position, time of formation, and temporally accurate gene expression); thus, different patterning mechanisms can generate similar neuroblast fates. In contrast, several later-forming neuroblasts show species-specific differences in position and/or gene expression; these neuroblast identities seem to have diverged, suggesting that evolution of the insect central nervous system can occur through changes in embryonic neuroblast identity.


To What Extent Can Motor Imagery Replace Motor Execution While Learning a Fine Motor Skill?
Motor imagery is generally thought to share common mechanisms with motor execution. In the present study, we examined to what extent learning a fine motor skill by motor imagery may substitute physical practice. Learning effects were assessed by manipulating the proportion of motor execution and motor imagery trials. Additionally, learning effects were compared between participants with an explicit motor imagery instruction and a control group. A Go/NoGo discrete sequence production (DSP) task was employed, wherein a five-stimulus sequence presented on each trial indicated the required sequence of finger movements after a Go signal. In the case of a NoGo signal, participants either had to imagine carrying out the response sequence (the motor imagery group), or the response sequence had to be withheld (the control group). Two practice days were followed by a final test day on which all sequences had to be executed. Learning effects were assessed by computing response times (RTs) and the percentages of correct responses (PCs). The electroencephalogram (EEG ) was additionally measured on this test day to examine whether motor preparation and the involvement of visual short term memory (VST M) depended on the amount of physical/mental practice. Accuracy data indicated strong learning effects. However, a substantial amount of physical practice was required to reach an optimal speed. EEG results suggest the involvement of VST M for sequences that had less or no physical practice in both groups. The absence of differences between the motor imagery and the control group underlines the possibility that motor preparation may actually resemble motor imagery.


Fatigue and risk of sickness absence in the working population: A systematic review and meta-analysis of longitudinal studies.
Objectives Fatigue, a common complaint in workers, has been related to sickness absence (SA). The purpose of this systematic review and meta-analysis was to determine the prospective association between fatigue and SA in the working population. Methods An electronic literature search was conducted in five databases: PubMed, Embase, CINAHL, Psyc-INFO and Cochrane CENTRAL. Longitudinal studies were selected that focused on fatigue and future SA in workers. Random-effects meta-analyses were conducted and pooled estimates [95% confidence intervals (CI)] were obtained for the association between fatigue and risk of long-term SA in total and by sex. Heterogeneity was assessed by I 2statistics. Results Of the 16 included studies in the review, 14 provided supportive evidence for an association between fatigue and SA. The meta-analysis of 9 studies (provided 15 estimates) that were mostly of high quality showed that baseline fatigue increased the risk of long-term SA by 35% (95%CI 1.23-1.47) in workers. Heterogeneity was low-moderate (I 2=40%). The pooled estimates for an increased risk for long-term SA were 35% (95% CI 1.18-1.54) in fatigued men and 22% (95% CI 0.93-1.60) in fatigued women however this relationship was not statistically significant. Conclusion There is conclusive evidence for the prospective association between worker fatigue and long-term SA. Whereas most studies in the review measured chronic fatigue and long-term SA, there was insufficient data for the meta-analysis to draw conclusions on fatigue type. Future research is needed in this area as well as greater exploration of fatigue and long-term SA in women.


Community-acquired pneumonia.
Community-acquired pneumonia (CAP) contributes significantly to morbidity and mortality, especially in the elderly. Recent advances aimed at improving outcomes and reducing CAP disease burden are summarized. Emerging data suggests that newer CAP risk stratification indices based on disease severity hold promise in predicting intensive care need. Additional evidence supports a role of procalcitonin and pro-adrenomedullin as biomarkers of disease severity and for guiding antimicrobial therapy. New diagnostic tools have greatly contributed to early diagnosis and better-targeted therapy. There is increasing recognition of the role of coinfections in CAP. In patients with severe disease, therefore, current guidelines advise against monotherapy. Although inclusion of coverage for atypical pathogens in nonsevere CAP has been challenged, evidence suggests that such coverage is beneficial in patients with severe disease. Use of steroids as adjunctive therapy for CAP, however, is associated with complications and prolonged hospitalization. Updated prevention strategies include approval of pneumococcal conjugate vaccine (PCV13) for adults at risk. Despite these developments research aimed at further reducing CAP-related morbidity and mortality is required. Increasing global life expectancy is likely to expand the at-risk population; therefore, research directed at CAP prevention in view of changing demography is essential.


Promotion of tissue inflammation by the immune receptor Tim-3 expressed on innate immune cells.
CD4+ T helper 1 (TH1) cells are important mediators of inflammation and are regulated by numerous pathways, including the negative immune receptor Tim-3. We found that Tim-3 is constitutively expressed on cells of the innate immune system in both mice and humans, and that it can synergize with Toll-like receptors. Moreover, an antibody agonist of Tim-3 acted as an adjuvant during induced immune responses, and Tim-3 ligation induced distinct signaling events in T cells and dendritic cells; the latter finding could explain the apparent divergent functions of Tim-3 in these cell types. Thus, by virtue of differential expression on innate versus adaptive immune cells, Tim-3 can either promote or terminate TH1 immunity and may be able to influence a range of inflammatory conditions.


Roles of the subfornical organ and area postrema in arterial pressure increases induced by 48-h water deprivation in normal rats.
In rats, water deprivation (WD) increases arterial blood pressure (BP) in part due to actions of elevated osmolality in the brain to increase vasopressin levels and sympathetic activity. However, the osmoreceptors that mediate this response have not been identified. To test the hypothesis that osmoregulatory circumventricular organs are involved, BP and heart rate (HR) were continuously recorded telemetrically during 48 h of WD in normal rats with lesions (x) or sham lesions (sham) of the subfornical organ (SFO) or area postrema (AP). Although WD increased BP in SFOx and SFOsham rats, no significant difference in the hypertensive response was observed between groups. HR decreased transiently but similarly in SFOx and SFOsham rats during the first 24 h of WD. When water was reintroduced, BP and HR decreased rapidly and similarly in both groups. BP (during lights off) and HR were both lower in APx rats before WD compared to APsham. WD increased BP less in APx rats, and the transient bradycardia was eliminated. Upon reintroduction of drinking water, smaller falls in both BP and HR were observed in APx rats compared to APsham rats. WD increased plasma osmolality and vasopressin levels similarly in APx and APsham rats, and acute blockade of systemic V1 vasopressin receptors elicited similar depressor responses, suggesting that the attenuated BP response is not due to smaller increases in vasopressin or osmolality. In conclusion, the AP, but not the SFO, is required for the maximal hypertensive effect induced by WD in rats.


Antiepileptic hypersensitivity and DRESS syndrome due to phenytoin in two pediatric cases.
Antiepileptic hypersensitivity syndrome (AHS) is a potentially life-threatening syndrome, especially in pediatric cases. Drug rash with eosinophilia and systemic symptoms (DRESS) syndrome reflects a serious hypersensitivity reaction to drugs. We report here two children with AHS due to phenytoin. Both cases were under treatment with phenytoin: the first case was a seven-year-old boy who was referred with the classic form of AHS. The second patient was a five-year-old girl who manifested with DRESS. The manifestations in both cases improved after withholding the phenytoin. Clinical presentations of adverse drug reactions are highly variable and must therefore be suspected in any patient who develops any unusual manifestation after taking antiepileptic drugs. Early recognition of AHS and withholding and/or changing the medication are necessary to prevent potentially fatal outcomes.


In vivo compartmentalization of human immunodeficiency virus: evidence from the examination of pol sequences from autopsy tissues.
High rates of mutation and replication of human immunodeficiency virus (HIV) allow for the continuous generation of diverse genetic variants in vivo. Selective pressures within the microenvironments of different anatomic compartments result in the emergence of dominant quasispecies which can be distinguished by their envelope sequences. It is not known whether comparable tissue-specific selective pressures lead to the independent evolution of pol sequences within different tissue compartments, nor is it known how differing rates of virus turnover in tissues might affect the pace of such evolution. These issues are of importance for the formulation of a model for the emergence of drug resistance in vivo and for a general understanding of virus trafficking and virus turnover. Regions of the HIV type 1 reverse transcriptase (RT) which carry the majority of the known resistance codons to RT inhibitors (700 nucleotides from each clone) were cloned and sequenced directly from autopsied brain, spleen, and lymph node specimens from four subjects who had received zidovudine therapy. Clones from proviral DNA (143) and from viral cDNA (14) were analyzed. In three of four subjects, a discordance in distribution of resistance codons was noted. Moreover, brain-derived sequences appeared to be phylogenetically distinct from spleen- and lymph node-derived sequences even after exclusion of resistance codons from analysis. In each case, evidence for differential immune selective pressure, based on comparison of inferred amino acid sequences corresponding to known major histocompatibility complex class I cytotoxic T-lymphocyte epitopes, was found. These observations support the concept of anatomically distinct, independently evolving quasispecies (virodemes).


Liver intravoxel incoherent motion (IVIM) magnetic resonance imaging: a comprehensive review of published data on normal values and applications for fibrosis and tumor evaluation.
A comprehensive literature review was performed on liver intravoxel incoherent motion (IVIM) magnetic resonance imaging (MRI) technique and its applications. Heterogeneous data have been reported. IVIM parameters are magnetic field strength dependent to a mild extent. A lower Dslow (D) value at 3 T than at 1.5 T and higher perfusion fraction (PF) value at 3 T than at 1.5 T were noted. An increased number of b values are associated with increased IVIM parameter measurement accuracy. With the current status of art, IVIM technique is not yet capable of detecting early stage liver fibrosis and diagnosing liver fibrosis grades, nor can it differentiate liver tumors. Though IVIM parameters show promise for tumor treatment monitoring, till now how PF and Dfast (D*) add diagnostic value to Dslow or apparent diffusion coefficient (ADC) remains unclear. This paper shows the state-of-art IVIM MR technique is still not able to offer reliable measurement for liver. More works on the measurement robustness are warranted as they are essential to justify follow-up clinical studies on patients.


A probabilistic method to estimate the burden of maternal morbidity in resource-poor settings: preliminary development and evaluation.
Maternal morbidity is more common than maternal death, and population-based estimates of the burden of maternal morbidity could provide important indicators for monitoring trends, priority setting and evaluating the health impact of interventions. Methods based on lay reporting of obstetric events have been shown to lack specificity and there is a need for new approaches to measure the population burden of maternal morbidity. A computer-based probabilistic tool was developed to estimate the likelihood of maternal morbidity and its causes based on self-reported symptoms and pregnancy/delivery experiences. Development involved the use of training datasets of signs, symptoms and causes of morbidity from 1734 facility-based deliveries in Benin and Burkina Faso, as well as expert review. Preliminary evaluation of the method compared the burden of maternal morbidity and specific causes from the probabilistic tool with clinical classifications of 489 recently-delivered women from Benin, Bangladesh and India. Using training datasets, it was possible to create a probabilistic tool that handled uncertainty of women's self reports of pregnancy and delivery experiences in a unique way to estimate population-level burdens of maternal morbidity and specific causes that compared well with clinical classifications of the same data. When applied to test datasets, the method overestimated the burden of morbidity compared with clinical review, although possible conceptual and methodological reasons for this were identified. The probabilistic method shows promise and may offer opportunities for standardised measurement of maternal morbidity that allows for the uncertainty of women's self-reported symptoms in retrospective interviews. However, important discrepancies with clinical classifications were observed and the method requires further development, refinement and evaluation in a range of settings.


The natural history of infantile neuroaxonal dystrophy.
Infantile neuroaxonal dystrophy (INAD) is a rapidly progressive neurodegenerative disorder of early onset causing premature death. It results from biallelic pathogenic variants in PLA2G6, which encodes a calcium-independent phospholipase A2. We aim to outline the natural history of INAD and provide a comprehensive description of its clinical, radiological, laboratory, and molecular findings. We comprehensively analyzed the charts of 28 patients: 16 patients from Riyadh, Saudi Arabia, 8 patients from North and South America and 4 patients from Europe with a molecularly confirmed diagnosis of PLA2G6-associated neurodegeneration (PLAN) and a clinical history consistent with INAD. In our cohort, speech impairment and loss of gross motor milestones were the earliest signs of the disease. As the disease progressed, loss of fine motor milestones and bulbar dysfunction were observed. Temporo-frontal function was among the last of the milestones to be lost. Appendicular spastic hypertonia, axial hypotonia, and hyperreflexia were common neurological findings. Other common clinical findings include nystagmus (60.7%), seizures (42.9%), gastrointestinal disease (42.9%), skeletal deformities (35.7%), and strabismus (28.6%). Cerebellar atrophy and elevations in serum AST and LDH levels were consistent features of INAD. There was a statistically significant difference when comparing patients with non-sense/truncating variants compared with missense/in-frame deletions in the time of initial concern (p = 0.04), initial loss of language (p = 0.001), initial loss of fine motor skills (p = 0.009), and initial loss of bulbar skills (p = 0.007). INAD is an ultra-rare neurodegenerative disorder that presents in early childhood, with a relentlessly progressive clinical course. Knowledge of the natural history of INAD may serve as a resource for healthcare providers to develop a targeted care plan and may facilitate the design of clinical trials to treat this disease.


Frequent mental distress, chronic conditions, and adverse health behaviors in the Behavioral Risk Factor Surveillance Survey, Jordan, 2007.
Recent evidence indicates that chronic diseases and mental illness are associated. In the Middle Eastern country of Jordan, chronic diseases and frequent mental distress (FMD) are increasing; however, the capacity for mental health care is limited. The objective of this study was to determine the association between FMD, chronic conditions, and adverse health behaviors in Jordan. The third cycle of the Jordan Behavioral Risk Factor Surveillance Survey (2007) served as the data source for this study. The sample consisted of 3,612 noninstitutionalized Jordanian adults aged 18 years or older. Logistic regression was used to obtain odds ratios for the association between chronic conditions, health behaviors, and FMD adjusted for age, sex, marital status, education, income, and employment. In the adjusted models, people with hypertension (adjusted odds ratio [AOR], 2.0; 95% confidence interval [CI], 1.6-2.7), high cholesterol (AOR, 2.3; 95% CI, 1.6-3.2), diabetes (AOR, 1.6; 95% CI, 1.1-2.4), and asthma (AOR, 2.2; 95% CI, 1.5-3.1) and smokers (AOR, 1.5; 95% CI, 1.1-2.0) were more likely to have FMD than people without each of these conditions. Adults who reported vigorous physical activity were less likely to have FMD (AOR, 0.6; 95% CI, 0.4-0.9) than their less active counterparts. In Jordan, FMD was associated with several chronic conditions. As a result, we suggest additional research to examine the complex relationship between FMD and chronic conditions. More doctors in the primary health care system should be trained in mental health.


Diazepam alters brain 5-HT function in man: implications for the acute and chronic effects of benzodiazepines.
The effect of diazepam on brain 5-HT-mediated neuroendocrine responses was studied in healthy male volunteers. An acute dose of diazepam (15 mg) significantly attenuated the prolactin and growth hormone responses to intravenous L-tryptophan. After 3 weeks administration of diazepam (25 mg/d) these responses had returned to normal despite much higher plasma diazepam concentrations, suggesting that tolerance had occurred. A reduction in brain 5-HT function may underlie some of the acute therapeutic actions of benzodiazepines. It is possible that excessive 'rebound' 5-HT activity may contribute to the abstinence syndrome seen on benzodiazepine withdrawal.


Tantalum Components in Difficult Acetabular Revisions Have Good Survival at 5 to 10 Years: Longer Term Followup of a Previous Report.
The best method for acetabular revisions in patients with severe bone loss remains controversial; typical approaches include jumbo cups, cages, cup-cages, and custom components. Tantalum (TM) components have good results at midterm followup, but the longer term survival and complications are not available. We previously reported on a series of such reconstructions; here we provide additional followup on that group along with a larger study cohort. (1) What is the survival at a minimum followup of 5 years of these components implanted in difficult revisions and what is the mechanism of failure? (2) What is the most common complication of these reconstructions, and what hip scores did these patients achieve? Between 2001 and 2010, one surgeon performed 150 acetabular revisions, of which 74 (49%) were done using TM components. The general indication for use of these devices was the surgeon's perception that there was sufficient bone loss to place the reconstruction at a high risk of mechanical failure (generally Paprosky Type 3 or 4 or lower Paprosky type with < 50% host bone coverage or morbid obesity). No cages were used during this time. Fifteen patients died and 11 were lost or did not return, leaving 48 hips (46 patients) with a mean followup of 8 years (range, 5-14 years). Of these, 39 were reported on in our previous series, and nine are new in the present series; the overall group here has an additional median of 5 years followup (range, 3-7 years). Five hips had six augments placed to obtain stability. Patients were evaluated by the Harris hip score and standard radiographs; survivorship was estimated using the cumulative incidence competing risks survival analysis. The primary outcome was fixation and survival of the TM component and the secondary outcome was complications. Cumulative incidence competing risks estimate survival free from aseptic loosening was 92% at 10 years (95% confidence interval [CI], 0.81-0.98). Dislocation, the most common complication, occurred in seven of 48 (15%) patients, and five of 48 (10%) had a reoperation for it. Survival free from any reoperation was 84% at 10 years (95% CI, 0.72-0.92). The Harris hip score improved from a mean of 50 points (SD 17) before surgery to 85 points (SD 10; p < 0.001) at latest followup. Given the findings of this study, TM components appear to provide durable fixation at midterm followup in complex acetabular revisions. Steps to minimize dislocation, the most frequent complication of these revisions, may include the routine use of larger femoral heads. Future studies likely will need to be multisurgeon or multicenter and should evaluate different techniques and components for long-term fixation and the prevention of dislocation. Level IV, therapeutic study.


The Cid1 family of non-canonical poly(A) polymerases.
Polyadenylation is an essential processing step for most eukaryotic mRNAs. In the nucleus, poly(A) polymerase adds poly(A) tails to mRNA 3' ends, contributing to their export, stability and translatability. Recently, a novel class of non-canonical poly(A) polymerases was discovered in yeast, worms and vertebrates. Different members of the Cid1 family, named after its founding member in the fission yeast Schizosaccharomyces pombe, are localized in the nucleus and the cytoplasm and are thought to target specific RNAs for polyadenylation. Polyadenylation of a target RNA by a Cid1-like poly(A) polymerase can lead to its degradation or stabilization, depending on the enzyme involved. Cid1-like proteins have important roles in diverse biological processes, including RNA surveillance pathways, DNA integrity checkpoint responses and RNAi-dependent heterochromatin formation.


Long telomeres are associated with clonality in wild populations of the fissiparous starfish Coscinasterias tenuispina.
Telomeres usually shorten during an organism's lifespan and have thus been used as an aging and health marker. When telomeres become sufficiently short, senescence is induced. The most common method of restoring telomere length is via telomerase reverse transcriptase activity, highly expressed during embryogenesis. However, although asexual reproduction from adult tissues has an important role in the life cycles of certain species, its effect on the aging and fitness of wild populations, as well as its implications for the long-term survival of populations with limited genetic variation, is largely unknown. Here we compare relative telomere length of 58 individuals from four populations of the asexually reproducing starfish Coscinasterias tenuispina. Additionally, 12 individuals were used to compare telomere lengths in regenerating and non-regenerating arms, in two different tissues (tube feet and pyloric cecum). The level of clonality was assessed by genotyping the populations based on 12 specific microsatellite loci and relative telomere length was measured via quantitative PCR. The results revealed significantly longer telomeres in Mediterranean populations than Atlantic ones as demonstrated by the Kruskal-Wallis test (K=24.17, significant value: P-value<0.001), with the former also characterized by higher levels of clonality derived from asexual reproduction. Telomeres were furthermore significantly longer in regenerating arms than in non-regenerating arms within individuals (pyloric cecum tissue: Mann-Whitney test, V=299, P-value<10(-6); and tube feet tissue Student's t=2.28, P-value=0.029). Our study suggests that one of the mechanisms responsible for the long-term somatic maintenance and persistence of clonal populations is telomere elongation.


Pancreatic stone protein predicts positive sputum bacteriology in exacerbations of COPD.
Pancreatic stone protein/regenerating protein (PSP/reg) serum levels are supposed to be increased in bacterial inflammation. PSP/reg levels also might be useful, therefore, as a predictor of bacterial infection in COPD. Two hundred consecutive patients presenting to the ED due to acute exacerbation of COPD were prospectively assessed. Patients were evaluated based on clinical, laboratory, and lung functional parameters at admission (exacerbation) and after short-term follow-up (14-21 days). PSP/reg serum values were measured by a newly developed enzyme-linked immunosorbent assay. PSP/reg levels were elevated in subjects with COPD exacerbation (23.8 ng/mL; 95% CI, 17.1-32.7) when compared with those with stable disease (19.1 ng/mL; 95% CI, 14.1-30.4; P 5 .03) and healthy control subjects (14.0 ng/mL; 95% CI , 12.0-19.0; P , .01). Higher PSP/reg values were observed in exacerbations with positive sputum bacteriology compared with those with negative sputum bacteriology (26.1 ng/mL [95% CI, 19.2-38.1] vs 20.8 ng/mL [95% CI , 15.6-27.2]; P , .01). Multivariate regression analysis revealed PSP/reg level as an independent predictor of positive sputum bacteriology. A combination of a PSP/reg cutoff value of . 33.9 ng/mL and presence of discolored sputum had a specificity of 97% to identify patients with pathogenic bacteria on sputum culture. In contrast, PSP/reg levels , 18.4 ng/mL and nonpurulent sputum ruled out positive bacterial sputum culture (sensitivity, 92%). In survival analysis, high PSP/reg levels at hospital admission were associated with increased 2-year mortality. Serum PSP/reg level might represent a promising new biomarker to identify bacterial etiology of COPD exacerbation.


Strengthening multisectoral coordination on antimicrobial resistance: a landscape analysis of efforts in 11 countries.
Increasingly, there has been recognition that siloed approaches focusing mainly on human health are ineffective for global antimicrobial resistance (AMR) containment efforts. The inherent complexities of AMR containment warrant a coordinated multisectoral approach. However, how to institutionalize a country's multisectoral coordination across sectors and between departments used to working in silos is an ongoing challenge. This paper describes the technical approach used by a donor-funded program to strengthen multisectoral coordination on AMR in 11 countries as part of their efforts to advance the objectives of the Global Health Security Agenda and discusses some of the challenges and lessons learned. The program conducted a rapid situational analysis of the Global Health Security Agenda and AMR landscape in each country and worked with the governments to identify the gaps, priorities, and potential activities in multisectoral coordination on AMR. Using the World Health Organization (WHO) Joint External Evaluation tool and the WHO Benchmarks for International Health Regulations (2005) Capacities as principal guidance, we worked with countries to achieve key milestones in enhancing effective multisectoral coordination on AMR. The program's interventions led to the achievement of key benchmarks recommended actions, including the finalization of national action plans on AMR and tools to guide their implementation; strengthening the leadership, governance, and oversight capabilities of multisectoral governance structures; establishing and improving the functions of technical working groups on infection prevention and control and antimicrobial stewardship; and coordinating AMR activities within and across sectors. A lot of learning still needs to be done to identify best practices for building mutual trust and adequately balancing the priorities of individual ministries with cross-cutting issues. Nevertheless, this paper provides some practical ideas for countries and implementing partners seeking to improve multisectoral coordination on AMR. It also demonstrates that the WHO benchmark actions, although not intended as an exhaustive list of recommendations, provide adequate guidance for increasing countries' capacity for effective multisectoral coordination on AMR in a standardized manner.


Traumatic aneurysms of the face and temple: a patient report and literature review, 1644 to 1998.
The branches of the external carotid artery are protected from injury in most locations by an adequate buffer of soft tissue. On occasion, the vessels approach the surface to cross bone structures, and in these key areas they become vulnerable to blunt trauma. The facial, superficial temporal, and terminal branches of the internal maxillary arteries are the branches most often affected via this mechanism of injury. In addition, damage to deeper branches of the internal maxillary artery and to the subparotid portion of the superficial temporal artery has been reported secondary to maxillary fractures and craniofacial surgery. A brief patient report illustrates the highlights of clinical examination, diagnostic study, and surgical management of an aneurysm of the facial artery. A review of the world literature since 1644 has revealed 386 patients with traumatic aneurysms of the face and temple.


A direct linkage between the phosphoinositide 3-kinase-AKT signaling pathway and the mammalian target of rapamycin in mitogen-stimulated and transformed cells.
The microbially derived antiproliferative agent rapamycin inhibits cell growth by interfering with the signaling functions of the mammalian target of rapamycin (mTOR). In this study, we demonstrate that interleukin-3 stimulation induces a wortmannin-sensitive increase in mTOR kinase activity in a myeloid progenitor cell line. The involvement of phosphoinositide 3'-kinase (PI3K) in the regulation of mTOR activity was further suggested by findings that mTOR was phosphorylated in vitro and in vivo by the PI3K-regulated protein kinase, AKT/PKB. Although AKT phosphorylated mTOR at two COOH-terminal sites (Thr2446 and Ser2448) in vitro, Ser2448 was the major phosphorylation site in insulin-stimulated or -activated AKT-expressing human embryonic kidney cells. Transient transfection assays with mTOR mutants bearing Ala substitutions at Ser2448 and/or Thr2446 indicated that AKT-dependent mTOR phosphorylation was not essential for either PHAS-I phosphorylation or p70S6K activation in HEK cells. However, a deletion of amino acids 2430-2450 in mTOR, which includes the potential AKT phosphorylation sites, significantly increased both the basal protein kinase activity and in vivo signaling functions of mTOR. These results demonstrate that mTOR is a direct target of the PI3K-AKT signaling pathway in mitogen-stimulated cells, and that the identified AKT phosphorylation sites are nested within a "repressor domain" that negatively regulates the catalytic activity of mTOR. Furthermore, the activation status of the PI3K-AKT pathway in cancer cells may be an important determinant of cellular sensitivity to the cytostatic effect of rapamycin.


From 1D helix to 0D loop: nitrite anion induced structural transformation associated with unexpected N-nitrosation of amine ligand.
An infinite Ag(I) coordination 41-helical chain, [Ag(Hdpma)](NO3)2·H2O (1), was synthesized by the self-assembly of AgNO3 and di(3-pyridylmethyl)amine (dpma). Helix 1 is 5-fold interweaved and has a topological diamondoid-like net that is extended by ligand-unsupported helix-to-helix argentophilic interactions. Two identical diamondoid-like nets with opposite chiralities interpenetrate to form the whole 3D framework as a meso compound. Typical anion-exchange reactions cause a remarkable single-crystal-to-single-crystal (SCSC) structural transformation from the 1D helix 1 to the 0D molecular loop [Ag(dpma-NO)(NO2)]2 (2) (induced by the nitrite anion, NO2(-)) and a 1D molecular ladder [Ag(dpma)(H2O)](NO3) (induced by the fluoride anion, F(-)). Molecular loop 2 is an N-nitroso compound. This work is the first to present observations of nitrite-dominated in situ N-nitrosation of an amine ligand which accompanies SCSC structural transformation via an anion-exchange reaction.


Robust Smartphone Assisted Biosensing Based on Asymmetric Nanofluidic Grating Interferometry.
Point-of-care systems enable fast therapy decisions on site without the need of any healthcare infrastructure. In addition to the sensitive detection, stable measurement by inexperienced persons outside of laboratory facilities is indispensable. A particular challenge in field applications is to reduce interference from environmental factors, such as temperature, to acceptable levels without sacrificing simplicity. Here, we present a smartphone-based point-of-care sensor. The method uses an optofluidic grating composed of alternating detection and reference channels arranged as a reflective phase grating. Biomolecules adsorbing to the detection channel alter the optical path length, while the parallel reference channels enable a direct common mode rejection within a single measurement. The optical setup is integrated in a compact design of a mobile readout device and the usability is ensured by a smartphone application. Our results show that different ambient temperatures do not have any influence on the signal. In a proof-of concept experiment we measured the accumulation of specific molecules in functionalized detection channels in real-time and without the need of any labeling. Therefore, the channel walls have been modified with biotin as capture molecules and the specific binding of streptavidin was detected. A mobile, reliable and robust point-of-care device has been realized by combining an inherently differential measurement concept with a smartphone-based, mobile readout device.


Dendritic phospholipid-based drug delivery systems.
A class of new dendritic phospholipid compounds with different hydrophilic dendritic poly(l-lysine) peripheries from generations 1 (G1) to 3 (G3) (DPL-1 to DPL-3) were synthesised and nano-drug delivery systems based on these compounds were prepared (DPN-2 and DPN-3). DPL-1 couldn't self-assemble into nanocarriers. The size, TEM image, and the CD spectrum of DPN-2 and DPN-3 were experimentally examined. The effect of the peripheral structure of dendritic phospholipid-based nanocarriers on their biological performance and drug delivery efficiency was studied. In vitro cytotoxicity studies demonstrated that the DOX-loaded DPN-3 shows higher cytotoxicity against 4T1 cells and BGC823 cells than DPN-2. DOX-loaded DPN-3 also showed excellent behaviours in cell internalization and 4T1 multicellular spheroid penetration. The composition of the hydrophilic block in dendritic phospholipids affected the self-assembly behaviour, properties and delivery efficiency of the formed nanocarriers. This work will be helpful for building drug delivery systems with characteristics of high delivery efficiency and low cytotoxicity for clinical applications.


A neural basis for social cooperation.
Cooperation based on reciprocal altruism has evolved in only a small number of species, yet it constitutes the core behavioral principle of human social life. The iterated Prisoner's Dilemma Game has been used to model this form of cooperation. We used fMRI to scan 36 women as they played an iterated Prisoner's Dilemma Game with another woman to investigate the neurobiological basis of cooperative social behavior. Mutual cooperation was associated with consistent activation in brain areas that have been linked with reward processing: nucleus accumbens, the caudate nucleus, ventromedial frontal/orbitofrontal cortex, and rostral anterior cingulate cortex. We propose that activation of this neural network positively reinforces reciprocal altruism, thereby motivating subjects to resist the temptation to selfishly accept but not reciprocate favors.


Learning Simpler Language Models with the Differential State Framework.
Learning useful information across long time lags is a critical and difficult problem for temporal neural models in tasks such as language modeling. Existing architectures that address the issue are often complex and costly to train. The differential state framework (DSF) is a simple and high-performing design that unifies previously introduced gated neural models. DSF models maintain longer-term memory by learning to interpolate between a fast-changing data-driven representation and a slowly changing, implicitly stable state. Within the DSF framework, a new architecture is presented, the delta-RNN. This model requires hardly any more parameters than a classical, simple recurrent network. In language modeling at the word and character levels, the delta-RNN outperforms popular complex architectures, such as the long short-term memory (LSTM) and the gated recurrent unit (GRU), and, when regularized, performs comparably to several state-of-the-art baselines. At the subword level, the delta-RNN's performance is comparable to that of complex gated architectures.


Prospective association between alcohol intake and hormone-dependent cancer risk: modulation by dietary fiber intake.
Alcohol intake is associated with increased circulating concentrations of sex hormones, which in turn may increase hormone-dependent cancer risk. This association may be modulated by dietary fiber intake, which has been shown to decrease steroid hormone bioavailability (decreased blood concentration and increased sex hormone-binding globulin concentration). However, this potential modulation has not been investigated in any prospective cohort. Our objectives were to study the relation between alcohol intake and the risk of hormone-dependent cancers (breast, prostate, ovarian, endometrial, and testicular) and to investigate whether dietary fiber intake modulated these associations. This prospective observational analysis included 3771 women and 2771 men who participated in the Supplémentation en Vitamines et Minéraux Antioxydants study (1994-2007) and completed at least 6 valid 24-h dietary records during the first 2 y of follow-up. After a median follow-up of 12.1 y, 297 incident hormone-dependent cancer cases, including 158 breast and 123 prostate cancers, were diagnosed. Associations were tested via multivariate Cox proportional hazards models. Overall, alcohol intake was directly associated with the risk of hormone-dependent cancers (tertile 3 vs. tertile 1: HR: 1.36; 95% CI: 1.00, 1.84; P-trend = 0.02) and breast cancer (HR: 1.70; 95% CI: 1.11, 2.61; P-trend = 0.04) but not prostate cancer (P-trend = 0.3). In stratified analyses (by sex-specific median of dietary fiber intake), alcohol intake was directly associated with hormone-dependent cancer (tertile 3 vs. tertile 1: HR: 1.76; 95% CI: 1.10, 2.82; P-trend = 0.002), breast cancer (HR: 2.53; 95% CI: 1.30, 4.95; P-trend = 0.02), and prostate cancer (HR: 1.37; 95% CI: 0.65, 2.89; P-trend = 0.02) risk among individuals with low dietary fiber intake but not among their counterparts with higher dietary fiber intake (P-trend = 0.9, 0.8, and 0.6, respectively). The P-interaction between alcohol and dietary fiber intake was statistically significant for prostate cancer (P = 0.01) but not for overall hormone-dependent (P = 0.2) or breast (P = 0.9) cancer. In line with mechanistic hypotheses and experimental data, this prospective study suggested that dietary fiber intake might modulate the association between alcohol intake and risk of hormone-dependent cancer. This trial was registered at clinicaltrials.gov as NCT00272428.


Pre- and perinatal hazards and family background in children with specific language impairments: a study of twins.
A clinical group composed of 84 twin pairs where one or both twins met stringent psychometric criteria for specific speech-language impairment was compared with 36 twin pairs with no history of speech-language difficulties. Twins with speech-language impairment tended to have more siblings than control twins and were significantly more likely to have an affected parent. Groups were closely similar in terms of length of gestation and mother's antenatal condition, except that maternal toxemia was unusually frequent in the clinical group. Children from the two groups did not differ in terms of Apgar scores or on a composite measure of perinatal hazards. Within the clinical group, MZ pairs with substantial differences in neonatal status did not differ in language outcome. It is suggested that if an association with toxemia can be replicated, this might reflect a common genetic basis for immune disorders and developmental language delay. Perinatal hazard was unrelated to subtype of speech-language impairment.


The clinical utility of lurasidone in schizophrenia: patient considerations.
Lurasidone is a novel antipsychotic agent approved for the treatment of schizophrenia in a number of countries including the United Kingdom, other European countries, the United States, and Canada. In addition to full antagonist activity at the dopamine D2 (Ki, 1 nM) and serotonin 5-HT2A (Ki, 0.5 nM) receptors, the pharmacodynamic profile of lurasidone is notable for its high affinity for serotonin 5-HT7 receptors (0.5 nM) and its partial agonist activity at 5-HT1A receptors (Ki, 6.4 nM). Long-term treatment of schizophrenia with lurasidone has been shown to reduce the risk of relapse in patients with schizophrenia. Lurasidone appears to be associated with minimal effects on body weight, and low risk for clinically meaningful alterations in glucose, lipids, or electrocardiography parameters. Evidence from two randomized trials also suggests improvement in functional capacity and cognitive functioning in people with schizophrenia. A significant evidence base supports the use of lurasidone as a promising agent for the treatment of schizophrenia.


Enabling appropriate use of antibiotics: review of European Union procedures of harmonising product information, 2007 to 2020.
IntroductionAntimicrobial resistance (AMR) is one of the most important challenges in modern clinical practice. The European regulatory network has a strategy to support prevention of AMR by applying specific referral procedures.AimThe aim of this study was to evaluate post-authorisation changes made in the product information of key antibiotics that underwent referral procedures between 2007 and 2020.MethodIn a comprehensive analysis of the changes made for antibiotics, we extracted information on changes from the European Commission community register of medicinal products and the European Medicines Agency's database for antibiotics that went through referrals. Changes made in the specific sections of the summary of product characteristics of each referral procedure were scrutinised.ResultsWe identified 15 antibiotics from seven classes of antibiotics during the study period. The outcome of all referrals included the restriction of antibiotic use. Therapeutic indications were revised for all antibiotics, with septicaemia and gonorrhoea most common diseases removed. Posology and/or method of administration was updated for all; the majority of referrals included adjustment of dosage for specific populations. Information on contraindication (most regarding hypersensitivity) and information on warnings was amended for all referrals.ConclusionOur findings highlight the importance of the regulatory actions. The changes made in the product information aim to ensure appropriate use. Ongoing harmonisation activities are likely to lead to further refinements and restrictions on individual antibiotics in support of rational use. However, further research is required to examine the impact of post-referral label changes on the clinical practice.


Depolarization after resonance energy transfer (DARET): a sensitive fluorescence-based assay for botulinum neurotoxin protease activity.
The DARET (depolarization after resonance energy transfer) assay is a coupled Förster resonance energy transfer (FRET)-fluorescence polarization assay for botulinum neurotoxin type A or E (BoNT/A or BoNT/E) proteolytic activity that relies on a fully recombinant substrate. The substrate consists of blue fluorescent protein (BFP) and green fluorescent protein (GFP) flanking SNAP-25 (synaptosome-associated protein of 25 kDa) residues 134-206. In this assay, the substrate is excited with polarized light at 387 nm, which primarily excites the BFP, whereas emission from the GFP is monitored at 509 nm. Energy transfer from the BFP to the GFP in the intact substrate results in a substantial depolarization of the GFP emission. The energy transfer is eliminated when the fluorescent domains separate on cleavage by the endopeptidase, and emission from the directly excited GFP product fragment is then highly polarized, resulting in an overall increase in polarization. This increase in polarization can be monitored to assay the proteolytic activity of BoNT/A and BoNT/E in real time. It allows determination of the turnover rate of the substrate and the kinetic constants (V(max) and k(cat)) based on the concentration of cleaved substrate determined directly from the measurements using the additivity properties of polarization. The assay is amenable to high-throughput applications.


The herpes simplex virus UL20 protein compensates for the differential disruption of exocytosis of virions and viral membrane glycoproteins associated with fragmentation of the Golgi apparatus.
The Golgi apparatus is fragmented and dispersed in Vero cells but not in human 143TK- cells infected with wild-type herpes simplex virus 1. Moreover, a recombinant virus lacking the gene encoding the membrane protein UL20 (UL20- virus) accumulates in the space between the inner and outer nuclear membranes of Vero cells but is exported and spreads from cell to cell in 143TK- cell cultures. Here we report that in Vero cells infected with UL20- virus, the virion envelope glycoproteins were of the immature type, whereas the viral glycoproteins associated with cell membranes were fully processed up to the addition of sialic acid, a trans-Golgi function. Moreover, the amounts of viral glycoproteins accumulating in the plasma membranes were considerably smaller than those detected on the surface of Vero cells infected with wild-type virus. In contrast, the amounts of viral glycoproteins present on the plasma membranes of 143TK- cells infected with wild-type or UL20- virus were nearly identical. We conclude that (i) in Vero cells infected with UL20- virus the block in the export of virions is at the entry into the exocytic pathway, and a second block in the exocytosis of viral glycoproteins associated with cytoplasmic membranes is due to an impairment of transport beyond Golgi fragments containing trans-Golgi enzymes and not to a failure of the Golgi oligosaccharide-processing functions; (ii) these defects are manifested in cells in which the Golgi apparatus is fragmented; and (iii) the UL20 protein compensates for these defects by enabling transport to and from the fragmented Golgi apparatus.


Generalized Hotelling's test for paired compositional data with application to human microbiome studies.
The human microbiome is a dynamic system that changes due to diseases, medication, change in diet, etc. The paired design is a common approach to evaluate the microbial changes while controlling for the inherent differences between people. For example, microbiome data may be collected from the same individuals before and after a treatment. Two challenges exist in analyzing this type of data. First, microbiome data are compositional such that the reads for all taxa in each sample are constrained to sum to a constant. Second, the number of taxa can be much larger than the sample size. Few statistical methods exist to analyze such data besides methods that test one taxon at a time. In this paper, we propose to first conduct a log-ratio transformation of the compositions, and then develop a generalized Hotelling's test (GHT) to evaluate whether the average microbiome compositions are equivalent in the paired samples. We replace the sample covariance matrix in standard Hotelling's statistic by a shrinkage-based covariance, calculated as a weighted average of the sample covariance and a positive definite target matrix. The optimal weighting can be obtained for many commonly used target matrices. We develop a permutation procedure to assess the statistical significance. Extensive simulations show that our proposed method has well-controlled type I error and better power than a few ad hoc approaches. We apply our method to examine the vaginal microbiome changes in response to treatments for menopausal hot flashes. An R package " GHT" is freely available at https://github.com/zhaoni153/GHT.


Impacts of horizontal gene transfer on the compact genome of the clavulanic acid-producing Streptomyces strain F613-1.
Mobile genetic elements involved in mediating horizontal transfer events contribute to bacterial evolution, and bacterial genomic plasticity and instability result in variation in functional genetic information in Streptomyces secondary metabolism. In a previous study, we reported the complete genome sequence of the industrial Streptomyces strain F613-1, which produces high yields of clavulanic acid. In this study, we used comparative genomics and bioinformatics to investigate the unique genomic features of this strain. Taken together, comparative genomics were used to systematically investigate secondary metabolism capabilities and indicated that frequent exchange of genetic materials between Streptomyces replicons may shape the remarkable diversities in their secondary metabolite repertoires. Moreover, a 136.9-kb giant region of plasticity (RGP) was found in the F613-1 chromosome, and the chromosome and plasmid pSCL4 are densely packed with an exceptionally large variety of potential secondary metabolic gene clusters, involving several determinants putatively accounting for antibiotic production. In addition, the differences in the architecture and size of plasmid pSCL4 between F613-1 and ATCC 27064 suggest that the pSCL4 plasmid could evolve from pSCL4-like and pSCL2-like extrachromosomal replicons. Furthermore, the genomic analyses revealed that strain F613-1 has developed specific genomic architectures and genetic patterns that are well suited to meet the requirements of industrial innovation processes.


Adverse effects of beta-agonists.
Short-acting beta-adrenergic receptor agonists have pharmacologically predictable dose-related and potency-related adverse effects, including tachycardia and tremor, and they also affect serum potassium and glucose. These effects all show tolerance with continued exposure. The potential for arrhythmia is increased by comorbidity and hypoxemia. Nonpharmacologically predictable effects include airway hyperresponsiveness to nonspecific and specific stimuli, including allergen and exercise, and increased airway inflammation. Genetic variants of the beta-adrenergic receptor alter susceptibility to adverse effects of beta-agonists on airway function. The impact of the enantiomers of beta-agonists on adverse effects remains unclear. The two epidemics of asthma death among young people were temporally associated with introduction of potent short-acting beta-agonists (isoproterenol and fenoterol) and appear to be related to adverse effects of these drugs on airway function and airway hyperresponsiveness rather than to cardiotoxicity. Compared with short-acting agents, long-acting beta-agonists show similar but less pronounced pharmacologically predictable effects, and they have not been shown to increase airway hyperresponsiveness in adults. Postmarketing surveillance studies have not suggested significant adverse effects of long-acting beta-agonists on morbidity and mortality.


Risk factors for crash involvement in older motorcycle riders.
A prospective cohort study was conducted to identify risk and protective factors for crash involvement in older motorcyclists. Over a 1-year study period from August 2013 to July 2014, study participants were recruited from local community centers of five cities in Taiwan. People aged ≥60 years who rode a motorcycle at least once per week were eligible and were invited to participate in the study. Among 256 older riders who completed the baseline assessment and at least one of the four follow-up assessments, 79 (33.7%) experienced a motorcycle crash over the study period. Results of the proportional hazards model showed that after controlling for age, gender, and riding distance, older riders who had sustained hearing impairment (hazard ratio (HR)=2.58; 95% confidence interval (CI), 1.30-5.15), rode a motorcycle at speeds of ≥41km/h (HR=2.31; 95% CI, 1.26-4.23), and had experienced a motorcycle crash in the past year (HR=1.81; 95% CI, 1.06-3.09) were more likely to be involved in a crash, compared to their counterparts. Conversely, older riders who were obese (HR=0.43; 95% CI, 0.22-0.82) were less likely to be involved in a crash than those with a normal weight, while longer functional reach distances (HR=0.96; 95% CI, 0.93-0.99) and higher Tinetti balance scores (HR=0.79; 95% CI, 0.69-0.91) were associated with a reduced risk of crash involvement. Among older people riding a motorcycle as their primary source of transportation, several factors associated with the occurrence of motorcycle crashes were identified. Restrictions and modifications of these risk factors may help design effective safety interventions for reducing crash and injury risks of this increasing riding population.


Formation of long-term memory representation in human temporal cortex related to pictorial paired associates.
It is widely held that long-term memory gradually develops in the temporal neocortex after initial memory encoding into the hippocampus. However, little is known as to whether and where long-term memory can be newly created in the human temporal neocortex. In this functional magnetic resonance imaging study, we detected brain activity in the temporal neocortex that was developed approximately 8 weeks after study of unfamiliar pictorial paired associates. Two sets of paired Fourier figures were studied, one approximately 8 weeks before test and the other immediately before test, keeping the correct performance during the tests balanced across the two sets of stimuli. Significant signal increase was observed in the right hippocampus during retrieval of newly studied pairs relative to initially studied pairs. In contrast, significant signal increase was observed in the anterior temporal cortex during retrieval of initially studied pairs relative to newly studied pairs. The greater activity during retrieval of older memory developed in the temporal neocortex provides direct evidence of formation of temporal neocortical representation for stable long-term memory.


A radiation hybrid map of the distal short arm of human chromosome 11, containing the Beckwith-Wiedemann and associated embryonal tumor disease loci.
We describe a high-resolution radiation hybrid (RH) map of the distal short arm of human chromosome 11 containing the Beckwith-Wiedemann gene and the associated embryonal tumor disease loci. Thirteen human 11p15 genes and 17 new anonymous probes were mapped by a statistical analysis of the cosegregation of markers in 102 rodent-human radiation hybrids retaining fragments of human chromosome 11. The 17 anonymous probes were generated from lambda phage containing human 11p15.5 inserts, by using ALU-PCR. A comprehensive map of all 30 loci and a framework map of nine clusters of loci ordered at odds of 1,000:1 were constructed by a multipoint maximum-likelihood approach by using the computer program RHMAP. This RH map localizes one new gene to chromosome 11p15 (WEE1), provides more precise order information for several 11p15 genes (CTSD, H19, HPX, ST5, RNH, and SMPD1), confirms previous map orders for other 11p15 genes (CALCA, PTH, HBBC, TH, HRAS, and DRD4), and maps 17 new anonymous probes within the 11p15.5 region. This RH map should prove useful in better defining the positions of the Beckwith-Wiedemann and associated embryonal tumor disease-gene loci.


Enhancement of cancer stem cell susceptibility to conventional treatments through complementary yoga therapy: possible cellular and molecular mechanisms.
Cancer stem cells (CSCs) are stem-like tumor populations that are reported to contribute towards tumor growth, maintenance and recurrence after therapy. Hypoxia increases CSC fraction and promotes acquisition of a stem-cell-like state. Cancer stem cells are critically dependant on the hypoxia-inducible factor-1 (HIF-1) for survival, self-renewal, tumor growth and maintenance of their undifferentiated phenotype. Recent researches show that stage of differentiation of the tumor cells is predictive of their susceptibility to natural killer cell (NK) cell mediated cytotoxicity and cancer stem cells are significant targets of NK cell cytotoxicity. Studies also show that reversion of tumor cells to a less-differentiated phenotype can be achieved by blocking NFκB. Yoga therapy (yogic lifestyle modifications encompassing physical postures, breathing practices, relaxation techniques and meditations) is known to modulate neural, endocrine and immune functions at the cellular level through influencing cell cycle control, aging, oxidative stress, apoptosis and several pathways of stress signaling molecules. Yoga therapy has also been shown to enhance natural killer cell activity and modulate stress and DNA damage in breast cancer patients receiving radiotherapy. Recent study found that brief daily yogic meditation may reverse the pattern of increased NFκB-related transcription of pro-inflammatory cytokines in leukocytes. Thus, yoga therapy has the potential to reduce cancer stem cell survival, self -renewal and tumor growth by modifying the tumor micro-environment through various mechanisms such as; 1) reducing HIF-1 activity by enhanced oxygenation, 2) promoting NK cell activity directly (or indirectly through down regulating NFκB expression), thereby enhancing NK cell mediated CSC lysis, and 3) by minimizing the aberrant expressions or activities of various hormones, cytokines, chemokines and tumor signaling pathways. Yoga therapy may have a synergistic effect with conventional modalities of treatment in preventing cancer progression and recurrences.


Palmitylation of an amino-terminal cysteine motif of protein tyrosine kinases p56lck and p59fyn mediates interaction with glycosyl-phosphatidylinositol-anchored proteins.
Cross-linking of glycosyl-phosphatidylinositol (GPI)-anchored membrane proteins on T cells can trigger cell activation. We and others have shown an association between GPI-anchored proteins and the protein tyrosine kinases (PTKs) p56lck and p59fyn, suggesting a pathway for signaling through GPI-anchored proteins. Studies of decay-accelerating factor (DAF) or CD59 in either the C32 cell line or the HeLa cell line transfected with PTK cDNA demonstrated that the GPI-anchored proteins associated noncovalently with p56lck and p59fyn but not with p60src. Nonmyristylated versions of p56lck and p59fyn also failed to associate with the GPI-anchored proteins. Mutational analysis of the PTK demonstrated that the association with the GPI-anchored proteins mapped to the unique amino-terminal domains of the PTK. A chimeric PTK consisting of the 10 amino-terminal residues of p56lck or p59fyn replacing the corresponding amino acids in p60src was sufficient for association with DAF, but the converse constructs containing the first 10 amino acids of p60src plus the remainder of p56lck or p59fyn did not associate with DAF. Mutation of cysteine to serine at positions 3 and 6 in p59fyn or positions 3 and 5 in p56lck abolished the association of these kinases with DAF. Mutation of serine to cysteine at positions 3 and 6 in p60src conferred on p60src the ability to associate with DAF. Direct labeling with [3H]palmitate demonstrated palmitylation of this amino-terminal cysteine motif in p56lck. Thus, palmitylation of the amino-terminal cysteine residue(s) together with myristylation of the amino-terminal glycine residue defines important motifs for the association of PTKs with GPI-anchored proteins.


Using the theory of planned behavior to understand health professionals' attitudes and intentions to refer cancer patients for psychosocial support.
To describe oncology professionals' patterns of referral to existing community and psychosocial support services, including complementary therapies utilizing the theory of planned behavior (TPB). An exploratory cross-sectional survey of 72 oncology professionals including nurses (73.6%), medical practitioners (19.4%) and allied health professionals (6.9%) from health institutions in South Australia assessed past referral patterns, perceived attitudes of peers, control over and attitudes toward, referral, past referral practices and how these impact on intention to refer. Referral to support services such as a cancer helpline, allied health or complementary services was infrequent. A hierarchical regression entering awareness, past referral and the TPB variables (attitude, subjective norm and perceived control) explained 51% of the variance on the outcome 'intention to refer'. Barriers to referral for support included lack of local services for remote patients, and financial considerations. Interventions with health professionals should focus on the development of a culture, which recognizes the importance of addressing a breadth of patient needs across the cancer trajectory. Education and support for health professionals is required to ensure that they feel comfortable discussing support needs and referring to appropriate support services.