A transcription-activating polymorphism in the ACHE promoter associated with acute sensitivity to anti-acetylcholinesterases.
Hypersensitivity to acetylcholinesterase inhibitors (anti-AChEs) causes severe nervous system symptoms under low dose exposure. In search of direct genetic origin(s) for this sensitivity, we studied six regions in the extended 22 kb promoter of the ACHE gene in individuals who presented adverse responses to anti-AChEs and in randomly chosen controls. Two contiguous mutations, a T-->A substitution, disrupting a putative glucocorticoid response element, and a 4-bp deletion, abolishing one of two adjacent HNF3 binding sites, were identified 17 kb upstream of the transcription start site. Allele frequencies for these mutations were 0.006 and 0.012, respectively, in 333 individuals of various ethnic origins, with a strong linkage between the deletion and the biochemically neutral H322N mutation in the coding region of ACHE. Heterozygous carriers of the deletion included a proband who presented with acute hypersensitivity to the anti-AChE pyridostigmine and another with unexplained excessive vomiting during a fourth pregnancy following three spontaneous abortions. Electromobility shift assays, transfection studies and measurements of AChE levels in immortalized lymphocytes as well as in peripheral blood from both carriers and non-carriers, revealed functional relevance for this mutation both in vitro and in vivo and showed it to increase AChE expression, probably by alleviating competition between the two hepatocyte nuclear factor 3 binding sites. Moreover, AChE-overexpressing transgenic mice, unlike normal FVB/N mice, displayed anti-AChE hypersensitivity and failed to transcriptionally induce AChE production following exposure to anti-AChEs. Our findings point to promoter polymorphism(s) in the ACHE gene as the dominant susceptibility factor(s) for adverse responses to exposure or to treatment with anti-AChEs.


A targeted approach for the synthesis of multi-phosphorylated peptides: a tool for studying the role of phosphorylation patterns in proteins.
Protein phosphorylation barcodes, clusters of several phosphorylation sites within a short unfolded region, control many cellular processes. Existing biochemical methods used to study the roles of these barcodes suffer from low selectivity and provide only qualitative data. Chemically synthesized multiphosphopeptide libraries are selective and specific, but their synthesis is extremely difficult using the current peptide synthesis methods. Here we describe a new microwave assisted approach for synthesizing a library of multiphosphopeptides, using the C-terminus of rhodopsin as a proof of concept. Our approach utilizes multiple protocols for synthesizing libraries of multiphosphopeptides instead of the inefficient single protocol methods currently used. Using our approach we demonstrated the synthesis with up to seven phosphorylated amino acids, sometimes next to each other, an accomplishment that was impractical before. Synthesizing the Rhodopsin derived multiphosphopeptide library enabled dissecting the precise phosphorylation barcode required for the recruitment, activation and modulation of the conformation of Arrestin. Since phosphorylation barcodes modulate the activity of hundreds of GPCRs, synthesizing libraries of multiphosphopeptides is the method of choice for studying their molecular mechanisms of action. Our approach provides an invaluable tool for evaluating how protein phosphorylation barcodes regulate their activity.


Mutation analysis of the RET receptor tyrosine kinase in Hirschsprung disease.
Hirschsprung disease (HSCR), or congenital aganglionic megacolon, is the most common cause of congenital bowel obstruction with an incidence of 1 in 5000 live births. Recently, linkage of an incompletely penetrant, dominant form of HSCR was reported, followed by identification of mutations in the RET receptor tyrosine kinase. To determine the frequency of RET mutations in HSCR and correlate genotype with phenotype, we have screened for mutations among 80 HSCR probands representing a wide range of phenotypes and family structures. Polymerase chain reaction (PCR) and single-strand conformation polymorphism (SSCP) analysis of RET's 20 exons for mutations among probands revealed eight putative mutations (10%). Sequence changes, which included missense, frameshift and complex mutations, were detected in both familial and isolated cases, among patients with both long- and short-segment HSCR and in three kindreds with other phenotypes (maternal deafness, talipes and malrotation of the gut, respectively). Two mutations (C609Y and C620R) we identified have previously been associated with multiple endocrine neoplasia type 2A (MEN2A), medullary thyroid carcinoma (MTC) and, on rare occasions, HSCR. Thus, while HSCR family members may be at risk for developing neuroendocrine tumors, it follows that identical mutations in RET may be able to participate in the pathogenesis of distinct phenotypes. Our data suggest that: (i) the overall frequency of RET mutations in HSCR patients is low and therefore, other genetic and/or environmental determinants contribute to the majority of HSCR susceptibility, and (ii) at present, there is no obvious relationship between RET genotype and HSCR phenotype.


Nivolumab: Immunotherapy in Malignant Melanoma.
Although patients diagnosed with melanoma that is confined to the skin have a five-year survival rate of 98%, this number drops to 16% with widely metastatic disease. Melanoma rates have been steadily increasing since the 1970s, but cytotoxic chemotherapy generally prolongs survival by about four months. Nivolumab is an effective immunotherapy agent. This article discusses the use of nivolumab for metastatic melanoma. Clinical trial and early postmarketing data were reviewed. In clinical trials, patients with advanced melanoma experienced partial sustained responses to nivolumab, a new targeted immunotherapy agent, for more than one year. Nivolumab helps the immune system mobilize lymphocytes that have been inactivated by melanoma cells, enhancing the body's ability to recognize the cancer as abnormal. Compared to conventional chemotherapy, nivolumab has been shown to greatly improve survival in widespread, inoperable malignant melanoma. Oncology nurses will administer, monitor, and educate patients about nivolumab.


Interrelationships among individual differences in alcohol demand, impulsivity, and alcohol misuse.
An Alcohol Purchase Task (APT) is a novel behavioral economic measure for characterizing the incentive value of alcohol to an individual (i.e., alcohol demand). Individual differences in alcohol demand have been associated with a number of alcohol-related outcomes and the current investigation sought to extend these previous findings in a number of ways. The goals of the study were: (a) to examine the relationship between alcohol demand and alcohol misuse in a large sample of community adults; (b) to examine sex differences in alcohol demand; and, (c) to examine the relationship between alcohol demand and impulsive personality traits, both in general and as moderating variables. Participants (N = 720; 39% female) were adult smokers who reported drinking in the last year and were recruited from the community at large. All four behavioral economic indices of demand from the APT were significantly associated with alcohol misuse, with Omax and intensity uniquely associated in combined analyses. Males exhibited significantly higher demand, but these differences were largely eliminated after adjusting for drinks per week and other covariates. Trait levels of urgency, sensation-seeking and lack of premeditation were significantly associated with intensity and urgency was associated with Omax, but no moderating relationships were present. The significant relationships between aspects of impulsivity and the demand indices may signify a common process underlying disinhibition and demand for alcohol. These findings further support the relationship between indices of alcohol demand and alcohol misuse and a link between demand and impulsivity. Methodological considerations and future directions are discussed.


Capillary origami: superhydrophobic ribbon surfaces and liquid marbles.
In the wetting of a solid by a liquid it is often assumed that the substrate is rigid. However, for an elastic substrate the rigidity depends on the cube of its thickness and so reduces rapidly as the substrate becomes thinner as it approaches becoming a thin sheet. In such circumstances, it has been shown that the capillary forces caused by a contacting droplet of a liquid can shape the solid rather than the solid shaping the liquid. A substrate can be bent and folded as a (pinned) droplet evaporates or even instantaneously and spontaneously wrapped on contact with a droplet. When this effect is used to create three dimensional shapes from initially flat sheets, the effect is called capillary origami or droplet wrapping.In this work, we consider how the conditions for the spontaneous, capillary induced, folding of a thin ribbon substrate might be altered by a rigid surface structure that, for a rigid substrate, would be expected to create Cassie-Baxter and Wenzel effects. For smooth thin substrates, droplet wrapping can occur for all liquids, including those for which the Young's law contact angle (defined by the interfacial tensions) is greater than 90° and which would therefore normally be considered relatively hydrophobic. However, consideration of the balance between bending and interfacial energies suggests that the tendency for droplet wrapping can be suppressed for some liquids by providing the flexible solid surface with a rigid topographic structure. In general, it is known that when a liquid interacts with such a structure it can either fully penetrate the structure (the Wenzel case) or it can bridge between the asperities of the structure (the Cassie-Baxter case).In this report, we show theoretically that droplet wrapping should occur with both types of solid-liquid contact. We also derive a condition for the transition between the Cassie-Baxter and Wenzel type droplet wrapping and relate it to the same transition condition known to apply to superhydrophobic surfaces. The results are given for both droplets being wrapped by thin ribbons and for solid grains encapsulating droplets to form liquid marbles.


D-Tryptophan-6 analog of luteinizing hormone-releasing hormone as a protective agent against testicular damage caused by cyclophosphamide in baboons.
Possible protective effects of the agonist [D-Trp6]LH-RH (the D-tryptophan-6 analog of luteinizing hormone-releasing hormone) against testicular damage caused by cyclophosphamide (Cytoxan) were investigated in subhuman primates. Three adult male baboons (Papio anubis) were first subjected to normal semen evaluation by using electroejaculation. The average baseline count for the animals ranged from 95.7 X 10(6) to 585.7 X 10(6) sperm per ml with 90% normal forms and 85% motility with excellent rapid forward progression. After baseline evaluations, two of the animals were treated with daily subcutaneous injections of 0.5 mg of the agonist [D-Trp6]LH-RH. There was an initial rise in serum testosterone after 1 week, but testosterone fell to castration values at 1 month and continued at these levels during treatment with the agonist. There was also an initial rise in sperm concentration 1 month after treatment was started, but after 2 months the animals were azoospermic. After 13 weeks of therapy with [D-Trp6]LH-RH, these two baboons and a third untreated control animal were given cyclophosphamide at a dose of about 3 mg/kg of body weight per day for 4 months. The two animals pretreated with [D-Trp6]LH-RH, continued to receive this agonist until 1 week after the last dose of Cytoxan. In one of the two baboons treated with Cytoxan and the LH-RH agonist, the white blood count fell below 4000 per microliter, and the dose of Cytoxan had to be reduced to 1.5 mg/kg per day for 12 days. The control animal developed azoospermia after 4 months of treatment with cyclophosphamide, and serum testosterone increased while sperm count decreased. Four weeks after the agonist was stopped, serum testosterone in both animals pretreated with [D-Trp6]LH-RH returned to normal levels. The control animal showed a small amount of nonmotile sperm 2.5 months after cessation of treatment, but after 9 months remains oligospermic with poor sperm motility. In one of the animals treated with LH-RH agonist, semen analysis returned to normal pretreatment values 8 months after withdrawal of treatment. The other animal remains oligospermic 10 months after therapy, but the motility is improving. These preliminary results suggest that treatment with LH-RH agonist might decrease the gonadal damage caused by some chemotherapeutic agents.


Schizophrenia or Atypical Lupus Erythematosus with Predominant Psychiatric Manifestations over 25 Years: Case Analysis and Review.
We observed a case over 25 years of relapsing-remitting schizophrenic spectrum disorder, varying regarding the main symptomatology between more depressive or more schizoaffective or rather typical schizophrenic syndrome. Diseased phases were repeatedly accompanied by minor skin lesions, which were initially classified as mixed tissue disorder. Psychotic phases were waxing-waning over years. During one later relapse, skin involvement was severe, classified to likely represent an allergic reaction to psychopharmaca; this generalized exanthema remitted rapidly with cortisone treatment and azathioprine. Under continued azathioprine and low dose neuroleptics, the patient remitted completely, appearing psychiatrically healthy for 16 years. When azathioprine was set off due to pregnancy, an extraordinary severe relapse of schizophrenia like psychosis accompanied by most severe skin lesions developed within a few weeks, then requiring 2 years of psychiatric inpatient treatment. Finally, a diagnosis of systemic lupus erythematodes plus neuropsychiatric lupus was made. A single CSF sample in 2013 showed suspicious biomarkers, matching with CSF cytokine profiling in schizophrenic and affective spectrum disorder patients and indicated mild neuroinflammation. Complex immune suppressive treatment was reinitiated short after relapse, but was only partially successful. However, surprisingly the psychosis and skin lesions remitted (in parallel) when belimumab was given (add-on). The very details of this complicated, long-term disease course are discussed also with regard to general ideas, in particular with respect to the question if this case of seemingly comorbid schizophrenia with minor autoimmunity signs represented a case of one emerging autoimmune disorder with variant manifestations systemically and within the CNS, though atypically with predominant appearance as a schizophrenia spectrum disorder.


Factors contributing to the upsurge of water-pipe tobacco smoking among Saudi females in selected Jeddah cafés and restaurants: A mixed method study.
Despite clear evidence indicating the health hazards of water tobacco smoking (WTS), there is a remarkable increase in the frequency of WTS in the Middle East and the Gulf region, particularly among young girls and women. The objective of this survey was to examine the prevalence of and the reasons for addiction to WTS and study in depth the factors contributing to the increased frequency of WTS among Saudi females. This study was conducted in different cafés and restaurants in Jeddah using a mixed method approach. A quantitative approach was carried out by a cross-sectional design, in which adult WTS Saudi females (n = 332) were selected from ten cafés. In addition, a qualitative approach was pursued involving five focus group discussions and three in-depth interviews of heavy smokers. Frequencies and percentages were calculated for the categorical variables, and Chi-square test and regression analysis were performed to establish association. Key themes were identified and built upon for the qualitative part. The mean age of female water-pipe (WP) smokers was 32.5 ± 11.9 years. Addicted to WTS were 39.6% of the women. Significant predictors of smokers' addiction to WTS according to regression analysis (p < 0.05) were increased frequency of WTS, perception that it improved mood, and insistence on carrying one's own WP to restaurants and cafés. Smoking frequency increased in pleasant weather (p = 0.025) and better mood (p = 0.033). This study showed that students and working women were more addicted to WTS (p < 0.001). Those who smoked daily preferred to smoke at home especially when alone (p < 0.001), while the preferred place for those who smoked weekly was restaurants in the company of their friends (p < 0.001). Most of the participants in this study believed that WTS was less harmful and less addictive than cigarette smoking. The only driving force to quit WTS was the effects on their beauty/skin. WTS is a public health problem, especially among young girls. Peer pressure, view that it is a fashion symbol, carrying one's own WP and wrong belief that WP was less harmful, improved mood, and effect of the weather are main factors leading to unintentional dependency on WTS. The only driving force to stop WTS is the effect it has on beauty/skin. It is important to understand the reasons behind the upsurge of WTS in this group for appropriate policy for intervention for its prevention and cessation.


Readmission Rates, Reasons, and Risk Factors in Elderly Patients Treated With Lumbar Fusion for Degenerative Pathology.
Retrospective database review. To determine readmission rates after 1 to 2 level, primary, elective lumbar spinal fusion surgery for degenerative pathology and elucidate risk factors that predict increased risk of 30-day readmission SUMMARY OF BACKGROUND DATA.: Early postoperative readmissions after spine surgery represent a significant source of increased cost and morbidity. As the elderly population represents a demographic with a growing need for spine surgery, readmissions within this population are of significant interest. Medicare data (2005-2012) from an insurance database was queried for patients who underwent primary 1 to 2 level posterolateral lumbar spine fusion surgeries for degenerative lumbar pathology. After applying specific exclusion criteria to select for elderly patients (65-84 yr) undergoing mostly elective procedures, 52,567 patients formed the final study population. Readmission rates for medical, surgical, and all reasons were calculated within 30 days, 90 days, and 1 year postoperatively. Risk factors for medical, surgical, and all 30-day readmissions were also determined. Within 30 days, 90 days, and 1 year, 1510 (2.9%), 2776 (5.3%), and 6574 (12.5%) patients were readmitted, respectively. At 30 days, surgical diagnoses constituted 50.1% of all readmissions. Wound infection was the reason for readmission in 25.8% of all readmissions within 30 days. Diagnoses of chronic pulmonary disease (OR 1.41 95% CI 1.22-1.63), obesity (OR 2.20 95% CI 1.90-2.54), and positive smoking history (OR 1.33 95% CI 1.15-1.54) were associated with increased risk of surgical readmission. Elderly patients undergoing lumbar spine fusion experience 30-day, 90-day, and 1-year readmission rates of 2.9, 5.3, and 12.5% for both medical and surgical reasons. Surgical site infection and wound complications are the most common surgery-related reasons for readmission. Medical diagnoses are more predominant during later readmissions, highlighting the comorbidity burden present in elderly patients. 4.


Current care for victims of sexual violence and future sexual assault care centres in Belgium: the perspective of victims.
Sexual violence is a global health problem. After ratifying the Convention of Istanbul in 2016, this Belgian study was set up to map the perspective of victims of rape on the current sexual violence care provision in Belgium and to inquire on their need for more specialised and holistic care in future Sexual Assault Care Centres. Sixteen rape victims participated in this sub-study. A mixed-method design (questionnaire, in-depth interview or small focus group) was applied depending on the time elapsed between rape and participation. Descriptive Thematic Framework Analysis was performed in duo. The participants thought it of utmost importance that every victim should receive all medical, psychological and forensic care without necessarily having to involve the police first. They stated that the current Belgian sexual violence care provision could be much more patient-centred, specifically the forensic examination and psychological care. Alongside medical and psychological consequences, victims emphasised the high personal financial and relational burden of sexual violence. The holistic care offered in Sexual Assault Care Centres was perceived to enhance the recovery process of victims of sexual violence. Their doors should be open to all victims and their relatives. They should not only provide acute care for the victim, but also improve victims' reintegration into society while reducing their personal costs significantly. All care for victims of sexual violence, especially forensic and psychological care, needs drastic improvement in Belgium. All participants agreed that having specialised, multidisciplinary and longitudinal care in a Sexual Assault Care Centre that would be open 24/7 for everyone, victims and their significant others, would be an improvement to the currently available care all over Belgium. This research was registered on April 1st 2016. Registration number B670201628242.


Translocation of oxysterol binding protein to Golgi apparatus triggered by ligand binding.
A cDNA encoding a cytoplasmic oxysterol binding protein was expressed at high levels by transfection in animal cells. This protein binds oxysterols such as 25-hydroxycholesterol that regulate sterol metabolism by transcriptional and posttranscriptional effects. In the transfected cells, some of the oxysterol binding protein (OSBP) was distributed diffusely in the cytoplasm, and some was bound to small vesicles near the nucleus, as revealed by indirect immunofluorescence. Upon addition of 25-hydroxycholesterol, most of the OSBP became concentrated in large perinuclear structures that stained with lentil lectin, a protein that stains the Golgi apparatus. The structures that contained OSBP were disrupted by brefeldin A, confirming their identification as Golgi. A mutant OSBP lacking the COOH-terminal oxysterol binding domain localized to the Golgi spontaneously, suggesting that this domain normally occludes the domain that binds to the Golgi and that sterols relieve this occlusion. The previously noted potential leucine zipper sequence in OSBP was not required for Golgi localization, nor was it essential for homodimer formation. We conclude that OSBP is triggered to bind extrinsically to Golgi membranes when it binds oxysterols and speculate that this translocation may play a role in the transport, metabolism, or regulatory actions of oxysterols.


Motor improvement and corticospinal modulation induced by hybrid assistive neuromuscular dynamic stimulation (HANDS) therapy in patients with chronic stroke.
We devised a therapeutic approach to facilitate the use of the hemiparetic upper extremity (UE) in daily life by combining integrated volitional control electrical stimulation with a wrist splint, called hybrid assistive neuromuscular dynamic stimulation (HANDS). Twenty patients with chronic hemiparetic stroke (median 17.5 months) had moderate to severe UE weakness. Before and immediately after completing 3 weeks of training in 40-minute sessions, 5 days per week over 3 weeks and wearing the system for 8 hours each day, clinical measures of motor impairment, spasticity, and UE functional scores, as well as neurophysiological measures including electromyography activity, reciprocal inhibition, and intracortical inhibition were assessed. A follow-up clinical assessment was performed 3 months later. UE motor function, spasticity, and functional scores improved after the intervention. Neurophysiologically, the intervention induced restoration of presynaptic and long loop inhibitory connections as well as disynaptic reciprocal inhibition. Paired pulse transcranial magnetic stimulation study indicated disinhibition of the short intracortical inhibition in the affected hemisphere. The follow-up assessment showed that improved UE functions were maintained at 3 months. The combination of hand splint and volitional and electrically induced muscle contraction can induce corticospinal plasticity and may offer a promising option for the management of the paretic UE in patients with stroke. A larger sample size with randomized controls is needed to demonstrate effectiveness.


Role of melatonin combined with exercise as a switch-like regulator for circadian behavior in advanced osteoarthritic knee.
Here, we show the role of melatonin combined with or without exercise as a determinant of multicellular behavior in osteoarthritis. We address the relationship between the molecular components governing local circadian clock and changes in the osteoarthritic musculoskeletal axis. Melatonin was injected subcutaneously in animals with advanced knee osteoarthritis (OA) for 4 weeks. Concurrently, moderate treadmill exercise was applied for 30 min/day. Morphometric, histological, and gene/protein-level analyses were performed in the cartilage, synovium, bone, and gastrocnemius muscle. Primary cultured chondrocytes repeatedly exposed to TNF-α were used in an in vitro study. The symptoms of OA include gait disturbance, osteophyte formation, and abnormal metabolism of the extracellular matrix (ECM) of the cartilage. Low-level expression of clock genes was accompanied by aberrant changes in cartilage specimens. Nanomolar doses of melatonin restored the expression of clock-controlled genes and corrected the abnormal chondrocyte phenotype. Melatonin combined with or without exercise prevented periarticular muscle damage as well as cartilage degeneration. But prolonged melatonin administration promoted the proteolytic cleavage of RANKL protein in the synovium, leading to severe subchondral bone erosion. These musculoskeletal changes apparently occurred via the regulation of molecular clock components, suggesting a role of melatonin as a switch-like regulator for the OA phenotype.


In Vitro Effectiveness of Meropenem and Cefmetazole Combination Treatment Against KPC-2-Producing Enterobacteriaceae.
Purpose: Optimal treatment regimens are yet to be established for carbapenemase-producing Enterobacteriaceae (CPE). We assessed the in vitro efficacy of meropenem (MEM) and cefmetazole (CMZ) combination treatment against blaKPC-2-positive Enterobacteriaceae, in comparison with that of double-carbapenem therapy using ertapenem (ERT). Materials and Methods: We performed checkerboard assay for 10 blaKPC-2-positive clinical isolates and Klebsiella pneumoniae BAA-1705 (possessing blaKPC-2), with synergistic effect being defined by a fractional inhibitory concentration index of ≤0.5. Subsequently, we conducted time-kill assays using K. pneumoniae BAA-1705 with an initial inoculum of 104-107 colony forming unit (CFU)/mL. Bactericidal effect was defined as the reduction of initial bacterial count by ≥103 CFU/mL in 24 hr. Finally, we applied scanning electron microscopy to observe morphological changes induced by the combination of MEM and CMZ. Results: Checkerboard assays revealed a synergistic effect in 7 out of 11 blaKPC-2 -positive Enterobacteriaceae when the MEM and CMZ combination was used, and no effect when the MEM and ERT combination was used. The minimum inhibitory concentration of MEM decreased 4-8-fold when combined with CMZ. Time-kill assays with an initial inoculum of 5 × 105 CFU/mL revealed regrowth under the combination of MEM and ERT (0.25 × minimum inhibitory concentration [MIC] each), whereas the combination of 0.25 × MIC each of MEM and CMZ exhibited bactericidal effect. Scanning electron microscopy results demonstrated that the combination of 0.5 × MIC MEM and 0.5 × MIC CMZ facilitated bacterial cell lysis compared with each antibiotic alone. Conclusion: The combination therapy using MEM and CMZ potentially has bactericidal effect against KPC-producing Enterobacteriaceae.


Percutaneous electrical neurostimulation of dermatome T6 for appetite reduction and weight loss in morbidly obese patients.
A continuous feeling of hunger is the major cause of dietary treatment failure in obese patients, making dietary leave. The aim of this study was to evaluate the effect of percutaneous electrical neurostimulation (PENS) of T6 dermatome on appetite, weight loss and dietary compliance. A prospective, randomized study was performed. The patients were randomized into two groups: those undergoing PENS of dermatome T6 associated with the implementation of a 1,200-Kcal diet (group 1) and those following only a 1,200-Kcal diet (group 2). A third group of obese patients (BMI > 30 Kg/m(2)) with fecal incontinence undergoing PENS of posterior tibial nerve was evaluated. One hundred five patients were included in the study, 45 in groups 1 and 2, and 15 in group 3. The median pain perception after PENS of dermatome T6 was 1. There were no complications. Only the patients in group 1 experienced significant reductions of weight, BMI, and appetite. All of the patients in group 1 experienced appetite reduction compared to 20 % of the patients in group 2 and 30 % of the patients in group 3 (p < 0.001). Weight loss ≥5 Kg was achieved in 76.7 % of the patients in group 1, 6.7 % of the patients in group 2, and 0 % of the patients in group 3 (p < 0.001). Dietary compliance after 12 weeks was 93.3 % in group 1, 56.7 % in group 2, and 50 % in group 3(p = 0.006). PENS of dermatome T6 was associated with appetite reduction in all of the patients and, along with a proper diet, achieved a significantly greater weight reduction than diet alone.


Multisensory interactions within human primary cortices revealed by BOLD dynamics.
Whether signals from different sensory modalities converge and interact within primary cortices in humans is unresolved, despite emerging evidence in animals. This is partially because of debates concerning the appropriate analyses of functional magnetic resonance imaging (fMRI) data in response to multisensory phenomena. Using event-related fMRI, we observed that simple auditory stimuli (noise bursts) activated primary visual cortices and that simple visual stimuli (checkerboards) activated primary auditory cortices, indicative of multisensory convergence. Moreover, analyses of blood oxygen level-dependent response dynamics revealed facilitation of hemodynamic response peak latencies and slopes for multisensory auditory-visual stimuli versus either unisensory condition, indicative of multisensory interactions within primary sensory cortices. Neural processing at the lowest cortical levels can be modulated by interactions between the senses. Temporal information in fMRI data can reveal these modulations and overcome analytic and interpretational challenges of more traditional procedures. In addition to providing an essential translational link with animal models, these results suggest that longstanding notions of cortical organization need to be revised to include multisensory interactions as an inherent component of functional brain organization.


Changes in white matter fiber density and morphology across the adult lifespan: A cross-sectional fixel-based analysis.
White matter (WM) fiber bundles change dynamically with age. These changes could be driven by alterations in axonal diameter, axonal density, and myelin content. In this study, we applied a novel fixel-based analysis (FBA) framework to examine these changes throughout the adult lifespan. Using diffusion-weighted images from a cohort of 293 healthy volunteers (89 males/204 females) from ages 21 to 86 years old, we performed FBA to analyze age-related changes in microscopic fiber density (FD) and macroscopic fiber morphology (fiber cross section [FC]). Our results showed significant and widespread age-related alterations in FD and FC across the whole brain. Interestingly, some fiber bundles such as the anterior thalamic radiation, corpus callosum, and superior longitudinal fasciculus only showed significant negative relationship with age in FD values, but not in FC. On the other hand, some segments of the cerebello-thalamo-cortical pathway only showed significant negative relationship with age in FC, but not in FD. Analysis at the tract-level also showed that major fiber tract groups predominantly distributed in the frontal lobe (cingulum, forceps minor) exhibited greater vulnerability to the aging process than the others. Differences in FC and the combined measure of FD and cross section values observed between sexes were mostly driven by differences in brain sizes although male participants tended to exhibit steeper negative linear relationship with age in FD as compared to female participants. Overall, these findings provide further insights into the structural changes the brain's WM undergoes due to the aging process.


Distribution and Biocontrol Potential of phlD(+) Pseudomonads in Corn and Soybean Fields.
ABSTRACT The abundance and diversity of phlD(+) Pseudomonas spp. colonizing the rhizospheres of young, field-grown corn and soybean plants were assayed over a 3-year period. Populations of these bacteria were detected on the large majority of plants sampled in the state of Ohio, but colonization was greater on corn. Although significant variation in the incidence of rhizosphere colonization was observed from site to site and year to year on both crops, the magnitude of the variation was greatest for soybean. The D genotype was detected on plants collected from all 15 counties examined, and it represented the most abundant subpopulation on both crops. Additionally, six other genotypes (A, C, F, I, R, and S) were found to predominate in the rhizosphere of some plants. The most frequently observed of these were the A genotype and a newly discovered S genotype, both of which were found on corn and soybean roots obtained from multiple locations. Multiple isolates of the most abundant genotypes were recovered and characterized. The S genotype was found to be phylogenetically and phenotypically similar to the D genotype. In addition, the novel R genotype was found to be most similar to the A genotype. All of the isolates displayed significant capacities to inhibit the growth of an oomycete pathogen in vitro, but such phenotypes were highly dependent on media used. When tested against multiple oomycete pathogens isolated from soybean, the A genotype was significantly more inhibitory than the D genotype when incubated on 1/10x tryptic soy agar and 1/5x corn meal agar. Seed inoculation with different isolates of the A, D, and S genotypes indicated that significant root colonization, generally in excess of log 5 cells per gram of root, could be attained on both crops. Field trials of the A genotype isolate Wayne1R indicated the capacity of inoculant populations to supplement the activities of native populations so as to increase soybean stands and yields. The relevance of these findings to natural and augmentative biocontrol of root pathogens by these bacteria is discussed.


United States anesthesiologists over 50: retirement decision making and workforce implications.
Anesthesiology is among the medical specialties expected to have physician shortage. With little known about older anesthesiologists' work effort and retirement decision making, the American Society of Anesthesiologists participated in a 2006 national survey of physicians aged 50-79 yr. Samples of anesthesiologists and other specialists completed a survey of work activities, professional satisfaction, self-defined health and financial status, retirement plans and perspectives, and demographics. A complex survey design enabled adjustments for sampling and response-rate biases so that respondents' characteristics resembled those in the American Medical Association Physician Masterfile. Retirement decision making was modeled with multivariable ordinal logistic regression. Life-table analysis provided a forecast of likely clinical workforce trends over an ensuing 30 yr. Anesthesiologists (N = 3,222; response rate = 37%) reported a mean work week of 49.4 h and a mean retirement age of 62.7 yr, both values similar to those of other older physicians. Work week decreased with age, and part-time work increased. Women worked a shorter work week (mean, 47.9 vs. 49.7 h, P = 0.024), partly due to greater part-time work (20.2 vs. 13.1%, P value less than 0.001). Relative importance of factors reported among those leaving patient care differed by age cohort, subspecialty, and work status. Poor health was cited by 64% of anesthesiologists retiring in their 50s as compared with 43% of those retiring later (P = 0.039). This survey lends support for greater attention to potentially modifiable factors, such as workplace wellness and professional satisfaction, to prevent premature retirement. The growing trend in part-time work deserves further study.


Time-dependent depletion of nitrite in pork/beef and chicken meat products and its effect on nitrite intake estimation.
The food additive nitrite (E249, E250) is commonly used in meat curing as a food preservation method. Because of potential negative health effects of nitrite, its use is strictly regulated. In an earlier study we have shown that the calculated intake of nitrite in children can exceed the acceptable daily intake (ADI) when conversion from dietary nitrate to nitrite is included. This study examined time-dependent changes in nitrite levels in four Swedish meat products frequently eaten by children: pork/beef sausage, liver paté and two types of chicken sausage, and how the production process, storage and also boiling (e.g., simmering in salted water) and frying affect the initial added nitrite level. The results showed a steep decrease in nitrite level between the point of addition to the product and the first sampling of the product 24 h later. After this time, residual nitrite levels continued to decrease, but much more slowly, until the recommended use-by date. Interestingly, this continuing decrease in nitrite was much smaller in the chicken products than in the pork/beef products. In a pilot study on pork/beef sausage, we found no effects of boiling on residual nitrite levels, but frying decreased nitrite levels by 50%. In scenarios of time-dependent depletion of nitrite using the data obtained for sausages to represent all cured meat products and including conversion from dietary nitrate, calculated nitrite intake in 4-year-old children generally exceeded the ADI. Moreover, the actual intake of nitrite from cured meat is dependent on the type of meat source, with a higher residual nitrite levels in chicken products compared with pork/beef products. This may result in increased nitrite exposure among consumers shifting their consumption pattern of processed meats from red to white meat products.


Search for techniparticles in e+jets events at D0.
We search for the technicolor process pp-->rhoT/omegaT-->WpiT in events containing one electron and two jets, in data corresponding to an integrated luminosity of 390 pb(-1), recorded by the D0 experiment at the Fermilab Tevatron. Technicolor predicts that technipions pi(T) decay dominantly into bb, bc, or bc, depending on their charge. In these events b and c quarks are identified by their secondary decay vertices within jets. Two analysis methods based on topological variables are presented. Since no excess above the standard model prediction was found, the result is presented as an exclusion in the pi(T) vs rho(T) mass plane for a given set of model parameters.


Remembrances of times East: absolute spatial representations of time in an Australian aboriginal community.
How do people think about time? Here we describe representations of time in Pormpuraaw, a remote Australian Aboriginal community. Pormpuraawans' representations of time differ strikingly from all others documented to date. Previously, people have been shown to represent time spatially from left to right or right to left, or from front to back or back to front. All of these representations are with respect to the body. Pormpuraawans instead arrange time according to cardinal directions: east to west. That is, time flows from left to right when one is facing south, from right to left when one is facing north, toward the body when one is facing east, and away from the body when one is facing west. These findings reveal a qualitatively different set of representations of time, with time organized in a coordinate frame that is independent from others reported previously. The results demonstrate that conceptions of even such fundamental domains as time can differ dramatically across cultures.


Faithful SGCE imprinting in iPSC-derived cortical neurons: an endogenous cellular model of myoclonus-dystonia.
In neuropathology research, induced pluripotent stem cell (iPSC)-derived neurons are considered a tool closely resembling the patient brain. Albeit in respect to epigenetics, this concept has been challenged. We generated iPSC-derived cortical neurons from myoclonus-dystonia patients with mutations (W100G and R102X) in the maternally imprinted ε-sarcoglycan (SGCE) gene and analysed properties such as imprinting, mRNA and protein expression. Comparison of the promoter during reprogramming and differentiation showed tissue-independent differential methylation. DNA sequencing with methylation-specific primers and cDNA analysis in patient neurons indicated selective expression of the mutated paternal SGCE allele. While fibroblasts only expressed the ubiquitous mRNA isoform, brain-specific SGCE mRNA and ε-sarcoglycan protein were detected in iPSC-derived control neurons. However, neuronal protein levels were reduced in both mutants. Our phenotypic characterization highlights the suitability of iPSC-derived cortical neurons with SGCE mutations for myoclonus-dystonia research and, in more general terms, prompts the use of iPSC-derived cellular models to study epigenetic mechanisms impacting on health and disease.


Hyperphosphatemia induces protective autophagy in endothelial cells through the inhibition of Akt/mTOR signaling.
Hyperphosphatemia-induced endothelial dysfunction has been shown to play a pathogenic role in the development of atherosclerosis in chronic kidney disease (CKD) through unclear mechanisms. Emerging evidence indicates that autophagy is involved in the maintenance of normal cardiovascular function. However, it is unclear whether autophagy participates in the molecular mechanism underlying high phosphate (Pi)-induced endothelial dysfunction. The autophagy activity was determined by the immunofluorescence staining of the expression of endothelial microtubule-associated protein 1 light chain 3 (LC3) in the 5/6 nephrectomy rat model of CKD and sham-operated control rats. The LC3-II/LC3-I ratio and the activation of the Akt/mammalian target of rapamycin (mTOR) signaling pathway were determined in cultured human microvascular endothelial cell (HMEC-1) endothelial cells that were exposed to a high concentration of Pi with or without the Pi influx blocker phosphonoformic acid, the autophagy inhibitor 3-methyladenine, and the autophagy inducer rapamycin. The impacts of autophagy on Pi-induced apoptotic damage were assessed by flow cytometry. The in vivo rat model of CKD revealed that hyperphosphatemia is associated with increased endothelial LC3 staining. The exposure of HMEC-1 cells to high Pi induced both dose-dependent and time-dependent increases in the LC3-II/LC3-I expression ratio accompanied by the inhibition of the Akt/mTOR signaling pathway. In HMEC-1 cells, high Pi-induced autophagy and the inhibition of Akt/mTOR signaling were reversed by phosphonoformic acid through the blockage of Pi influx. Apoptosis, characterized by the levels of cleaved caspase 3 and poly(ADP-ribose) polymerase, along with autophagy was induced by high Pi, and the inhibition of autophagy by 3-methyladenine significantly aggravated high Pi-induced apoptosis. The flow cytometry results confirmed that the blockage of autophagy promoted the apoptosis of endothelial cells. Hyperphosphatemia induces endothelial autophagy, possibly through the inhibition of the Akt/mTOR signaling pathway, which may play a protective role against high Pi-induced apoptosis.


Rev-erb-alpha: an integrator of circadian rhythms and metabolism.
The endogenous circadian clock ensures daily rhythms in diverse behavioral and physiological processes, including locomotor activity and sleep/wake cycles, but also food intake patterns. Circadian rhythms are generated by an internal clock system, which synchronizes these daily variations to the day/night alternance. In addition, circadian oscillations may be reset by the time of food availability in peripheral metabolic organs. Circadian rhythms are seen in many metabolic pathways (glucose and lipid metabolism, etc.) and endocrine secretions (insulin, etc.). As a consequence, misalignment of the internal timing system vs. environmental zeitgebers (light, for instance), as experienced during jetlag or shift work, may result in disruption of physiological cycles of fuel utilization or energy storage. A large body of evidence from both human and animal studies now points to a relationship between circadian disorders and altered metabolic response, suggesting that circadian and metabolic regulatory networks are tightly connected. After a review of the current understanding of the molecular circadian core clock, we will discuss the hypothesis that clock genes themselves link the core molecular clock and metabolic regulatory networks. We propose that the nuclear receptor and core clock component Rev-erb-alpha behaves as a gatekeeper to timely coordinate the circadian metabolic response.


Participatory research with a rural Aboriginal Community Controlled Health Organisation: lessons learned using the CONSIDER statement.
In Australia, Aboriginal Community Controlled Health Organisations (ACCHOs) are geographically proximal to where Aboriginal and Torres Strait Islander People reside and are valued for providing holistic and culturally safe primary health care. Partnering with ACCHOs in research is appropriate for redressing health inequities experienced by Aboriginal and Torres Strait Islander People, which includes a high burden of chronic disease. Historically, some approaches to Aboriginal and Torres Strait Islander health research have been unethical. Greater accountability in the research process, transparency in reporting, and use of culturally appropriate research methodologies are key recommendations to improving the ethical integrity of research. The need for strengthening the reporting of health research involving Aboriginal and Torres Strait Islander People and Indigenous peoples globally led to the development of the CONSolIDated critERia for strengthening the reporting of health research involving Indigenous peoples (CONSIDER statement), which is a synthesis of international ethical guidelines. This project report uses the CONSIDER statement to critically reflect on participatory research undertaken in partnership with an ACCHO in the rural context and to identify lessons of value for future research. By using the CONSIDER statement as a tool for critical reflection, it was identified that processes used to establish a research partnership with an ACCHO were key to setting the research agenda, including identifying ethical issues, the needs of local Aboriginal and Torres Strait Islander People, and expectations from the research. The participation of Aboriginal community members throughout the entire research process was not only methodologically important but was also ethically appropriate. Research activities in this project included opportunities for Aboriginal community members to directly share their perspectives and experiences and develop local solutions to issues affecting them. Outcomes included evidence to support future funding applications, community-derived priorities that assisted with government reporting, and locally identified methods for addressing chronic disease management. Key to this was building the research capacity and capability of local Aboriginal community members, which also reflected the ethical principles of reciprocity and equity. This also provided opportunities for non-Indigenous researchers to learn from local Aboriginal community members and develop skills in culturally appropriate research. Using the CONSIDER statement was beneficial in enabling researchers to critically reflect on a participatory research project undertaken in partnership with a rural ACCHO. Researchers identified that participatory approaches can be used to generate research of relevance to local Aboriginal community members and their ACCHOs, and to support health service reporting, and future funding applications. Research timelines and activities needed to be flexible and adaptable, to allow for staff turnover and unforeseen events of cultural significance. Similarly, it is important for researchers to be receptive to change and open to learning. Although research partnerships are established on trust and mutual respect, it is recommended that greater formal provisions are required to protect the intellectual property of Aboriginal and Torres Strait Islander communities involved in research. These lessons are likely to be transferrable to other settings and are of value to researchers seeking to partner with ACCHOs in research.


Atherosclerosis and myocardial bridging: Not a benign combination. An autopsy case report.
Myocardial bridging is a congenital coronary anomaly with a variety of clinical manifestations. Traditionally, myocardial bridging has been considered a benign condition, but some cases of myocardial ischemia, infarction and sudden cardiac death due to myocardial bridging have been reported. Various studies have suggested that in their intramyocardial segments, these vessels are protected from obstructive atherosclerosis, with atherosclerosis being present in the proximal part of the artery. We report a case in a 45-year-old male who had a 2.5-cm long myocardial bridging over the left anterior descending artery, with obstructive atherosclerosis being present in the proximal as well as the intramyocardial part (part of the artery below the myocardial bridge). Atherosclerosis occurring in the intramyocardial segment is a rare occurrence, and combined with systolic narrowing by the myocardial bridge can lead to ischemia of the cardiac musculature.


Effect of acidotic blood reperfusion on reperfusion injury after coronary artery occlusion in the dog heart.
A prolongation of the intracellular acidosis after myocardial ischemia can protect the myocardium against reperfusion injury. In isolated hearts, this was achieved by prolongation of the extracellular acidosis. The aim of this study was to investigate whether regional reperfusion with acidotic blood after coronary artery occlusion can reduce infarct size and improve myocardial function in vivo. Anesthetized open-chest dogs were instrumented for measurement of regional myocardial function, assessed by sonomicrometry as systolic wall thickening (sWT). Infarct size was determined by triphenyltetrazolium staining after 3 h of reperfusion. The left anterior descending coronary artery (LAD) was perfused through a bypass from the left carotid artery. The animals underwent 1 h of LAD occlusion and subsequent bypass-reperfusion with normal blood (control, n = 6) or blood equilibrated to pH = 6.8 by using 0.1 mM HCl during the first 30 min of reperfusion (HCl, n = 5). Regional collateral blood flow (RCBF) at 30-min occlusion was measured by using colored microspheres. There was no difference in recovery of sWT in the LAD-perfused area between the two groups at the end of the experiments [-2.8+/-1.2% (HCl) vs. -4.4+/-2.5% (control); mean +/- SEM; p = NS]. RCBF was comparable in both groups. Infarct size (percentage of area at risk) was reduced in the treatment group (12.8+/-2.8%) compared with the control group (26.2+/-4.8%; p < 0.05). These results indicate that reperfusion injury after coronary artery occlusion can be reduced by a prolonged local extracellular acidosis in vivo.


Conversion of deoxynivalenol to 3-acetyldeoxynivalenol in barley-derived fuel ethanol co-products with yeast expressing trichothecene 3-O-acetyltransferases.
The trichothecene mycotoxin deoxynivalenol (DON) may be concentrated in distillers dried grains with solubles (DDGS; a co-product of fuel ethanol fermentation) when grain containing DON is used to produce fuel ethanol. Even low levels of DON (≤ 5 ppm) in DDGS sold as feed pose a significant threat to the health of monogastric animals. New and improved strategies to reduce DON in DDGS need to be developed and implemented to address this problem. Enzymes known as trichothecene 3-O-acetyltransferases convert DON to 3-acetyldeoxynivalenol (3ADON), and may reduce its toxicity in plants and animals. Two Fusarium trichothecene 3-O-acetyltransferases (FgTRI101 and FfTRI201) were cloned and expressed in yeast (Saccharomyces cerevisiae) during a series of small-scale ethanol fermentations using barley (Hordeum vulgare). DON was concentrated 1.6 to 8.2 times in DDGS compared with the starting ground grain. During the fermentation process, FgTRI101 converted 9.2% to 55.3% of the DON to 3ADON, resulting in DDGS with reductions in DON and increases in 3ADON in the Virginia winter barley cultivars Eve, Thoroughbred and Price, and the experimental line VA06H-25. Analysis of barley mashes prepared from the barley line VA04B-125 showed that yeast expressing FfTRI201 were more effective at acetylating DON than those expressing FgTRI101; DON conversion for FfTRI201 ranged from 26.1% to 28.3%, whereas DON conversion for FgTRI101 ranged from 18.3% to 21.8% in VA04B-125 mashes. Ethanol yields were highest with the industrial yeast strain Ethanol Red®, which also consumed galactose when present in the mash. This study demonstrates the potential of using yeast expressing a trichothecene 3-O-acetyltransferase to modify DON during commercial fuel ethanol fermentation.


Physician communication and physical activity among Latinas.
Research suggests that individuals who talk with their physicians about lifestyle behaviors are more physically active. Research on this topic is limited in the U.S. Latino population. This study examines doctor-patient communication from the perspective of enrollees in a physical activity (PA) intervention. Three hundred and eighty-seven Latinos were surveyed at program enrollment. Analysis examined the extent to which physician communication about healthy lifestyles and weight was associated with self-reported PA, including leisure-time PA (LTPA), transportation PA (TPA), and occupational PA (OPA). Physician communication included asking, advising, and assisting. Most of the respondents reported no LTPA (46%) and no TPA (60%). The percent reporting no occupational activity, which included housework if a homemaker, was lower at 36%. Greater physician assistance was associated with a greater likelihood of doing any LTPA (P ≤ .05). A similar trend was observed for TPA (P ≤ .10). Latinos who reported physician assistance to engage in healthy lifestyle behaviors reported more LTPA. Providers who assist their patients in obtaining resources to support PA have the potential to increase levels of PA.


Osteoporosis in celiac disease and in endocrine and reproductive disorders.
As the increase in lifespan brings to light diseases that were previously not clinically detectable, osteoporosis has become an issue of worldwide significance. The disease is marked by a loss of bone mass; the bones become less dense, fragile and more prone to fracturing. Because it is regulated by endocrine and environmental factors, osteoporosis presents a multifactorial etiopathogenesis, with the genetic component accounting for 70% of an individual variation in bone mass density (BMD), the principal determinant, with age, of fracture risk. Pathological conditions such as celiac disease (CD) exacerbate the process of bone loss, so that the occurrence of osteoporosis in celiac subjects is of particular note: indeed, the screening of osteoporosis patients for this disease is advisable, since it may be the only sign of undiagnosed CD. An increase in interleukin IL-1beta, of the IL-1 system, in the relatives of celiac patients confirms the genetic predisposition to osteoporosis and its presence is evidence of an association between the two conditions. The direct effect on the bones of CD is secondary to poor absorption of calcium and vitamin D. In women osteoporosis is indirectly associated with early menopause and amenorrhea, and it may follow prolonged breast-feeding and frequent pregnancies, while in men it is associated with hypogonadism and GH deficit. These endocrine and non-endocrine factors exert their effects on bones by modulating the RANK/RANK-L/OPG system. An appropriate lifestyle from adolescence onwards, together with early diagnosis of and treatment for CD and primary and secondary endocrine pathologies are important for the prevention of damage to the bones.


The impact of weakly bound ⁸⁹Zr on preclinical studies: non-specific accumulation in solid tumors and aspergillus infection.
Preclinical studies involving (89)Zr often report significant bone accumulation, which is associated with dissociation of the radiometal from the tracer. However, experiments determining the uptake of unbound (89)Zr in disease models are not performed as routine controls. The purpose of the present study was to investigate the impact of free or weakly bound (89)Zr on PET quantifications in disease models, in order to determine if such control experiments are warranted. Chemical studies were carried out to find a (89)Zr compound that would solubilize the (89)Zr as a weak chelate, thus mimicking free or weakly bound (89)Zr released in circulation. (89)Zr oxalate had the desired characteristics, and was injected into mice bearing FaDu and HT29 solid tumor xenografts, and mice infected in the lungs with the mold Aspergillus fumigatus, as well as in healthy controls (naïve). PET/CT or PET/MR imaging followed to quantify the distribution of the radionuclide in the disease models. (89)Zr oxalate was found to have a plasma half-life of 5.1 ± 2.3 h, accumulating mainly in the bones of all animals. Both tumor types accumulated (89)Zr on the order of 2-4 %ID/cm(3), which is comparable to EPR-mediated accumulation of certain species. In the aspergillosis model, the concentration of (89)Zr in lung tissue of the naïve animals was 6.0 ± 1.1 %ID/g. This was significantly different from that of the animals with advanced disease, showing 11.6 ± 1.8 %ID/g. Given the high levels of (89)Zr accumulation in the disease sites in the present study, we recommend control experiments mapping the biodistribution of free (89)Zr in any preclinical study employing (89)Zr where bone uptake is observed. Aqueous (89)Zr oxalate appears to be a suitable compound for such studies. This is especially relevant in studies where the tracer accumulation is based upon passive targeting, such as EPR.


Human dendritic cell subsets from spleen and blood are similar in phenotype and function but modified by donor health status.
Mouse dendritic cells (DC) have been extensively studied in various tissues, especially spleen, and they comprise subsets with distinct developmental origins, surface phenotypes, and functions. Considerably less is known about human DC due to their rarity in blood and inaccessibility of other human tissues. The study of DC in human blood has revealed four subsets distinct in phenotype and function. In this study, we describe four equivalent DC subsets in human spleen obtained from deceased organ donors. We identify three conventional DC subsets characterized by surface expression of CD1b/c, CD141, and CD16, and one plasmacytoid DC subset characterized by CD304 expression. Human DC subsets in spleen were very similar to those in human blood with respect to surface phenotype, TLR and transcription factor expression, capacity to stimulate T cells, cytokine secretion, and cross-presentation of exogenous Ag. However, organ donor health status, in particular treatment with corticosteroid methylprednisolone and brain death, may affect DC phenotype and function. DC T cell stimulatory capacity was reduced but DC were qualitatively unchanged in methylprednisolone-treated deceased organ donor spleen compared with healthy donor blood. Overall, our findings indicate that human blood DC closely resemble human spleen DC. Furthermore, we confirm parallels between human and mouse DC subsets in phenotype and function, but also identify differences in transcription factor and TLR expression as well as functional properties. In particular, the hallmark functions of mouse CD8α(+) DC subsets, that is, IL-12p70 secretion and cross-presentation, are not confined to the equivalent human CD141(+) DC but are shared by CD1b/c(+) and CD16(+) DC subsets.


Association of virus specific replicative ribonucleic acid with nuclear membrane in chick embryo cells infected with japanese encephalitis virus.
Using high resolution electron microscopic autoradiography and velocity sedimentation, RNA synthesis was examined in chick embryo cells infected with Japanese encephalitis virus (JEV). RNA was labelled with 3H-uridine for 5 min or 10 min at 15 h after infection in the presence of actinomycin D and D-glucosamine. Microautoradiography showed significantly numbers of silver grains on the nuclear membranes of 5 min pulse-labelled thin cell sections. The RNA species in membrane fractions obtained from the nucleus and cytoplasm of the infected cells were analysed by sucrose density gradient sedimentation. Radioactive 23S replicative form RNA and 8-12S RNA were obtained from the outer membrane fractions of the nuclear envelope. Labelled 42S virus RNA was obtained from the fractions containing large vesicle membranes and plasma membranes. These results suggest that JEV-RNA synthesis is initiated in the perinuclear region in close association with the outer membranes of the nuclear envelope.


What influences allied health clinician participation in research in the public hospital setting: a qualitative theory-informed approach.
Using theoretical frameworks from implementation science, we aimed to systematically explore the barriers and enablers to research active allied health professionals (AHP) participating and leading research in the hospital setting. A qualitative interview study informed by behaviour change theory. Single Australian tertiary hospital and health service. We recruited a convenience sample of 21 AHPs working within a hospital who were seeking to actively participate in/or lead research within their workplace. Semistructured interviews explored perceived barriers and enablers to research participation, informed by the 14 domains of the theoretical domains framework (TDF). Transcribed interviews were deductively coded and mapped to the TDF. A deeper level of inductive coding was used to identify emergent themes that influenced behaviour change, according to the three key constructs of: capability, opportunity and motivation (COM-B). Barriers and enablers to research participation were identified within nine predominant domains of the TDF. Most enablers to engaging in research related to the motivation or opportunity constructs of the COM-B. These enablers included positive beliefs about the consequences of research participation, enabling social influences, peer support and motivation for skill development and to inform practice. Predominant barriers related to environmental context and resources (eg, reduced funding or time), emotional responses of being overwhelmed and perceptions of reduced capability. This study identified key barriers and enablers to behaviour change related to AHPs participating and/or leading research. Motivation and opportunities to participate in research may be enabled by maximising social influence opportunities, reiterating beliefs about positive consequences of research and considering AHP's emotional responses. Implementation science frameworks may provide a more systematic and holistic understanding of factors which influence research participation including enhancing knowledge, motivation and opportunity.


Linear-nonlinear-time-warp-poisson models of neural activity.
Prominent models of spike trains assume only one source of variability - stochastic (Poisson) spiking - when stimuli and behavior are fixed. However, spike trains may also reflect variability due to internal processes such as planning. For example, we can plan a movement at one point in time and execute it at some arbitrary later time. Neurons involved in planning may thus share an underlying time course that is not precisely locked to the actual movement. Here we combine the standard Linear-Nonlinear-Poisson (LNP) model with Dynamic Time Warping (DTW) to account for shared temporal variability. When applied to recordings from macaque premotor cortex, we find that time warping considerably improves predictions of neural activity. We suggest that such temporal variability is a widespread phenomenon in the brain which should be modeled.


Comparison of the pharmacology and signal transduction of the human cannabinoid CB1 and CB2 receptors.
The recently cloned CB2 cannabinoid receptor subtype was stably transfected into AtT-20 and Chinese hamster ovary cells to compare the binding and signal transduction properties of this receptor with those of the CB1 receptor subtype. The binding of [3H]CP 55,940 to both CB1 and CB2 was of similar high affinity (2.6 and 3.7 nM, respectively) and saturable. In competitive binding experiments, (-)-delta 9-tetrahydrocannabinol and CP 55,940 were equipotent at the CB1 and CB2 receptors, but WIN 55212-2 and cannabinol bound with higher affinity to the CB2 than the CB1 receptor. HU 210 had a higher affinity for the CB1 receptor. Anandamide, a recently identified endogenous cannabinoid agonist, was essentially equipotent at both receptor subtypes. The structurally related fatty acid ethanolamides dihomo-gamma-linolenylethanolamide and mead ethanolamide also bound with relatively equal affinity to both receptors, but adrenylethanolamide had a higher affinity for the CB1 receptor. The rank order of potency and efficacy for binding of the selected agonists to the CB1 and CB2 receptors was mimicked in functional inhibition of cAMP accumulation experiments for all compounds tested. Both CB1 and CB2 receptors couple to the inhibition of cAMP accumulation that was pertussis toxin sensitive. SR141716A, a CB1 receptor antagonist, was a poor antagonist at the CB2 receptor in both binding and functional inhibition of cAMP accumulation experiments. When expressed in AtT-20 cells, the CB1 receptor mediated an inhibition of Q-type calcium channels and an activation of inward rectifying potassium channels. In contrast, the CB2 receptor did not modulate the activity of either channel under identical assay conditions. Similar to results obtained for CB1 receptor, the CB2 receptor did not couple to the activation of phospholipases A2, C, or D or to the mobilization of intracellular Ca2+. Except for its inability to couple to the modulation of Q-type calcium channels or inwardly rectifying potassium channels, the CB1 and CB2 receptors display similar pharmacological and biochemical properties.


The Effect of Radiation on Complication Rates and Patient Satisfaction in Breast Reconstruction using Temporary Tissue Expanders and Permanent Implants.
The optimal method of reconstruction following mastectomy for breast cancer patients receiving radiation therapy (RT) is controversial. This study evaluated patient satisfaction and complication rates among patients who received implant-based breast reconstruction. The specific treatment algorithm analyzed included patients receiving mastectomy and immediate temporary tissue expander (TE), followed by placement of a permanent breast implant (PI). If indicated, RT was delivered to the fully expanded TE. Records of 218 consecutive patients with 222 invasive (85%) or in situ (15%) breast lesions from the Salt Lake City region treated between 1998 and 2009 were retrospectively reviewed, 28% of whom received RT. Median RT dose was 50.4 Gy, and 41% received a scar boost at a median dose of 10 Gy. Kaplan-Meier analyses were performed to evaluate the cumulative incidence of surgical complications, including permanent PI removal. Risk factors associated with surgical events were analyzed. To evaluate cosmetic results and patient satisfaction, an anonymous survey was administered. Mean follow-up was 44 months (range 6-144). Actuarial 5-year PI removal rates for non-RT and RT patients were 4% and 22%, respectively. On multivariate analysis (MVA), the only factor associated with PI removal was RT (p = 0.009). Surveys were returned describing the outcomes of 149 breasts. For the non-RT and RT groups, those who rated their breast appearance as good or better were 63% versus 62%, respectively. Under 1/3 of each group was dissatisfied with their reconstruction. RT did not significantly affect patient satisfaction scores, but on MVA RT was the only factor associated with increased PI removal. This reconstruction technique may be considered an acceptable option even if RT is needed, but the increased complication risk with RT must be recognized.


High-risk premenopausal women's experiences of undergoing prophylactic oophorectomy: a descriptive study.
Women who are at increased risk of developing ovarian cancer because of their family history may need to make decisions about the medical management of their cancer risk--whether to have ovarian screening or undergo prophylactic surgery. This qualitative study explores the perceived physical and emotional implications of undergoing preventative surgery using data collected during interviews with 23 high-risk premenopausal women who had undergone prophylactic oophorectomy because of their family history of cancer. Despite the fact that all of these women regarded their decision to undergo surgery extremely positively, 20 women also described what they regarded as the costs of undergoing surgery. These included post-operative complications, the onset of menopausal symptoms, side effects of hormone replacement therapy, and negative effects on body image and gender identity. The perceived benefits of surgery were described as risk reduction, enabling one to fulfil family obligations, removing the need for gynecological screening, cessation of menstruation, and positive side effects of hormone replacement therapy. This study suggests there is a need to inform women about potential physical and emotional sequelae of oophorectomy prior to undergoing this procedure.


Sex-dependent effects of chromogranin B P413L allelic variant as disease modifier in amyotrophic lateral sclerosis.
Recent genetic studies yielded conflicting results regarding a role for the variant chromogranin B (CHGB)P413L allele as a disease modifier in ALS. Moreover, potential deleterious effects of the CHGBP413L variant in ALS pathology have not been investigated. Here we report that in transfected cultured cells, the variant CHGBL413 protein exhibited aberrant properties including mislocalization, failure to interact with mutant superoxide dismutase 1 (SOD1) and defective secretion. The CHGBL413 transgene in SOD1G37R mice precipitated disease onset and pathological changes related to misfolded SOD1 specifically in female mice. However, the CHGBL413 variant also slowed down disease progression in SOD1G37R mice, which is in line with a very slow disease progression that we report for a Swedish woman with ALS who is carrier of two mutant SOD1D90A alleles and two variant CHGBP413L and CHGBR458Q alleles. In contrast, overexpression of the common CHGBP413 allele in SOD1G37R mice did not affect disease onset but significantly accelerated disease progression and pathological changes. As in transgenic mice, the CHGBP413L allele conferred an earlier ALS disease onset in women of Japanese and French Canadian origins with less effect in men. Evidence is presented that the sex-dependent effects of CHGBL413 allelic variant in ALS may arise from enhanced neuronal expression of CHGB in females because of a sex-determining region Y element in the gene promoter. Thus, our results suggest that CHGB variants may act as modifiers of onset and progression in some ALS populations and especially in females because of higher expression levels compared to males.


The Role of PGC1α in Cancer Metabolism and its Therapeutic Implications.
PGC1α is a transcription factor coactivator that influences a majority of cellular metabolic pathways. Abnormal expression of PGC1α is associated with several chronic diseases and, in recent years, it has been shown to be a critical controller of cancer development. PGC1α acts as a stress sensor in cancer cells and can be activated by nutrient deprivation, oxidative damage, and chemotherapy. It influences mitochondria respiration, reactive oxygen species defense system, and fatty acid metabolism by interacting with specific transcription factors. The characteristic traits of PGC1α in maintaining metabolic homeostasis promote cancer cell survival and tumor metastasis in harsh microenvironments. Not only does PGC1α act as a coactivator, but is also itself controlled by oncogenes and transcription factors. PGC1α and these molecules can form signaling axes that include PML/PGC1α/PPARα, MITF/PGC1α, and PGC1α/ERRα, which are important in regulating metabolic adaptation in specific cancer types. Some of these PGC1α-associated pathways are inherently activated in cancer cells, and others are induced by stress, which enable cancer cells to acquire resistance against therapy. Notably, certain therapeutic-resistant cancer cells are addicted to PGC1α-dependent metabolic activities. Suppression of PGC1α expression resensitizes these cells to therapeutic treatments, which implicates PGC1α as a promising target in cancer molecular classification and therapy. Mol Cancer Ther; 15(5); 774-82. ©2016 AACR.


Potentiation of CD3-induced expression of the linker for activation of T cells (LAT) by the calcineurin inhibitors cyclosporin A and FK506.
The activation of blood cells, including T cells, triggers intracellular signals that control the expression of critical molecules, including cytokines and cytokine receptors. We show that T-cell receptor (TCR) ligation increases the cellular level of the protein linker for activation of T cells (LAT), a molecule critical for T-cell development and function. T-cell activation increased LAT messenger RNA, as determined by reverse transcription-polymerase chain reaction and by Northern blotting. The TCR-induced increase in LAT expression involved the activation of the serine/threonine kinases PKC and MEK, because inhibitors of these kinases blocked the increase in LAT. Accordingly, the PKC activator phorbol myristate acetate up-regulated LAT expression. Strikingly, the calcineurin inhibitors cyclosporin A (CsA) and FK506 strongly potentiated TCR-induced LAT expression, suggesting that the activation of calcineurin following TCR ligation negatively regulates LAT expression. Accordingly, Ca(++ )ionophores, which can activate calcineurin by increasing intracellular Ca(++), blocked the TCR-induced increase in cellular LAT. CsA and FK506 blocked the Ca(++ )ionophores' inhibitory effect on LAT expression. Notably, CsA and FK506 preferentially up-regulated TCR-induced LAT expression; under the same conditions, these compounds did not increase the expression of 14 other molecules that previously had been implicated in T-cell activation. These data show that TCR-induced LAT expression involves the activation of the PKC-Erk pathway and is negatively regulated by the activation of calcineurin. Furthermore, the potentiation of TCR-induced LAT expression by CsA and FK506 suggests that the action of these agents involves up-regulating the cellular level of critical signaling molecules. These findings may have important therapeutic implications. (Blood. 2000;95:2733-2741)


ChIP-seq defined genome-wide map of TGFβ/SMAD4 targets: implications with clinical outcome of ovarian cancer.
Deregulation of the transforming growth factor-β (TGFβ) signaling pathway in epithelial ovarian cancer has been reported, but the precise mechanism underlying disrupted TGFβ signaling in the disease remains unclear. We performed chromatin immunoprecipitation followed by sequencing (ChIP-seq) to investigate genome-wide screening of TGFβ-induced SMAD4 binding in epithelial ovarian cancer. Following TGFβ stimulation of the A2780 epithelial ovarian cancer cell line, we identified 2,362 SMAD4 binding loci and 318 differentially expressed SMAD4 target genes. Comprehensive examination of SMAD4-bound loci, revealed four distinct binding patterns: 1) Basal; 2) Shift; 3) Stimulated Only; 4) Unstimulated Only. TGFβ stimulated SMAD4-bound loci were primarily classified as either Stimulated only (74%) or Shift (25%), indicating that TGFβ-stimulation alters SMAD4 binding patterns in epithelial ovarian cancer cells. Furthermore, based on gene regulatory network analysis, we determined that the TGFβ-induced, SMAD4-dependent regulatory network was strikingly different in ovarian cancer compared to normal cells. Importantly, the TGFβ/SMAD4 target genes identified in the A2780 epithelial ovarian cancer cell line were predictive of patient survival, based on in silico mining of publically available patient data bases. In conclusion, our data highlight the utility of next generation sequencing technology to identify genome-wide SMAD4 target genes in epithelial ovarian cancer and link aberrant TGFβ/SMAD signaling to ovarian tumorigenesis. Furthermore, the identified SMAD4 binding loci, combined with gene expression profiling and in silico data mining of patient cohorts, may provide a powerful approach to determine potential gene signatures with biological and future translational research in ovarian and other cancers.


Clinically silent infections in patients with oligoarthritis: results of a prospective study.
Oligoarticular synovitis of undetermined origin can closely resemble an incomplete form of reactive arthritis/Reiter's syndrome. Eighty three patients with oligoarthritis of undetermined origin were studied prospectively to identify asymptomatic infections potentially triggering the inflammatory response in the synovial fluid. At the time of initial evaluation, 57 (69%) of the patients with oligoarthritis and 4/20 (20%) of the control subjects were carriers of clinically silent infections. Evidence for persistent or prior chlamydial infections was frequently and exclusively found in the study group (30/83 (36%) patients v no controls), whereas undetected urogenital infections with mycoplasma were present in nine (11%) patients and four (20%) controls. Eleven (13%) of the patients carried cellular and humoral responses to Borrelia burgdorferi. The HLA-B27 haplotype represented a major risk factor for the development of oligoarthritis but not for development of sacroiliitis. Re-evaluation after one year showed that the course and outcome of the oligoarticular disease did not correlate with a specific infectious organism and were not affected by antibiotic treatment sufficient to treat the carrier state.


The fastest animals and vehicles are neither the biggest nor the fastest over lifetime.
Here we show how the size of a body affects its maximum average speed of movement through its environment. The theoretical challenge was to predict that 'outliers' must exist, such as the cheetah for terrestrial animals and the jet fighter for airplanes. We show that during a travel that starts from rest and continues at cruising speed, the body size for minimum travel time, or maximum average speed, is not the biggest. The results are compared with extensive data for military aircraft for chase, attack and reconnaissance, in addition to data for commercial aircraft. The paper also explains why in earlier studies of flying (animals, airplanes) the airplane data deviated upward (toward greater speeds) relative to the theoretical trend followed by flying animals, and why the fastest animal flyers are one thousand times smaller than the fastest swimmers. Unlike the biggest animals and airplanes (elephant, whale, commercial jet), which move constantly, the fastest animals and airplanes spend most of their lives at rest. When judged for speed averaged over lifetime, the fastest 'sprinters' are in fact the slowest movers (as in Aesop's fable 'The Tortoise and the Hare').


Soft chemistry of ion-exchangeable layered metal oxides.
Soft chemical reactions such as ion-exchange and acid-base reactions have been extensively investigated to synthesize novel metastable layered inorganic solids, to exfoliate them into individual nanosheets, and to re-assemble them as thin films and nanocomposite materials. These reactions proceed at relatively low temperature and enable the synthesis of a rich variety of structures by stepwise reactions. In recent years, the toolbox of soft chemical reactions has been utilized to rationally design and tailor the properties of functional layered transition metal oxides. Layer-by-layer assembly and intercalation chemistry have provided insight into covalent interactions that stabilize oxide-supported nanoparticle catalysts. In addition, topochemical reactions have been utilized to tune the compositions of layered perovskite oxides in order to break inversion symmetry, resulting in piezoelectric and ferroelectric properties. This review focuses on the use of soft chemical approaches to design functional layered transition metal oxides with tunable properties. Soft chemical reactions enable the design of functional materials for diverse applications that include artificial photosynthesis, catalysis, energy storage, fuel cells, optical sensors, ferroics, and high-k dielectrics.


A new functional CYP3A4 intron 6 polymorphism significantly affects tacrolimus pharmacokinetics in kidney transplant recipients.
Tacrolimus (Tac) is a potent immunosuppressant with considerable toxicity. Tac pharmacokinetics varies between individuals and thus complicates its use in preventing rejection after kidney transplantation. This variability might be caused by genetic polymorphisms in metabolizing enzymes. We used TaqMan analyses to evaluate the impact of a newly discovered CYP3A4 (cytochrome P450, family 3, subfamily A, polypeptide 4) single-nucleotide polymorphism (SNP) (rs35599367C>T; CYP3A4*22) on Tac pharmacokinetics in 185 renal transplant recipients who participated in an international randomized controlled clinical trial (fixed-dose, concentration-controlled study). The overall mean daily-dose requirement to reach the same predose Tac blood concentration was 33% lower for carriers of the T variant allele than for rs35599367CC patients (95% CI, -46% to -20%; P = 0.018). When combined with the *3 genotype of the CYP3A5 (cytochrome P450, family 3, subfamily A, polypeptide 5) gene, the rs35599367C>T SNP was also associated with a risk of supratherapeutic Tac concentrations (>15 μg/L) during the first 3 days after surgery, with an odds ratio of 8.7 for carriers of the CYP3A4 T allele plus CYP3A5*3/*3 (P = 0.027) and 4.2 for the CYP3A4 CC homozygotes plus CYP3A5*3/*3 (P = 0.002), compared with CYP3A4 CC homozygotes having 1 or 2 CYP3A5*1 alleles. The overall increase in the Tac dose-adjusted trough blood concentration was +179% for carriers of the CYP3A4 T allele with CYP3A5*3/*3 (P < 0.001), +101% for CYP3A4 CC homozygotes with CYP3A5*3/*3 (P < 0.001), and +64% for CYP3A4 T allele carriers with CYP3A5*1 (P = 0.020),compared with CYP3A4 CC homozygotes with CYP3A5*1. The CYP3A4 rs35599367C>T polymorphism is associated with a significantly altered Tac metabolism and therefore increases the risk of supratherapeutic Tac concentrations early after transplantation. Analysis of this CYP3A4*22 SNP may help in identifying patients at risk of Tac overexposure.


Antidepressant monotherapy and combination of antidepressants in the treatment of resistant depression in current clinical practice: A retrospective study.
Abstract Objectives. The aim of this study was to compare efficacy of antidepressant monotherapies and combinations of antidepressants in the treatment of resistant patients in current clinical practice. Methods. We reviewed chart documents of resistant depressive inpatients treated at least 4 weeks with a new treatment. Depressive symptoms and clinical status were assessed using Montgomery and Åsberg Depression Rating Scale (MADRS), Beck Depression Inventory-Short Form and Clinical Global Impression at the baseline, week 2 and in the end of treatment. Results. We identified 81 patients (27 with combinations and 51 with monotherapies) that were suitable for analyses. The combination group achieved higher reduction of MADRS score (14.6 vs 10.2 pts., p=0.02) and response rate (≥ 50% reduction of MADRS, 67% vs 39%, p=0.03). Number needed to treat for response was 4. Conclusions. Based on our results, we suggest that combination of antidepressants might be more effective than monotherapy in clinical practice.


Research Review: The effects of mindfulness-based interventions on cognition and mental health in children and adolescents - a meta-analysis of randomized controlled trials.
Mindfulness based interventions (MBIs) are an increasingly popular way of attempting to improve the behavioural, cognitive and mental health outcomes of children and adolescents, though there is a suggestion that enthusiasm has moved ahead of the evidence base. Most evaluations of MBIs are either uncontrolled or nonrandomized trials. This meta-analysis aims to establish the efficacy of MBIs for children and adolescents in studies that have adopted a randomized, controlled trial (RCT) design. A systematic literature search of RCTs of MBIs was conducted up to October 2017. Thirty-three independent studies including 3,666 children and adolescents were included in random effects meta-analyses with outcome measures categorized into cognitive, behavioural and emotional factors. Separate random effects meta-analyses were completed for the seventeen studies (n = 1,762) that used an RCT design with an active control condition. Across all RCTs we found significant positive effects of MBIs, relative to controls, for the outcome categories of Mindfulness, Executive Functioning, Attention, Depression, Anxiety/Stress and Negative Behaviours, with small effect sizes (Cohen's d), ranging from .16 to .30. However, when considering only those RCTs with active control groups, significant benefits of an MBI were restricted to the outcomes of Mindfulness (d = .42), Depression (d = .47) and Anxiety/Stress (d = .18) only. This meta-analysis reinforces the efficacy of using MBIs for improving the mental health and wellbeing of youth as assessed using the gold standard RCT methodology. Future RCT evaluations should incorporate scaled-up definitive trial designs to further evaluate the robustness of MBIs in youth, with an embedded focus on mechanisms of action.


IR and X-ray time-resolved simultaneous experiments: an opportunity to investigate the dynamics of complex systems and non-equilibrium phenomena using third-generation synchrotron radiation sources.
Third-generation storage rings are modern facilities working with high currents and designed to host powerful radiation sources, like undulators and wigglers, and to deliver high-brilliance beams to users. Many experiments at high spatial resolution, such as spectromicroscopy at the nanometre scale and with high temporal resolution to investigate kinetics down to the picosecond regime, are now possible. The next frontier is certainly the combination of different methods in a unique set-up with the ultimate available spatial and temporal resolutions. In the last decade much synchrotron-based research has exploited the advantage of complementary information provided by time-resolved X-ray techniques and optical methods in the UV/Vis and IR domains. New time-resolved and concurrent approaches are necessary to characterize complex systems where physical-chemical phenomena occur under the same experimental conditions, for example to detect kinetic intermediates via complementary but independent observations. In this contribution we present scientific cases from original works and literature reviews to support the proposed IR/X-ray simultaneous approach, with both probes exploiting synchrotron radiation sources. In addition, simple experimental layouts that may take advantage of the high brilliance and the wide spectral distribution of the synchrotron radiation emission will be given for specific researches or applications to investigate dynamic processes and non-equilibrium phenomena occurring in many condensed matter and biological systems, of great interest for both fundamental research and technological applications.


The effectiveness of condoms in reducing heterosexual transmission of HIV.
It is not established whether the condom is as effective at preventing heterosexual transmission of HIV as it is for preventing conception. An overall estimate of condom effectiveness for HIV prevention is needed. Information on condom usage and HIV serology was obtained from 25 published studies of serodiscordant heterosexual couples. Condom usage was classified as always (in 100% of acts of intercourse), sometimes (1-99%, 0-99% or 1-100%) or never (0%). Studies were stratified by design, direction of transmission and condom usage group. Condom efficacy was calculated from the HIV transmission rates for always-users and never-users. For always-users, 12 cohort samples yielded a consistent HIV incidence of 0.9 per 100 person-years (95% confidence interval, 0.4-1.8). For 11 cohort samples of never-users, incidence was estimated at 6.8 per 100 person-years (95% confidence interval, 4.4-10.1) for male-to-female transmission, 5.9 per 100 (95% confidence interval, 1.5-15.1) for female-to-male transmission and 6.7 per 100 (95% confidence interval, 4.5-9.6) in samples that specified the direction of transmission. Generally, the condom's effectiveness at preventing HIV transmission is estimated to be 87%, but it may be as low as 60% or as high as 96%. Consistent use of condoms provides protection from HIV. The level of protection approximates 87%, with a range depending upon the incidence among condom nonusers. Thus, the condom's efficacy at reducing heterosexual transmission may be comparable to or slightly lower than its effectiveness at preventing pregnancy


A church-based cholesterol education program.
The leading cause of death among black people in the United States is coronary heart disease, accounting for about 25 percent of the deaths. The Task Force on Black and Minority Health formed by the Secretary of Health and Human Services in 1985 subsequently recommended increased efforts to reduce risk factors for coronary heart disease in the black population. A stated focus of the National Heart, Lung, and Blood Institute's National Cholesterol Education Program has been that of reaching minority groups. This report describes a pilot cholesterol education program conducted in black churches by trained members of those churches. Cholesterol screening, using a Reflotron, and other coronary heart disease risk factor screening was conducted in six churches with predominantly black members and at a neighborhood library. A total of 348 persons with cholesterol levels of 200 milligrams per deciliter (mg per dl) or higher were identified. At the time of screening, all were provided brief counseling on lowering their cholesterol and were given a copy of the screening results. Half of those identified, all members of one church, were invited to attend a 6-week nutrition education class of 1 hour each week about techniques to lower blood cholesterol. Information about cholesterol was also mailed to them. They were designated as the education group. Persons in the church were trained to teach the classes. A report of the screening results was sent to the personal physicians of the remaining 174 people in other churches who had cholesterol levels of 200 mg per dl or higher. This group served as a usual care comparison group.Six months after the initial screening, members of both groups were invited for followup screening.Among the 75 percent of the education group who returned for followup screening there was a 23.4 mg per dl (10 percent) decrease in the mean cholesterol level. Thirty-six percent of the usual care group returned for followup screening; their mean cholesterol level had decreased 38.7 mg per dl (16 percent).In this study, the support of churches provided access to large numbers of people. The mean serum cholesterol reductions occurring with both screening and referral and screening and education were statistically significant and large enough to be of clinical importance.The authors recommend that the approach taken in this study be investigated further by the National Cholesterol Education Program as a model for reaching the black population with coronary heart disease risk reduction programs.


Fluorine in pharmaceuticals: looking beyond intuition.
Fluorine substituents have become a widespread and important drug component, their introduction facilitated by the development of safe and selective fluorinating agents. Organofluorine affects nearly all physical and adsorption, distribution, metabolism, and excretion properties of a lead compound. Its inductive effects are relatively well understood, enhancing bioavailability, for example, by reducing the basicity of neighboring amines. In contrast, exploration of the specific influence of carbon-fluorine single bonds on docking interactions, whether through direct contact with the protein or through stereoelectronic effects on molecular conformation of the drug, has only recently begun. Here, we review experimental progress in this vein and add complementary analysis based on comprehensive searches in the Cambridge Structural Database and the Protein Data Bank.


MESSA: MEta-Server for protein Sequence Analysis.
Computational sequence analysis, that is, prediction of local sequence properties, homologs, spatial structure and function from the sequence of a protein, offers an efficient way to obtain needed information about proteins under study. Since reliable prediction is usually based on the consensus of many computer programs, meta-severs have been developed to fit such needs. Most meta-servers focus on one aspect of sequence analysis, while others incorporate more information, such as PredictProtein for local sequence feature predictions, SMART for domain architecture and sequence motif annotation, and GeneSilico for secondary and spatial structure prediction. However, as predictions of local sequence properties, three-dimensional structure and function are usually intertwined, it is beneficial to address them together. We developed a MEta-Server for protein Sequence Analysis (MESSA) to facilitate comprehensive protein sequence analysis and gather structural and functional predictions for a protein of interest. For an input sequence, the server exploits a number of select tools to predict local sequence properties, such as secondary structure, structurally disordered regions, coiled coils, signal peptides and transmembrane helices; detect homologous proteins and assign the query to a protein family; identify three-dimensional structure templates and generate structure models; and provide predictive statements about the protein's function, including functional annotations, Gene Ontology terms, enzyme classification and possible functionally associated proteins. We tested MESSA on the proteome of Candidatus Liberibacter asiaticus. Manual curation shows that three-dimensional structure models generated by MESSA covered around 75% of all the residues in this proteome and the function of 80% of all proteins could be predicted. MESSA is free for non-commercial use at http://prodata.swmed.edu/MESSA/


Pseudomonas pseudomallei infection from drowning: the first reported case in Taiwan.
We report a case of Pseudomonas pseudomallei infection, in which the patient acquired the bacteria by aspiration of river water after a drowning incident near Manila, the Philippines. The pulmonary form of melioidosis was noted at the onset, but septicemia developed at a later stage. Positive blood cultures were obtained 17 days after the accident. The patient was treated successfully with a combination of amikacin and cephalothin. This is the first report of P. pseudomallei infection documented in Taiwan.


Reflexive optokinetic nystagmus in younger and older observers under photopic and mesopic viewing conditions.
To investigate the effect of age on optokinetic nystagmus (OKN) in response to stimuli designed to preferentially stimulate the M-pathway. OKN was recorded in 10 younger (32.3 +/- 5.98 years) and 10 older (65.6 +/- 6.53) subjects with normal vision. Vertical gratings of 0.43 or 1.08 cpd drifting at 5 degrees /s or 20 degrees /s and presented at either 8% or 80% contrast were displayed on a large screen as full-field stimulation, central stimulation within a central Gaussian-blurred window of 15 degrees diameter, or peripheral stimulation outside this window. All conditions apart from the high-contrast condition were presented in a random order at two light levels, mesopic (1.8 cdm(-2)) and photopic (71.5 cdm(-2)). Partial-field data indicated that central stimulation, mesopic light levels, and lower temporal frequency each significantly increased slow-phase velocity (SPV). Although there was no overall difference between groups for partial-field stimulation, full-field stimulation, or low-contrast stimulation, a change in illumination revealed a significant interaction with age: there was a larger decrease in SPV going from photopic to mesopic conditions for the older group than the younger group, especially for higher temporal frequency stimulation. OKN becomes reflexive in conditions conducive to M-pathway stimulation, and this rOKN response is significantly diminished in older healthy adults than in younger healthy adults, indicative of decreased M-pathway sensitivity.