Dauer-independent insulin/IGF-1-signalling implicates collagen remodelling in longevity.
Interventions that delay ageing mobilize mechanisms that protect and repair cellular components, but it is unknown how these interventions might slow the functional decline of extracellular matrices, which are also damaged during ageing. Reduced insulin/IGF-1 signalling (rIIS) extends lifespan across the evolutionary spectrum, and in juvenile Caenorhabditis elegans also allows the transcription factor DAF-16/FOXO to induce development into dauer, a diapause that withstands harsh conditions. It has been suggested that rIIS delays C. elegans ageing through activation of dauer-related processes during adulthood, but some rIIS conditions confer robust lifespan extension unaccompanied by any dauer-like traits. Here we show that rIIS can promote C. elegans longevity through a program that is genetically distinct from the dauer pathway, and requires the Nrf (NF-E2-related factor) orthologue SKN-1 acting in parallel to DAF-16. SKN-1 is inhibited by IIS and has been broadly implicated in longevity, but is rendered dispensable for rIIS lifespan extension by even mild activity of dauer-related processes. When IIS is decreased under conditions that do not induce dauer traits, SKN-1 most prominently increases expression of collagens and other extracellular matrix genes. Diverse genetic, nutritional, and pharmacological pro-longevity interventions delay an age-related decline in collagen expression. These collagens mediate adulthood extracellular matrix remodelling, and are needed for ageing to be delayed by interventions that do not involve dauer traits. By genetically delineating a dauer-independent rIIS ageing pathway, our results show that IIS controls a broad set of protective mechanisms during C. elegans adulthood, and may facilitate elucidation of processes of general importance for longevity. The importance of collagen production in diverse anti-ageing interventions implies that extracellular matrix remodelling is a generally essential signature of longevity assurance, and that agents promoting extracellular matrix youthfulness may have systemic benefit.


Risk of geographic atrophy in the comparison of age-related macular degeneration treatments trials.
To describe risk factors for geographic atrophy (GA) in the Comparison of Age-related Macular Degeneration Treatments Trials (CATT). Cohort within a randomized clinical trial. We analyzed 1024 CATT patients with no GA visible on color fundus photographs (CFPs) and/or fluorescein angiograms (FAs) at enrollment. Eyes were assigned to ranibizumab (0.5 mg) or bevacizumab (1.25 mg) treatment and to a 2-year monthly or pro re nata (PRN) injection regimen, or monthly injections for 1 year and PRN for 1 year. Demographic, genetic, and baseline ocular characteristics and lesion features of CFP/FA and optical coherence tomography (OCT) were evaluated as risk factors for GA through 2 years of follow-up. Time-dependent Cox proportional hazard models were used to estimate adjusted hazard ratios (aHRs). Development of GA. By 2 years, GA developed in 187 of 1024 patients (18.3%). Baseline risk factors for GA development included baseline visual acuity (VA) ≤20/200 (aHR, 2.65; 95% confidence interval [CI], 1.43-4.93), retinal angiomatous proliferation (RAP; aHR, 1.69; 95% CI, 1.16-2.47), GA in the fellow eye (aHR, 2.07; 95% CI, 1.40-3.08), and intraretinal fluid at the foveal center (aHR, 2.10; 95% CI, 1.34-3.31). Baseline factors associated with lower risk for GA development included blocked fluorescence (aHR, 0.49; 95% CI, 0.29-0.82), OCT measurements of subretinal fluid thickness of >25 μ (aHR, 0.52; 95% CI, 0.35-0.78), subretinal tissue complex thickness of >275 compared with ≤75 μ (aHR, 0.31; 95% CI, 0.19-0.50), and vitreomacular attachment (aHR, 0.55; 95% CI, 0.31-0.97). Ranibizumab compared with bevacizumab had a higher risk (aHR, 1.43; 95% CI, 1.06-1.93), and monthly dosing had a higher risk (aHR, 1.59; 95% CI, 1.17-2.16) than PRN dosing. There were no strong associations between development of GA and the presence of risk alleles for CFH, ARMS 2, HTRA1, C3, or TLR3. Approximately one fifth of CATT patients developed GA within 2 years of treatment. Independent baseline risk factors included poor VA, RAP, foveal intraretinal fluid, monthly dosing, and treatment with ranibizumab. Anti-vascular endothelial growth factor therapy may have a role in the development of GA.


Assessment of attractiveness of plants as roosting sites for the melon fly, Bactrocera cucurbitae, and oriental fruit fly, Bactrocera dorsalis.
The use of toxic protein bait sprays to suppress melon fly, Bactrocera cucurbitae (Coquillett) (Diptera: Tephritidae), populations typically involves application to vegetation bordering agricultural host areas where the adults seek shelter ("roost"). Although bait spray applications for suppression of oriental fruit fly, Bactrocera dorsalis (Hendel), populations have traditionally been applied to the host crop, rather than to crop borders, roosting by oriental fruit flies in borders of some crop species, such as papaya, Carica papaya L. (Brassicales: Caricaceae), suggests that bait spray applications to crop borders could also help in suppression of B. dorsalis populations. In order to develop improved recommendations for application of bait sprays to border plants for suppression of melon fly and oriental fruit fly populations, the relative attractiveness of a range of plant species, in a vegetative (non-flowering) stage, was tested to wild melon fly and oriental fruit fly populations established in a papaya orchard in Hawaii. A total of 20 plant species were evaluated, divided into four categories: 1) border plants, including corn, Zea mays L. (Poales: Poaceae), windbreaks and broad-leaved ornamentals, 7 species; 2) weed plants commonly found in agricultural fields in Hawaii, 6 species; 3) host crop plants, 1 species- zucchini, Cucurbita pepo L. (Violales: Curcurbitaceae), and 4) locally grown fruit trees, 6 species. Plants were established in pots and placed in an open field, in clusters encircling protein bait traps, 20 m away from the papaya orchard. Castor bean, Ricinus communis L. (Euphorbiales: Euphorbiaceae), panax, Polyscias guilfoylei (Bull) Bailey (Apiales: Araliaceae), tiger's claw, Erythnna variegata L. (Fabales: Fabaceae), and guava, Psidium guajava L. (Myrtales: Myrtaceae) were identified as preferred roosting hosts for the melon fly, and tiger's claw, panax, castor bean, Canada cocklebur, Xanthium strumarium L. (Asterales: Asteraceae), Brazilian pepper tree, Schinus terebinthifolius Raddi (Sapindales: Anacardiaceae), ti plant, Cordyline terminate (L.) Chev.(Liliales: Liliaceae), guava and several Citrus spp. were identified as preferred roosting hosts for oriental fruit fly. Guava had not previously been identified as a preferred roosting host for melon fly. Other than for the use of panax as a roosting host, there has previously been little attention to roosting hosts for oriental fruit fly. Establishment of preferred roosting hosts as crop borders may help to improve suppression of both fruit fly species by providing sites for bait spray applications. Further research is needed to assess the use of vegetation bordering other host crops as roosting hosts, especially for oriental fruit fly.


Shedding light on avian influenza H4N6 infection in mallards: modes of transmission and implications for surveillance.
Wild mallards (Anas platyrhychos) are considered one of the primary reservoir species for avian influenza viruses (AIV). Because AIV circulating in wild birds pose an indirect threat to agriculture and human health, understanding the ecology of AIV and developing risk assessments and surveillance systems for prevention of disease is critical. In this study, mallards were experimentally infected with an H4N6 subtype of AIV by oral inoculation or contact with an H4N6 contaminated water source. Cloacal swabs, oropharyngeal swabs, fecal samples, and water samples were collected daily and tested by real-time RT-PCR (RRT-PCR) for estimation of viral shedding. Fecal samples had significantly higher virus concentrations than oropharyngeal or cloacal swabs and 6 month old ducks shed significantly more viral RNA than 3 month old ducks regardless of sample type. Use of a water source contaminated by AIV infected mallards, was sufficient to transmit virus to naïve mallards, which shed AIV at higher or similar levels as orally-inoculated ducks. Bodies of water could serve as a transmission pathway for AIV in waterfowl. For AIV surveillance purposes, water samples and fecal samples appear to be excellent alternatives or additions to cloacal and oropharyngeal swabbing. Furthermore, duck age (even within hatch-year birds) may be important when interpreting viral shedding results from experimental infections or surveillance. Differential shedding among hatch-year mallards could affect prevalence estimates, modeling of AIV spread, and subsequent risk assessments.


Psittacine beak and feather disease virus in budgerigars and ring-neck parakeets in South Africa.
Psittacine beak and feather disease (PBFD) is a common disease of the psittacine species and is caused by the psittacine beak and feather disease virus (PBFDV). In this study the occurrence of the disease in ring-neck parakeets and budgerigars in South Africa suffering from feathering problems, using polymerase chain reaction as a diagnostic test was investigated. The genetic variation between viral isolates was also studied. Results indicate that PBFDV can be attributed to being the cause of feathering problems in some of the ring-neck parakeets and budgerigars in South Africa. Genetic variation of isolates occurs between species and individuals. A cheap and easy to use method of blood sample collection on filter paper for diagnostic purposes was also evaluated. It proved to be less stressful to the birds and did not inhibit further processes.


WOMEN'S EMPOWERMENT AND FAMILY PLANNING: A REVIEW OF THE LITERATURE.
This paper reviews the literature examining the relationship between women's empowerment and contraceptive use, unmet need for contraception and related family planning topics in developing countries. Searches were conducted using PubMed, Popline and Web of Science search engines in May 2013 to examine literature published between January 1990 and December 2012. Among the 46 articles included in the review, the majority were conducted in South Asia (n=24). Household decision-making (n=21) and mobility (n=17) were the most commonly examined domains of women's empowerment. Findings show that the relationship between empowerment and family planning is complex, with mixed positive and null associations. Consistently positive associations between empowerment and family planning outcomes were found for most family planning outcomes but those investigations represented fewer than two-fifths of the analyses. Current use of contraception was the most commonly studied family planning outcome, examined in more than half the analyses, but reviewed articles showed inconsistent findings. This review provides the first critical synthesis of the literature and assesses existing evidence between women's empowerment and family planning use.


Recent advances in the prevention, early diagnosis, and treatment of congenital dislocation of the hip in Japan.
Results of animal experiments and then of clinical study of newborn infants suggested that the main mechanical factor causing hip dislocation is prolonged tension on the hamstrings and iliopsoas and that each of these muscles has a synergistic effect in the production of hip dislocation during the perinatal period. It was, therefore, presumed that the high incidence of congenital dislocation of the hip (CDH) in Japan might be due mainly to the Japanese tradition of forcibly maintaining the legs of infants in an extended position with a "swathing diaper." The incidence of CDH in Japanese infants prior to 1965 was as high as 1.1%-3.5%. In an attempt to reduce the incidence of CDH, examination of newborns was performed on a national scale. However, early screening methods for hip abnormalities were not adequately reliable in Japan to allow identification of conditions that would later become CDH. In 1975 a national campaign to avoid prolonged extension of the hips and knees of infants during the early postnatal period was initiated. As a result, there has been a remarkable reduction in the incidence of CDH in infants, to less than 0.2%.


Role of selective serotonin reuptake inhibitors in psychiatric disorders: a comprehensive review.
The selective serotonin reuptake inhibitors (SSRIs) have emerged as a major therapeutic advance in psychopharmacology. As a result, the discovery of these agents marks a milestone in neuropsychopharmacology and rational drug design, and has launched a new era in psychotropic drug development. Prior to the SSRIs, all psychotropic medications were the result of chance observation. In an attempt to develop a SSRI, researchers discovered a number of nontricyclic agents with amine-uptake inhibitory properties, acting on both noradrenergic and serotonergic neurons with considerable differences in potency. A given drug may affect one or more sites over its clinically relevant dosing range and may produce multiple and different clinical effects. The enhanced safety profile includes a reduced likelihood of pharmacodynamically mediated adverse drug-drug interactions by avoiding affects on sites that are not essential to the intended outcome. SSRIs were developed for inhibition of the neuronal uptake pump for serotonin (5-HT), a property shared with the TCAs, but without affecting the other various neuroreceptors or fast sodium channels. The therapeutic mechanism of action of SSRIs involves alteration in the 5-HT system. The plethora of biological substrates, receptors and pathways for 5-HT are candidates to mediate not only the therapeutic actions of SSRIs, but also their side effects. A hypothesis to explain these immediate side effects is that 5-HT is increased at specific 5-HT receptor subtypes in discrete regions of the body where the relevant physiologic processes are regulated. Marked differences exist between the SSRIs with regard to effects on specific cytochrome P450 (CYP) enzymes, and thus the likelihood of clinically important pharmacokinetic drug-drug interactions. Although no clear relationship exists between the clinical efficacy, plasma concentration of SSRIs, nor any threshold that defines toxic concentrations, but therapeutic drug monitoring (TDM) may be useful in special populations, such as in elderly patients, poor metabolizers (PM) of sparteine (CYP2D6) or mephenytoin (CYP2C19), and patients with liver and kidney impairment. Several meta-analyses have reviewed the comparative efficacy of TCAs and SSRIs, and concluded that both TCAs and SSRIs have similar efficacy in the treatment of depression. SSRIs have demonstrated better efficacy and tolerability in the treatment of obsessive compulsive disorder (OCD). They have also been found to be effective in the treatment for social anxiety disorder both in reducing total levels of social anxiety and in improving overall clinical condition. The benefit of SSRIs in anorexia nervosa (AN) is apparently short-term unless medication is given in the context of nutritional or behavioral therapy. No single antidepressant can ever be recommended for every patient, but in a vast majority of patients, SSRIs should be considered as one of the first-line drugs in the treatment of depression.


Requirement of the Pseudomonas aeruginosa CbrA sensor kinase for full virulence in a murine acute lung infection model.
Pseudomonas aeruginosa is an opportunistic pathogen that is a major cause of respiratory tract and other nosocomial infections. The sensor kinase CbrA is a central regulator of carbon and nitrogen metabolism and in vitro also regulates virulence-related processes in P. aeruginosa. Here, we investigated the role of CbrA in two murine models of infection. In both peritoneal infections in leukopenic mice and lung infection models, the cbrA mutant was less virulent since substantially larger numbers of cbrA mutant bacteria were required to cause the same level of infection as wild-type or complemented bacteria. In contrast, in the chronic rat lung model the cbrA mutant grew and persisted as well as the wild type, indicating that the decrease of in vivo virulence of the cbrA mutant did not result from growth deficiencies on particular carbon substrates observed in vitro. In addition, a mutant in the cognate response regulator CbrB showed no defect in virulence in the peritoneal infection model, ruling out the involvement of certain alterations of virulence properties in the cbrA mutant including defective swarming motility, increased biofilm formation, and cytotoxicity, since these alterations are controlled through CbrB. Further investigations indicated that the mutant was more susceptible to uptake by phagocytes in vitro, resulting in greater overall bacterial killing. Consistent with the virulence defect, it took a smaller number of Dictyostelium discoideum amoebae to kill the cbrA mutant than to kill the wild type. Transcriptional analysis of the cbrA mutant during D. discoideum infection led to the conclusion that CbrA played an important role in the iron metabolism, protection of P. aeruginosa against oxidative stress, and the regulation of certain virulence factors.


Is there foul play in the leaf pocket? The metagenome of floating fern Azolla reveals endophytes that do not fix N2 but may denitrify.
Dinitrogen fixation by Nostoc azollae residing in specialized leaf pockets supports prolific growth of the floating fern Azolla filiculoides. To evaluate contributions by further microorganisms, the A. filiculoides microbiome and nitrogen metabolism in bacteria persistently associated with Azolla ferns were characterized. A metagenomic approach was taken complemented by detection of N2 O released and nitrogen isotope determinations of fern biomass. Ribosomal RNA genes in sequenced DNA of natural ferns, their enriched leaf pockets and water filtrate from the surrounding ditch established that bacteria of A. filiculoides differed entirely from surrounding water and revealed species of the order Rhizobiales. Analyses of seven cultivated Azolla species confirmed persistent association with Rhizobiales. Two distinct nearly full-length Rhizobiales genomes were identified in leaf-pocket-enriched samples from ditch grown A. filiculoides. Their annotation revealed genes for denitrification but not N2 -fixation. 15 N2 incorporation was active in ferns with N. azollae but not in ferns without. N2 O was not detectably released from surface-sterilized ferns with the Rhizobiales. N2 -fixing N. azollae, we conclude, dominated the microbiome of Azolla ferns. The persistent but less abundant heterotrophic Rhizobiales bacteria possibly contributed to lowering O2 levels in leaf pockets but did not release detectable amounts of the strong greenhouse gas N2 O.


Predicting When to Administer Blood Products During Tactical Aeromedical Evacuation: Evaluation of a US Model.
The administration of blood products to battlefield casualties in the prehospital arena has contributed significantly to the survival of critically injured patients in Afghanistan over the past 5 years. Given as part of an established military "chain of survival," blood product administration has represented a step-change improvement in capability for both UK and US tactical aeromedical evacuation (TACEVAC) platforms. The authors explore current concepts, analyzing and exploring themes associated with early use of blood products (fresh frozen plasma [FFP] and red blood cells [RBCs]), and they compare and evaluate a US/UK study analyzing the differences and recommending future strategy. The subject matter expert (SME) consensus guidelines developed for use by the US Army Air Ambulance units commonly known as call sign "DUSTOFF." These TACEVAC assets in Afghanistan were validated in this retrospective study. Using statistical analysis, the authors were able to ascertain that the current DUSTOFF SME-derived guidelines offer a sensitivity of 63.04% and a specificity of 89.07%. By adjusting the indicators to include a single above-ankle amputation with a systolic blood pressure (SBP) less than 90 mmHg and pulse greater than 120/min, the sensitivity could be increased to 67.39% while maintaining the specificity at 89.07%. In our data set, a single amputation above the ankle, in combination with an SBP of less than 100 mmHg and a pulse of greater than 120/min, increased the sensitivity to 76% but with a slight drop in specificity to 86%. Further study of military prehospital casualty data is under way to identify additional physiological parameters that will allow simple scoring tools in the remote setting to guide the administration of prehospital blood products.


Human ehrlichiosis in the United States, 1985 to 1990.
To describe the epidemiology, clinical features, laboratory manifestations, response to therapy, and factors related to morbidity and mortality in a large group of patients with ehrlichiosis. Case-series. Laboratory-based surveillance in the United States. 237 patients whose serum had a fourfold increase or decrease in antibodies to Ehrlichia canis or E. chaffeensis. Epidemiologic, clinical, laboratory data, hospitalization, duration of illness, complications, and treatment response. From 1985 through 1990, 237 case-patients were identified in 21 states; rates exceeded 1 per 100,000 per year in only 5 counties. Incidence rates increased with age and were higher among men. Most case-patients had nonspecific illness and were not suspected of having a rickettsial infection. Many patients (60.8%) were hospitalized. Leukocyte and platelet counts typically decreased and liver function tests typically increased through day 7. Three (6.1%) of 49 outpatients treated only with tetracycline were hospitalized compared with 35 (92%) of 38 outpatients treated only with antibiotics other than tetracycline or chloramphenicol (P < 0.001). Among hospitalized patients, recovery was faster for those initially treated with tetracycline (median, 16 days) or chloramphenicol (median, 12 days) than for those initially treated with other antibiotics (median, 27 days; P = 0.03 for both comparisons). In a logistic regression analysis, severe illness or death was more probable among case-patients 60 years or older (odds ratio [OR], 4.60; 95% CI, 1.87 to 11.2) and among those who did not receive tetracycline or chloramphenicol until 8 or more days after symptom onset (OR, 4.38; CI, 1.36 to 14.0). The findings of this study are primarily representative of more seriously ill patients with human ehrlichiosis. Although rates are low, ehrlichiosis is found in many areas of the United States. Patients with a history of tick exposure, acute febrile illness, decreasing leukocyte counts, and decreasing platelet counts may have ehrlichiosis. Prompt treatment with tetracycline or chloramphenicol markedly decreases the morbidity.


Long-term efficacy and safety of secukinumab 150 mg in ankylosing spondylitis: 5-year results from the phase III MEASURE 1 extension study.
This study aimed to report end-of-study results on efficacy and safety of secukinumab 150 mg through 5 years in patients with ankylosing spondylitis (AS; MEASURE 1 extension trial (NCT01863732)). After the 2-year core trial, 274 patients receiving subcutaneous secukinumab 150 or 75 mg (following intravenous loading or initial placebo treatment to 16/24 weeks) every 4 weeks were invited to enter the 3-year extension study. Dose escalation from 75 to 150 mg (approved dose) was allowed at or after week 156 based on the judgement of the treating physician. Assessments at week 260 (5 years) included Assessment of SpondyloArthritis international Society (ASAS) 20/40 and other efficacy outcomes. Data are presented as observed. Safety assessment included all patients who received ≥1 dose of study treatment. Of the 274 patients who entered the extension study, 84% (230/274) completed 5 years of treatment. ASAS20/40 responses were 78.6/65.2%, Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) 50 response was 63.4% and mean (±SD) BASDAI total score was 2.6±1.76 with secukinumab 150 mg at 5 years. Improvements in efficacy outcomes were sustained through 5 years. A total of 82 patients on secukinumab 75 mg (56.2%) had their dose escalated to 150 mg after week 168; ASAS40, ASAS-PR, ASAS 5/6 and BASDAI50 responses were improved in patients whose dose was escalated from secukinumab 75 to 150 mg. Secukinumab was well tolerated with a safety profile consistent over the course of the study. Secukinumab 150 mg provided sustained efficacy across multiple domains of AS with a favourable and consistent safety profile through 5-year treatment. Over 50% of patients required dose escalation from 75 to 150 mg and efficacy improved in these patients.


The relation between various conformity indices and the influence of the target coverage difference in prescription isodose surface on these values in intracranial stereotactic radiosurgery.
The purpose of this study was to describe the relation between various frequently used conformity indices (CIs) and to examine the influence of the target coverage (TC) difference in prescription isodose surface (IDS) on these CI values in dynamic conformal arc (DCA) plans. 73 plans for simple-shaped brain metastases that were previously characterised for dose distribution with regard to the effect of the target volume (TV) and the depth from the skin surface were reviewed. Three different-definition CI values for each TV were calculated at the 80% IDS, and at D99, D95, D90 and D85, considering the interplanner variability in the TC values for the prescription IDS. The CI used as the Radiation Therapy Oncology Group criterion showed nearly perfect values at D90. The CI defined in the BrainSCAN (BrainLAB AG, Feldkirchen, Germany) treatment planning system (CI(BS)) denoted lower (superior) values as the TC of the reference IDS decreased. Nakamura's CI (NCI) had lower variability but demonstrated lower (superior) values at D95. NCI showed the most stringent (higher) values at an 80% IDS, but the differences between the plans were less distinct with NCI. The TC difference in IDS chosen for dose prescription or evaluation significantly led to CI value variability in a definition-dependent manner, even when NCI was applied. Definition of the reference IDS at a specific TC value according to clinical situation would reduce the CI value variability to a minimum and would make the CI(BS) sufficient for the objective metric with a perfect value of 1.


The Evolution of Chunks in Sequence Learning.
Chunking mechanisms are central to several cognitive processes and notably to the acquisition of visuo-motor sequences. Individuals segment sequences into chunks of items to perform visuo-motor tasks more fluidly, rapidly, and accurately. However, the exact dynamics of chunking processes in the case of extended practice remain unclear. Using an operant conditioning device, 18 Guinea baboons (Papio papio) produced a fixed sequence of nine movements during 1000 trials by pointing to a moving target on a touch screen. Response times analyses revealed a specific chunking pattern of the sequence for each baboon. More importantly, we found that these patterns evolved during the course of the experiment, with chunks becoming progressively fewer and longer. We identified two chunk reorganization mechanisms: the recombination of preexisting chunks and the concatenation of two distinct chunks into a single one. These results provide new evidence on chunking mechanisms in sequence learning and challenge current models of associative and statistical learning.


The effect of fentanyl, DNQX and MK-801 on dorsal horn neurones responsive to colorectal distension in the anaesthetized rat.
Certain dorsal horn neurones respond in a graded manner to noxious colorectal distension (CRD). Morphine inhibits these responses in the spinalized rat, but the role of excitatory amino acids in baseline visceral nociceptive transmission is less clear. This study examines the effect of the mu-opiate receptor agonist fentanyl, and the non-NMDA and NMDA antagonists DNQX and MK-801, respectively, on such responses to CRD in the sodium pentobarbitone-anaesthetized rat. Male rats were prepared for extracellular recording from the lumbosacral spinal cord. 90 neurones responsive to CRD, located throughout the dorsal horn, were classified according to their response duration and latency to 60 mmHg distension, as SL-A (short latency-abrupt; 59%), SL-S (short latency-sustained; 23%), L-L (long-latency; 10%) and Inhib (inhibited; 8%). Convergent cutaneous receptive fields were mapped for 79/90 neurones and classified as LT (low threshold), WDR (wide dynamic range) or HT (high threshold). CRD (20-100 mm Hg) elicited graded responses in most neurones. In 6/6 SL-S neurones, fentanyl (1-8 microg kg-1) dose-dependently inhibited the response to 60 mm Hg CRD, in a naloxone-sensitive manner, with an ID50 value (+/-95% confidence limits) of 2.48 (1.7-3. 7) microg kg-1. In 6/6 SL-A neurones, fentanyl had no significant effect on the response to CRD. DNQX (0.03-3 mg kg-1) produced a dose-dependent inhibition of the response to CRD in 5/5 SL-A neurones, with an ID50 value of 0.32 (0.01-41.1) mg kg-1. MK-801 (0. 03-0.3 mg kg-1) had no significant effect on responses to CRD in 6/6 SL-A neurones. The differential inhibitory effects of fentanyl on two neuronal subtypes may indicate functional differences. In SL-A neurones AMPA/kainate, but not NMDA receptors are involved in mediating baseline nociceptive neurotransmission.


Summary Findings of a Systematic Literature Review of the Ultrasound Assessment of Bone Erosions in Rheumatoid Arthritis.
Bone erosions in rheumatoid arthritis (RA) have been studied in an increasing amount of research. Both earlier and present classification criteria of RA contain erosions as a significant classification component. Ultrasound (US) can detect bone changes in accessible surfaces. Therefore, the study group performed a systematic literature review of assessment of RA bone erosions with US. A systematic search of PubMed and Embase was performed. Data on the definitions of RA bone erosions, their size, scoring, relation to synovitis, comparators, and elements of the OMERACT (Outcome Measures in Rheumatology Clinical Trials) filter were collected and analyzed. The selection process identified 58 original research papers. The assessed joints were most frequently metacarpophalangeal (MCP; 41 papers), proximal interphalangeal (19 papers), and metatarsophalangeal joints (MTP; 18 papers). The OMERACT definition of RA bone erosion on US was used most often (17 papers). Second and fifth MCP and fifth MTP were recommended as target joints. Conventional radiography was the most frequently used comparator (27 papers), then magnetic resonance imaging (17 papers) and computed tomography (5 papers). Reliability of assessment was presented in 20 papers and sensitivity to change in 11 papers. This paper presents results of a systematic literature review of bone erosion assessment in RA with US. The survey suggests that US can be a helpful adjunct to the existing methods of imaging bone erosions in RA. It analyzes definitions, scoring systems, used comparators, and elements of the OMERACT filter. It also presents recommendations for a future research agenda based on the results of the review.


Spatially extensive summation of contrast energy is revealed by contrast detection of micro-pattern textures.
Vision must analyze the retinal image over both small and large areas to represent fine-scale spatial details and extensive textures. The long-range neuronal convergence that this implies might lead us to expect that contrast sensitivity should improve markedly with the contrast area of the image. But this is at odds with the orthodox view that contrast sensitivity is determined merely by probability summation over local independent detectors. To address this puzzle, I aimed to assess the summation of luminance contrast without the confounding influence of area-dependent internal noise. I measured contrast detection thresholds for novel Battenberg stimuli that had identical overall dimensions (to clamp the aggregation of noise) but were constructed from either dense or sparse arrays of micro-patterns. The results unveiled a three-stage visual hierarchy of contrast summation involving (i) spatial filtering, (ii) long-range summation of coherent textures, and (iii) pooling across orthogonal textures. Linear summation over local energy detectors was spatially extensive (as much as 16 cycles) at Stage 2, but the resulting model is also consistent with earlier classical results of contrast summation (J. G. Robson & N. Graham, 1981), where co-aggregation of internal noise has obscured these long-range interactions.


Anatomy and techniques in posterior urethroplasty.
Given its complex anatomy, injury to the posterior urethra may result in a number of reconstructive challenges. With the appropriate operative planning and experience, surgical repair can be very successful. This review discusses the applicable techniques for the perineal approach to posterior urethral stenosis, including bulbomembranous anastomosis for pelvic fracture urethral injury and repair of vesicourethral anastomotic stenosis (VUAS) following prostate surgery. The advanced techniques reviewed include an adaptation allowing a bulbar artery sparing approach to posterior urethroplasty and an intrasphincteric urethroplasty procedure which may allow continence preservation in patients with membranous urethral stenosis.


Lower-limb pain, disease, and injury burden as determinants of muscle strength deficit after hip fracture.
Hip fracture may result in an asymmetrical lower-limb strength deficit. The deficit may be related to the trauma, surgical treatment, pain, or disuse of the fractured limb. However, disease and injury burden or musculoskeletal pain in the other limb may reduce muscle strength on that side, reducing the asymmetrical deficit. The aim of our study was to explore the asymmetrical strength deficit and to determine the potential underlying factors in patients from six months to seven years after a hip fracture. The asymmetrical deficit was calculated ([fractured limb/sum of both lower limbs] x 100%) for isometric knee extension torque, rate of force development during isometric testing, and leg extension power. The asymmetrical measures for lower-limb muscle mass (fractured limb--nonfractured limb), and that of lower-limb pain and disease and injury burden (nonfractured limb--fractured limb), were calculated. Half of the participants had no consistent asymmetrical deficit on the fractured side. Regression analyses showed that asymmetrical measures of lower-limb pain, muscle mass, and disease and injury burden predicted asymmetrical deficit in knee extension torque (R(2) = 0.43) and in the rate of force development (R(2) = 0.36). More intense pain and disease and injury burden affecting the nonfractured limb and smaller muscle mass relative to the fractured limb were associated with a smaller asymmetrical deficit. Following a hip fracture, the prevention of decreases in muscle strength and power as well as a large asymmetrical deficit by the use of targeted pain management and rehabilitation may help to reduce the risk of subsequent mobility limitations and falls.


Non-specific effect of beettahistine on cochlear electrophysiology in guinea pig.
Beettahistine hydrochloride (BH) is reported to be beneficial in the treatment of certain type of vestibulo-cochlear disorders. Experimentally is shown that BH inhibits vestibular firing rate and improves cochlear blood flow by dilatating the larger feeding vessels. Both these effects are weak, and hardly can explain the clinical benefits reported for the drug. We investigated the effect of BH on the organ of Corti electrophysiology in vivo. Two microliters of 1, 2, 5 and 10% saline solutions of BH was applied (in increasing order) to the round window (RW) membrane in an anesthetized guinea pig (n = 5). Summating potential (SP), action potential (AP), and cochlear microphonics (CM) were recorded at 16 kHz frequency using RW Ag wire electrode. The repeated applications of BH with increasing concentrations produced a dose-dependent threshold shift in CAP. The I/O function for 20, 30, 40, 50, 60, 70, and 80 dB at 16 kHz indicated that there was a saturation before complete blockade of the responsiveness in all measured parameters. SP and CM changes nearly followed CAP changes. The changes recover during 2 hours follow-up period. Our findings indicate that BH affects the organ of Corti electrophysiology. That the drug effect saturates before a complete blockade suggests non-specific effect of BH on the organ of Corti structures and cochlear nerve.


Race and healthcare disparities: overcoming vulnerablity.
The paper summarizes recently published data and recommendations about healthcare disparities experienced by African Americans who have Medicare or other healthcare coverage. Against this background the paper addresses the ethics of such disparities and how disadvantages of vulnerable populations like African Americans are typically maintained in decision making about how to respond to such disparities. Considering how to respond to disparities reveals much that vulnerable populations would bring to the policy-making table, if they can also be heard when they get there. The paper argues that vulnerable populations like African Americans need fair representation in bodies deciding what to do about such disparities and that fairness requires proportional representation at all levels of decisions that affect healthcare--a radical change. In this decision setting, how to provide adequate protection of minorities needs much further attention. The most attractive decision-making model is deliberative democracy. The paper shows that in deliberation, fair representation requires not only having a voice in decisions, but a fair hearing of those voices. Achieving a fair hearing requires changes in norms of communication and training of all to give importance to greetings and other measures of civility and trust building, and to be open to diverse forms of expression. Decisions about how to respond to healthcare disparities would include what programs to initiate for whom, how to evaluate the programs, and what to do in response to such evaluations. Conclusions are that achieving such goals will take a sea change in how healthcare institutions and providers do their business, and that social activism at every level will be needed to effect these changes. The discussion highlights many ethical issues that need much greater attention.


Fundamental movement skills proficiency in children with developmental coordination disorder: does physical self-concept matter?
The purpose of this study was to (1) examine differences in fundamental movement skills (FMS) proficiency, physical self-concept, and physical activity in children with and without developmental coordination disorder (DCD), and (2) determine the association of FMS proficiency with physical self-concept while considering key confounding factors. Participants included 43 children with DCD and 87 age-matched typically developing (TD) children. FMS proficiency was assessed using the Test of Gross Motor Development - second edition. Physical self-concept and physical activity were assessed using self-report questionnaires. A two-way (group by gender) ANCOVA was used to determine whether between-group differences existed in FMS proficiency, physical self-concept, and physical activity after controlling for age and BMI. Partial correlations and hierarchical multiple regression models were used to examine the relationship between FMS proficiency and physical self-concept. Compared with their TD peers, children with DCD displayed less proficiency in various components of FMS and viewed themselves as being less competent in physical coordination, sporting ability, and physical health. Physical coordination was a significant predictor of ability in object control skills. DCD status and gender were significant predictors of FMS proficiency. Future FMS interventions should target children with DCD and girls, and should emphasize improving object control skills proficiency and physical coordination. Children with DCD tend to have not only lower FMS proficiency than age-matched typically developing children but also lower physical self-concept. Self-perceptions of physical coordination by children with DCD are likely to be valuable contributors to development of object control skills. This may then help to develop their confidence in performing motor skills. Children with DCD need supportive programs that facilitate the development of object control skills. Efficacy of training programs may be improved if children experience a greater sense of control and success when performing object control skills.


Contrasting physiological effects of partial root zone drying in field-grown grapevine (Vitis vinifera L. cv. Monastrell) according to total soil water availability.
Different spatial distributions of soil moisture were imposed on field-grown grapevines by applying the same irrigation volumes to the entire (DI; deficit irrigation) or part of the (PRD; partial root zone drying) root zone. Five treatments were applied: controls irrigated at 60% ETc (crop evapotranspiration) for the whole season (308 mm year(-1)); DI-1 and PRD-1 that received the same irrigation as controls before fruit set, 30% ETc from fruit set to harvest and 45% ETc post-harvest (192 mm year(-1)); and DI-2 and PRD-2 that were the same, except that 15% ETc was applied from fruit set to harvest (142 mm year(-1)). Compared with DI-1, PRD-1 maintained higher leaf area post-veraison and increased root water uptake, whole-plant hydraulic conductance, leaf transpiration, stomatal conductance, and photosynthesis, but decreased intrinsic gas exchange efficiency without causing differences in leaf xylem abscisic acid (ABA) concentration. Compared with DI-2, PRD-2 increased leaf xylem ABA concentration and decreased root water uptake, whole-plant hydraulic conductance, leaf transpiration, stomatal conductance, and photosynthesis, mainly at the beginning of PRD cycles. Distinctive PRD effects (e.g. greater stomatal closure) depended on the volumetric soil water content of the wet root zone, as predicted from a model of root-to-shoot ABA signalling.


Fluoroquinolones and surgical prophylaxis.
The objective of surgical prophylaxis is to prevent wound infections associated with surgery. The rates of wound infections vary according to the procedure: less than 3 infections per 100 for clean procedures; up to 4 per 100 for clean-contaminated procedures; and up to 9 per 100 for contaminated procedures. Surgical antimicrobial prophylaxis has been shown in many randomised clinical trials to reduce the incidence of postoperative wound infections. Such prophylaxis is actually recommended in many clean-contaminated and some clean procedures. Because of their antimicrobial, pharmacokinetic, and antiadhesive properties, the fluoroquinolones have been recently proposed as prophylactic agents. Fluoroquinolones have proved to be useful in surgical prophylaxis and clinical trials have been performed in orthopaedic, cardiovascular, biliary, colorectal and urological surgery. According to the surgical procedure, fluoroquinolones were compared either with the standard antimicrobial regimen or with placebo. Different regimens of fluoroquinolones were also compared. Generally, fluoroquinolones have been demonstrated to be as effective as the reference prophylactic agent. In transurethral surgery, fewer postoperative wound infections were reported in the treated group than in the placebo group. In most studies, single dose prophylaxis was as effective as a multiple dose regimen. It is important to note that strict methodology was limited to a few clinical trials. In most of the studies, patients were not randomised in a double-blind fashion and small patient numbers often prevented the formation of satisfactory conclusions. Further trials are needed to define the role of the fluoroquinolones in surgical prophylaxis. It will be important to evaluate not only the efficacy but also the cost-benefit of perioperative prophylaxis with the fluoroquinolones. Clinical trials are also required in other high risk clean procedures such as neurosurgery involving shunts and ocular surgery. However, the risks related to the extensive use of fluoroquinolones in surgical prophylaxis must be considered, including the development and dissemination of resistant pathogens and the occurrence of adverse effects. In the future, surgical prophylaxis with prosthetic devices coated with fluoroquinolones should be considered.


Altered small-intestinal permeability associated with diarrhoea in human-immunodeficiency-virus-infected Caucasian and African subjects.
1. Small-intestine integrity in Caucasian and African patients infected with human immunodeficiency virus was determined by measuring the permeation across the mucosa of two sugars, lactulose and mannitol. 2. The sugars were assayed by h.p.l.c. and pulsed amperometric detection in 6 h urine samples. Stool microscopy for enteropathogens was performed in all patients. 3. The ratio of lactulose to mannitol recovered in urine was increased in Caucasian and African patients with advanced human immunodeficiency virus infection. Asymptomatic human-immunodeficiency-virus-infected subjects had a normal lactulose/mannitol ratio. African patients with diarrhoea showed a twofold reduction in mannitol excretion. Such a change in mannitol absorption was not detected in Caucasian patients and occurred regardless of the presence of enteropathogens. 4. Altered small-intestinal permeability is associated with symptomatic diarrhoea in human immunodeficiency virus infection in both Caucasian and African patients.


Mental Health Outcomes Among Military Service Members After Severe Injury in Combat and TBI.
Studies examining the mental health outcomes of military personnel deployed into combat zones have focused on the risk of developing post-traumatic stress disorder conferred by mild or moderate traumatic brain injury (TBI). However, other mental health outcomes among veterans who sustained critical combat injuries have not been described. We examined the associations of moderate and severe TBI and combat injury with the risk for anxiety and mood disorders, adjustment reactions, schizophrenia and other psychotic disorders, cognitive disorders, and post-traumatic stress disorder. We conducted a retrospective cohort study of U.S. military service members critically injured in combat during military operations in Iraq and Afghanistan from February 1, 2002, to February 1, 2011. Health care encounters from (1) the Department of Defense (DoD) Trauma Registry (TR), (2) acute and ambulatory care in military facilities, and (3) civilian facilities are reimbursed by Tricare. Service members who sustained severe combat injury require critical care. We estimated the risk of mental health outcomes using risk-adjusted logit models for demographic and clinical factors. We explored the relationship between TBI and the total number of mental health diagnoses. Of the 4,980 subjects who met inclusion criteria, most injuries occurred among members of the Army (72%) or Marines (25%), with mean (SD) age of 25.5(6.1) years. The prevalence of moderate or severe TBI was 31.6% with explosion as the most common mechanism of injury (78%). We found 71% of the cohort was diagnosed with at least one poor mental health condition, and the adjusted risk conferred by TBI ranged from a modest increase for anxiety disorder (odds ratio, 1.27; 95% confidence interval [CI], 1.11-1.45) to a large increase for cognitive disorder (odds ratio, 3.24; 95% CI, 2.78-3.77). We found TBI was associated with an increased number of mental health diagnoses (incidence rate ratio, 1.52; 95% CI, 1.42-1.63). Combat-associated TBI may have a broad effect on several mental health conditions among critically injured combat casualties. Early recognition and treatment for trauma-associated mental health are crucial to improving outcomes among service personnel as they transition to post-deployment care in the DoD, Department of Veterans Affairs, or community health systems.


Modification of surface pretreatment of white spot lesions to improve the safety and efficacy of resin infiltration.
A low-viscosity resin (infiltrant) was used to inhibit the progression of white spot lesions (WSLs) and resolve associated esthetic issues. An alternative pretreatment was explored to increase the pore volume of the surface layer of the WSLs. Also, the penetration effects of the infiltrant were evaluated for various pretreatments. Sixty two artificial lesions were fabricated on bovine teeth. As a positive control, 15% HCl gel was applied for 120 seconds. Further, 37% H3PO4 gel was applied for 30 seconds using three methods. The samples were divided as follows: H3PO4 only group, H3PO4 sponge group, and H3PO4 brush group. The acid was gently rubbed with the applicators (i.e., a sponge or brush) throughout the application time. To compare the effects of resin infiltration, twenty paired halves of specimens were treated with an infiltrant (ICON®). Thicknesses of the removed surface layers and infiltrated areas were evaluated by confocal laser scanning microscope. The positive control and the 37% H3PO4 brush group failed to show significant differences in the removed thickness (p > 0.05); however, the mean percentage of the infiltrated area was higher in the 37% H3PO4 brush group (84.13 ± 7.58%) than the positive control (63.51 ± 7.62%, p < 0.001). Scanning electron microscope observations indicate higher pore volumes for the 37% H3PO4 brush group than for the positive control. Application of 37% H3PO4 with a brush for 30 seconds increased the pore volume of WSL surface layers and the percentage of infiltrated areas in comparison to the use of 15% HCl for 120 seconds.


Measures of impulsivity in cigarette smokers and non-smokers.
Drug users are thought to be more "impulsive" than non-users. This study examined whether regular smokers are more impulsive than never smokers using personality and behavioral measures of impulsivity. Twenty regular smokers (>/=15 cigarettes/day) and 20 never smokers were recruited. Participants completed five personality questionnaires to assess impulsivity: Adjective Checklist, Barratt's Impulsivity Scale, the Tridimensional Personality Questionnaire, Eysenck's Personality Questionnaire, and the Sensation-Seeking Scale. Participants also performed three behavioral choice tasks designed to assess impulsivity. In the delay task, participants chose between small, immediate and large, delayed monetary rewards. Impulsivity was defined as a relative preference for the small, immediate alternative. In the probability task, participants chose between small, certain and large, uncertain monetary rewards. Impulsivity was defined as a relative preference for the large but more risky alternative. In the work task, participants chose between small monetary rewards obtained by performing a negligible amount of work and a larger amount of money requiring more work. Impulsivity was defined as a relative preference for the smaller, easier alternative. On the personality questionnaires, smokers had statistically higher impulsivity scores on most scales. On the behavioral choice tasks, smokers chose small, immediate money over large, delayed money more frequently, signifying greater levels of impulsivity. There were no differences between the groups' choices on the other tasks. Correlations between questionnaire and task data were small, as were correlations between data from each task. Together, these results indicate that the smokers were more impulsive than never smokers.


Success of Intubation Rescue Techniques after Failed Direct Laryngoscopy in Adults: A Retrospective Comparative Analysis from the Multicenter Perioperative Outcomes Group.
Multiple attempts at tracheal intubation are associated with mortality, and successful rescue requires a structured plan. However, there remains a paucity of data to guide the choice of intubation rescue technique after failed initial direct laryngoscopy. The authors studied a large perioperative database to determine success rates for commonly used intubation rescue techniques. Using a retrospective, observational, comparative design, the authors analyzed records from seven academic centers within the Multicenter Perioperative Outcomes Group between 2004 and 2013. The primary outcome was the comparative success rate for five commonly used techniques to achieve successful tracheal intubation after failed direct laryngoscopy: (1) video laryngoscopy, (2) flexible fiberoptic intubation, (3) supraglottic airway as part of an exchange technique, (4) optical stylet, and (5) lighted stylet. A total of 346,861 cases were identified that involved attempted tracheal intubation. A total of 1,009 anesthesia providers managed 1,427 cases of failed direct laryngoscopy followed by subsequent intubation attempts (n = 1,619) that employed one of the five studied intubation rescue techniques. The use of video laryngoscopy resulted in a significantly higher success rate (92%; 95% CI, 90 to 93) than other techniques: supraglottic airway conduit (78%; 95% CI, 68 to 86), flexible bronchoscopic intubation (78%; 95% CI, 71 to 83), lighted stylet (77%; 95% CI, 69 to 83), and optical stylet (67%; 95% CI, 35 to 88). Providers most frequently choose video laryngoscopy (predominantly GlideScope [Verathon, USA]) to rescue failed direct laryngoscopy (1,122/1,619; 69%), and its use has increased during the study period. Video laryngoscopy is associated with a high rescue intubation success rate and is more commonly used than other rescue techniques.


Enzymatically structured emulsions in simulated gastrointestinal environment: impact on interfacial proteolysis and diffusion in intestinal mucus.
Fundamental knowledge of physicochemical interactions in the gastrointestinal environment is required in order to support rational designing of protein-stabilized colloidal food and pharmaceutical delivery systems with controlled behavior. In this paper, we report on the colloidal behavior of emulsions stabilized with the milk protein sodium caseinate (Na-Cas), and exposed to conditions simulating the human upper gastrointestinal tract. In particular, we looked at how the kinetics of proteolysis was affected by adsorption to an oil-water interface in emulsion and whether the proteolysis and the emulsion stability could be manipulated by enzymatic structuring of the interface. After cross-linking with the enzyme transglutaminase, the protein was digested with use of an in vitro model of gastro-duodenal proteolysis in the presence or absence of physiologically relevant surfactants (phosphatidylcholine, PC; bile salts, BS). Significant differences were found between the rates of digestion of Na-Cas cross-linked in emulsion (adsorbed protein) and in solution. In emulsion, the digestion of a population of polypeptides of M(r) ca. 50-100 kDa was significantly retarded through the gastric digestion. The persistent interfacial polypeptides maintained the original emulsion droplet size and prevented the system from phase separating. Rapid pepsinolysis of adsorbed, non-cross-linked Na-Cas and its displacement by PC led to emulsion destabilization. These results suggest that structuring of emulsions by enzymatic cross-linking of the interfacial protein may affect the phase behavior of emulsion in the stomach and the gastric digestion rate in vivo. Measurements of ζ-potential revealed that BS displaced the remaining protein from the oil droplets during the simulated duodenal phase of digestion. Diffusion of the postdigestion emulsion droplets through ex vivo porcine intestinal mucus was only significant in the presence of BS due to the high negative charge these biosurfactants imparted to the droplets. This implies that the electrostatic repulsion produced can prevent the droplets from being trapped by the mucus matrix and facilitate their transport across the small intestine mucosal barrier.


PCR-CTPP design for enzyme-free SNP genotyping using memetic algorithm.
In recent years, many single nucleotide polymorphisms (SNPs) have been successfully genotyped by polymerase chain reaction with confronting two-pair primers (PCR-CTPP). However, computation experiments of feasible CTPP primers are still challenging. The melting temperatures between four primers must be within a very narrow range, and many primer constraints need to be conformed to. PCR-CTPP is a simple, time- and cost-effective SNP genotyping method applied in molecular biology and biomedical fields. In this study, an MA (memetic algorithm)-based method is proposed to enable the design of feasible CTPP primer sets. Overall, 288 SNPs which exclude the deletion/insertion polymorphisms (DIPs) and multi-nucleotide polymorphisms (MNPs) in the SLC6A4 gene were tested in silico. The results were compared with a GA (genetic algorithm)-based method and indicate that the proposed method provides more feasible CTPP primers than the GA-based method. The MA-based CTPP primer design method provides critical melting temperatures and all kinds of evaluation of the common primer constraints. It could conceivably assist biologists and other researchers in obtaining feasible CTTP primer sets. The MA-CTPP algorithm is implemented in JAVA and a user-friendly input interface is freely available at http://bio.kuas.edu.tw/ma-ctpp/.


VGLUT2 controls heat and punctuate hyperalgesia associated with nerve injury via TRPV1-Cre primary afferents.
Nerve injury induces a state of prolonged thermal and mechanical hypersensitivity in the innervated area, causing distress in affected individuals. Nerve injury-induced hypersensitivity is partially due to increased activity and thereby sustained release of neurotransmitters from the injured fibers. Glutamate, a prominent neurotransmitter in primary afferents, plays a major role in development of hypersensitivity. Glutamate is packed in vesicles by vesicular glutamate transporters (VGLUTs) to enable controlled release upon depolarization. While a role for peripheral VGLUTs in nerve injury-induced pain is established, their contribution in specific peripheral neuronal populations is unresolved. We investigated the role of VGLUT2, expressed by transient receptor potential vanilloid (TRPV1) fibers, in nerve injury-induced hypersensitivity. Our data shows that removal of Vglut2 from Trpv1-Cre neurons using transgenic mice abolished both heat and punctuate hyperalgesia associated with nerve injury. In contrast, the development of cold hypersensitivity after nerve injury was unaltered. Here, we show that, VGLUT2-mediated glutamatergic transmission from Trpv1-Cre neurons selectively mediates heat and mechanical hypersensitivity associated with nerve injury. Our data clarifies the role of the Trpv1-Cre population and the dependence of VGLUT2-mediated glutamatergic transmission in nerve injury-induced hyperalgesia.


Projecting the need for gynecologic oncologists for the next 40 years.
To estimate the ratio of gynecologic cancer cases to practicing gynecologic oncologists in the United States over the next 40 years. Using population projections from the U.S. Census Bureau and incidence and mortality rates from Surveillance, Epidemiology and End Results surveys, we estimated the annual number of new gynecologic cancer cases through 2050; the effects of human papillomavirus (HPV) vaccination was included in cervical cancer estimates. The number of practicing gynecologic oncologists was projected through 2050 using data from the 2005 Society of Gynecologic Oncologists Practice Survey, current Society of Gynecologic Oncologists membership information, American Board of Obstetrics and Gynecology and Gynecologic Oncology oral examination results, and mortality estimates from U.S. life tables. Projected time in practice was sex-dependent based on Society of Gynecologic Oncologists Practice Survey. For sensitivity analyses, we varied annual number and sex distribution of fellowship graduates, HPV vaccination coverage rates, and future incidence of overweight and obesity. At constant training rates, the annual number of new cancer cases per practicing gynecologic oncologist will rise from 112 in 2010 to 133 in 2050, a 19% increase. If the annual number of fellowship graduates increases by 25%, the ratio of cancer cases per gynecologic oncologist will decrease to 106, a 5% decrease. Projections are more sensitive to changes in physician demographics than to changes in HPV vaccination coverage rates. The gynecologic cancer caseload of practicing gynecologic oncologists will increase by almost 20% over the next 40 years at constant training rates. Changes in the projected sex distribution of fellowship graduates and their time in practice affect these projections.


Leucocyte Membrane-Coated Janus Microcapsules for Enhanced Photothermal Cancer Treatment.
Polyelectrolyte multilayer (PEM) capsules are promising candidates for many kinds of cancer detection and treatment but are usually intended to deliver cargo to specific sites or to destroy cancer cells based on photothermal effects from the outside. In this publication we prove that it is possible to kill cancer cells from the inside based on phagocytosed PEM capsules. In addition we show how to open the cells and bring the PEM capsules to the surface of cancer cells based on photothermal effects and rapid evaporation of water. Diffusion-based temperature determinations of the photothermal effect up to the evaporation temperature of water are presented.


Developmental predictors of inattention-hyperactivity from pregnancy to early childhood.
The objective of the study was to characterize the developmental sequence of pre- and postnatal risk factors for inattention-hyperactivity symptoms in preschoolers. Longitudinal data came from a French population based birth cohort study (EDEN; N = 1311 mother-child pairs followed from the pregnancy onwards). Inattention-hyperactivity symptoms were assessed with the Strengths and Difficulties Questionnaire when participating children were 3 years of age. Potential risk factors were classified in four domains (fetal exposures and child somatic characteristics, child temperament, child neurodevelopmental status, psychosocial environment) and four periods (before pregnancy, prenatal/birth, infancy, toddlerhood). Their role as potential moderator or mediator was tested with path analysis to determine the developmental sequence. A low family socioeconomic status before pregnancy was the main environmental risk factor for inattention-hyperactivity symptoms at 3 years, and its effect occurred via two pathways. The first was a risk pathway, where lower SES was associated with higher maternal depression and anxiety during pregnancy; then to higher maternal and child distress and dysregulation in infancy; and in turn to higher levels of inattention-hyperactivity at 3 years. The second was a protective pathway, where higher SES was associated with longer duration of breastfeeding during infancy; then to better child neurodevelopmental status in toddlerhood; and in turn to lower levels of inattention-hyperactivity at 3 years. This study identified psychosocial factors at several developmental periods that represent potential targets for preventing the emergence of inattention-hyperactivity symptoms in early childhood.


Fish otoliths: daily growth layers and periodical patterns.
The early-stage annual rings in otoliths from some cold-temperate fish consist of thin growth bands, the number of which corresponds to that of the days in a year. This indicates that growth takes place by daily increments. Other recurrent patterns show a fortnightly and monthly periodicity. Spawning rings are microscopically distinguishable from winter rings.


Prediction of the risk of coronary arterial lesions in Kawasaki disease by brain natriuretic peptide.
Kawasaki disease (KD) is an acute systemic vasculitis associated with the development of coronary arterial lesions (CALs) occurring in 3-5% of children treated by intravenous immune globulin (IVIG). However, a considerable number of patients who are not responding to IVIG are at much higher risk. Although studies have explored potential biomarkers to predict patients with KD who are at risk of CAL, no useful single marker exists. We hypothesized that the serum concentrations of the N-terminal moiety of brain natriuretic peptide (NT-proBNP) can be useful to predict CAL. Forty-three children with KD (29 males and 14 females) were enrolled in this study. Despite IVIG, 6 of the 43 patients developed CAL. There were, however, no significant differences in variables between children with CAL and those without CAL: These include age, gender, day of the illness, leukocyte count, and the serum levels of sodium, C-reactive protein, and albumin. The serum NT-proBNP level was significantly higher in children with CAL than those without CAL (2,611 ± 1,699 vs. 1,073 ± 1,427 pg/ml; P = 0.03): the cutoff value of 1,000 pg/ml to predict CAL produced a specificity of 0.68, sensitivity of 0.83, and an odds ratio as high as 10.4. In conclusion, NT-proBNP is increased in KD patients who are developing CAL, and patients with an elevated serum NT-proBNP >1,000 pg/ml have a risk of CAL ~10 times higher than that of patients with a modest increase.


Finite-temperature second-order many-body perturbation and Hartree-Fock theories for one-dimensional solids: an application to Peierls and charge-density-wave transitions in conjugated polymers.
Finite-temperature extensions of ab initio Gaussian-basis-set spin-restricted Hartree-Fock (HF) and second-order many-body perturbation (MP2) theories are implemented for infinitely extended, periodic, one-dimensional solids and applied to the Peierls and charge-density-wave (CDW) transitions in polyyne and all-trans polyacetylene. The HF theory predicts insulating CDW ground states for both systems in their equidistant structures at low temperatures. In the same structures, they turn metallic at high temperatures. Starting from the "dimerized" low-temperature equilibrium structures, the systems need even higher temperatures to undergo a Peierls transition, which is accompanied by geometric as well as electronic distortions from dimerized to non-dimerized forms. The conventional finite-temperature MP2 theory shows a sign of divergence in any phase at any nonzero temperature and is useless. The renormalized finite-temperature MP2 (MP2R) theory is divergent only near metallic electronic structures, but is well behaved elsewhere. MP2R also predicts CDW and Peierls transitions occurring at two different temperatures. The effect of electron correlation is primarily to lower the Peierls transition temperature.


The effect of two hologram-copying parameters on the quality of copies.
Two parameters are discussed: (1) the orientation of the plate assembly, consisting of the original hologram and a copy plate, relative to a laser copying beam, and (2) the separation between the original hologram and the copy plate. The data presented demonstrate that the optimum arrangement for the production of hologram copies requires that the plate assembly be held in vacuum contact, and that the laser copy beam enters the plate assembly in the reference beam direction of the original hologram. These optimum copies display reconstructed virtual images identical in angular extent and similar in quality to those reconstructed from the original. Copies made at angles other than the optimum angle display only certain portions of the original scene. The portion of the scene displayed is related to the copy angle and the angle in which light was scattered when the original hologram was exposed.


Impact and determinants of sex preference in Nepal.
Gender discrimination and son preference are key demographic features of South Asia and are well documented for India. However, gender bias and sex preference in Nepal have received little attention. 1996 Nepal Demographic and Health Survey data on ever-married women aged 15-49 who did not desire any more children were used to investigate levels of gender bias and sex preference. The level of contraceptive use and the total fertility rate in the absence of sex preference were estimated, and logistic regression was performed to analyze the association between socioeconomic and demographic variables and stopping childbearing after the birth of a son. Commonly used indicators of gender bias, such as sex ratio at birth and sex-specific immunization rates, do not suggest a high level of gender discrimination in Nepal. However, sex preference decreases contraceptive use by 24% and increases the total fertility rate by more than 6%. Women's contraceptive use, exposure to the media, parity, last birth interval, educational level and religion are linked to stopping childbearing after the birth of a boy, as is the ethnic makeup of the local area. The level of sex preference in Nepal is substantial. Sex preference is an important barrier to the increase of contraceptive use and decline of fertility in the country; its impact will be greater as desired family size declines.


[Malnutrition and obesity in Brazil: dealing with the problem through a unified nutritional agenda].
Brazil, like other developing countries, is currently experiencing a nutritional transition that is often determined by poor eating. Population-based surveys have shown a continuing downward trend in undernutrition in this country, together with increases in excess weight at different stages of life. Monitoring the nutritional profile helps generate an attitude of surveillance and orientation of health promotion activities. The Family Health Strategy, together with various situational aspects in Brazil, has shown tangible results in the reduction of undernutrition; still, poor eating has played a major role in the increased prevalence of obesity and other chronic non-communicable diseases, besides having a heavy impact on individual quality of life and placing a significant burden on the Unified National Health System. Intervening in this contemporary public health dilemma requires prioritizing a unified nutritional agenda focused on the entire course of life, breaking the vicious circle that begins during the intrauterine period and lasts throughout life.


Analysis of the organization of multicopy linear- and circular-plasmid-carried open reading frames in Borrelia burgdorferi sensu lato isolates.
Plasmid cp8.3 of Borrelia afzelii IP21 carries several open reading frames (ORFs) and a 184-bp inverted repeat (IR) element. It has been speculated that this plasmid may encode factors involved in virulence or infectivity. In this report, we have characterized the distribution, molecular variability, and organization of ORFs 1, 2, and 4 and the IR elements among isolates of the Borrelia burgdorferi sensu lato complex. ORFs 1 and 2 are contained within a segment of cp8.3 that is bordered by the IR elements, while ORF 4 resides just outside of the IR-bordered region. By PCR, ORF 4 was amplified from most isolates while ORFs 1 and 2 were amplified from only some B. afzelii isolates. However, Southern hybridization analyses with ORF 1, 2, and 4 probes detected related sequences even in some isolates that were PCR negative. The ORF restriction fragment length polymorphism patterns varied widely even among isolates of the same species. Two-dimensional contour-clamped homogeneous electric field-pulsed-field gel electrophoresis and Southern hybridization detected ORF 1-, 2-, and 4-related sequences on linear and circular plasmids. In addition, an ORF 4-related sequence was detected on a previously uncharacterized, circular plasmid that is greater than 70 kb in size. The IR elements originally identified on plasmid cp8.3 of B. afzelii IP21 were also analyzed by Southern hybridization. Related sequences were detected in some but not all B. burgdorferi sensu lato isolates. These sequences are carried on plasmids in addition to cp8.3 in some isolates. Single-primer PCR analyses demonstrated that in some isolates these sequences exist with IR orientation. The data presented here demonstrate that the IR elements and the ORF 1-, 2-, and 4-related sequences are multicopy and are variable in organization and in genomic location among isolates of the B. burgdorferi sensu lato complex. These analyses provide additional evidence for the highly variable organization of the plasmid component of the B. burgdorferi sensu lato genome.


Advances in the treatment of gastroenteropancreatic neuroendocrine tumors.
Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are a rare and heterogeneous class of neoplasms. While surgical resection is the mainstay of treatment, non-surgical therapies play a role in the setting of unresectable and metastatic disease. The goals of medical therapy are directed both at alleviating symptoms of peptide release and shrinking tumor mass. Biotherapies such as somatostatin analogs and interferon can decrease the secretion of peptides and inhibit their end-organ effects. A second objective for treatment of unresectable GEP-NETs is limiting tumor growth. Options for limiting tumor growth include somatostatin analogs, systemic chemotherapy, locoregional therapies, ionizing radiation, external beam radiation, and newer targeted agents. In particular, angiogenesis inhibitors, tyrosine kinase inhibitors, and mTOR inhibitors have shown early promising results. The rarity of these tumors, their resistance to standard chemotherapy, and the excellent performance status of most of these patients, make a strong argument for consideration of novel therapeutic trials.


Hypersensitivity reaction associated with phenytoin.
Hypersensitivity reactions with antiepileptic drugs (AEDs) are generally associated with aromatic AEDs. We present a case of hypersensitivity reactions followed by administration of phenytoin with diazepam and ranitidine in a patient with generalized tonic-clonic seizures. Antigen-antibody reactions or decreased levels of epoxide hydrolase are well known with phenytoin. Increased level of serum phenytoin causing toxicities due to competitive inhibition with diazepam on co-administration was also reported in the literature. Prevention of the adverse effects with AEDs is a multi-stage process, which requires implementation of preventive measures through careful monitoring and prompts interventions.


A critical overview of the current myofascial pain literature - January 2018.
The majority of papers included in the quarterly review discuss various aspects of dry needling (DN), which continues to be of interest to researchers and clinicians. A study by Liu et al. is the first paper to examine the effects of DN of acetylcholine, esterase and receptors. The study provides support for the integrated trigger point hypothesis and for DN. A paper by Hightower and colleagues found an intriguing link between low magnesium levels in the drink water supply, vitamin D, and myofascial pain, cancer, tendon ruptures, and colon polyps. Contributions originated in the Brazil, China, Germany, Iran, India, Poland, South Korea, Spain, Taiwan, Turkey, and the US.


Circulating pentraxin 3 levels are higher in metabolic syndrome with subclinical atherosclerosis: evidence for association with atherogenic lipid profile.
Metabolic syndrome is characterized by increased cardiovascular risk. Pentraxin 3 (PTX3), an acute phase protein, is involved in atherosclerosis. No information is available on PTX3 plasma concentrations in metabolic syndrome and on its associations with metabolic alterations and subclinical atherosclerosis. The aim of this study was to assess PTX3 plasma levels in metabolic syndrome patients compared to control subjects and their potential associations with anthropometric and clinical components of the syndrome as well as with carotid artery intima-media thickness (cIMT), a marker of subclinical atherosclerosis. Plasma was obtained from metabolic syndrome patients (NCEP-ATP III criteria n = 41, 20 M/21F) and by age-matched control subjects (n = 32, 16 M/16F). PTX3 was measured using sandwich ELISA and cIMT with ultrasound. Compared to those of the control subjects, plasma levels of PTX3 were higher (? * 100%, P = 0.0009) in metabolic syndrome patients. In univariate analysis, plasma PTX3 was negatively (P = 0.005) associated with high-density lipoprotein (HDL) cholesterol and positively (P = 0.046) with plasma triglycerides and with cIMT (P = 0.045) in the patients (n = 41). In multivariate analysis the direct association between PTX3 and cIMT was no longer significant after correction for HDL. None of these associations were detected in the control patients. These data demonstrate that PTX3, a novel marker of vascular disease, is higher in patients with metabolic syndrome associated with subclinical atherosclerosis. In addition, PTX3 is significantly independently correlated with low HDL cholesterol, but not with cIMT, suggesting a novel association between PTX3 and atherogenic lipid profile.


To Run or Not to Run? Automatic Evaluations and Reflective Attitudes Toward Exercise.
Using an evaluative priming procedure, this study tested whether automatic evaluations of running differ among groups based on their amount of exercise and whether they were runners or not. Ninety-five participants (26 ± 5.06 years; 46% female) were divided into five groups: an inactive group, active exercisers, highly active exercisers, active runners, and highly active runners. A priming effect score was calculated based on the concept of response facilitation or inhibition: the reaction is faster when the target and prime are valence congruent and becomes slower if they are incongruent. The highly active runner group differed significantly from the inactive group (p < .01) and from the active exerciser group (p < .05). Furthermore, reflective evaluations were measured via questionnaires. The results show that priming effect scores can detect automatic evaluations of running, and they differ not only because of the amounts of physical exercise but also because of their preferred type of exercise.


Nanoscale mechanics of microgel particles.
Microgel particles are highly tuneable materials that are useful for a wide range of industrial applications, such as drug delivery, sensing, nanoactuation, emulsion stabilisation and use as cell substrates. Microgels have also been used as model systems investigating physical phenomena such as crystallization, glass-formation, jamming, ageing and complex flow behaviour. The responsiveness of microgel systems such as poly(N-isopropylacrylamide) (PNIPAm) to external stimuli has been established in fundamental investigations and in applications and recent work has begun to quantify the mechanics of individual particles. However little focus has been placed on determining their internal mechanical properties, which is likely to relate to their nonuniform internal structure. In this work we combine atomic force microscopy, force spectroscopy and dynamic light scattering to mechanically profile the internal structure of microgel particles in the size range of ∼100 nm, which is commonly used both in practical applications and in fundamental studies. Nanoindentation using thermally stable cantilevers allows us to determine the particle moduli and the deformation profiles during particle compression with increasing force, while peak force nanomechanical mapping (PF-QNM) AFM is used to capture high resolution images of the particles' mechanical response. Combining these approaches with dynamic light scattering allows a quantitative profile of the particles' internal elastic response to be determined. Our results provide clear evidence for a radial distribution in particle mechanical response with a softer outer "corona" and a stiffer particle core. We determine the particle moduli in the core and corona, using different force microscopy approaches, and find them to vary systematically both in the core (∼17-50 kPa) and at the outer periphery of the particles (∼3-40 kPa). Importantly, we find that highly crosslinked particles have equivalent moduli across their radial profile, reflecting their significantly lower radial heterogeneity. This ability to accurately and precisely probe microgel radial profiles has clear implications both for fundamental science and for industrial applications.


Cognitive therapy for post-traumatic stress disorder: development and evaluation.
The paper describes the development of a cognitive therapy (CT) program for post-traumatic stress disorder (PTSD) that is based on a recent cognitive model (Behav. Res. Therapy 38 (2000) 319). In a consecutive case series, 20 PTSD patients treated with CT showed highly significant improvement in symptoms of PTSD, depression and anxiety. A subsequent randomized controlled trial compared CT (N = 14) and a 3-month waitlist condition (WL, N = 14). CT led to large reductions in PTSD symptoms, disability, depression and anxiety, whereas the waitlist group did not improve. In both studies, treatment gains were well maintained at 6-month follow-up. CT was highly acceptable, with an overall dropout rate of only 3%. The intent-to-treat effect sizes for the degree of change in PTSD symptoms from pre to post-treatment were 2.70-2.82 (self-report), and 2.07 (assessor-rated). The controlled effect sizes for CT versus WL post-treatment scores were 2.25 (self-report) and 2.18 (assessor-rated). As predicted by the cognitive model, good treatment outcome was related to greater changes in dysfunctional post-traumatic cognitions. Patient characteristics such as comorbidity, type of trauma, history of previous trauma, or time since the traumatic event did not predict treatment response, however, low educational attainment and low socioeconomic status were related to better outcome.


Bioregion heterogeneity correlates with extensive mitochondrial DNA diversity in the Namaqua rock mouse, Micaelamys namaquensis (Rodentia: Muridae) from southern Africa--evidence for a species complex.
Intraspecific variation within the diverse southern African murine rodents has not been extensively investigated, yet cryptic diversity is evident in several taxa studied to date. The Namaqua rock mouse, Micaelamys namaquensis Smith, 1834 is a widespread endemic murine rodent from the subregion. Currently, a single species with four subspecies is recognised, but in the past up to 16 subspecies were described. Thus, this species is a good candidate for the investigation of patterns and processes of diversification in a diverse but under-studied mammalian subfamily and geographic region. Here, we report genetic differentiation based on mitochondrial DNA (mtDNA) cytochrome b (cyt b) sequences among samples collected over an extensive coverage of the species' range. Cytochrome b sequences of 360 widely sampled individuals identified 137 unique maternal alleles. Gene tree and phylogeographic analyses of these alleles suggest the presence of at least eight lineages or haplogroups (A-H), with varying degrees of intra-lineage diversity. This differentiation is in contrast with the most recent taxonomic treatment based on cranial morphometrics which only recognised four subspecies. The mtDNA diversity strongly supports earlier views that this taxon may represent a species complex. We further show statistical support for the association of several of these lineages with particular vegetation biomes of southern Africa. The time to the most recent common ancestor (TMRCA) dates to the Pliocene (~5 Mya) whereas coalescent-based divergence time estimates between lineages vary between 813 Kya [0.22-1.36] and 4.06 Mya [1.21-4.47]. The major diversification within lineages occurred during the Pleistocene. The identification of several regions of sympatry of distinct lineages offers future opportunities for the elucidation of the underlying speciation processes in the suggested species complex. Similar to other African murine rodents, M. namaquensis radiated during the Pliocene and Pleistocene coinciding with major periods of aridification and the expansion of savanna habitats. The suggested species complex is represented by at least eight lineages of which the majority are confined to only one or a few neighbouring biomes/bioregions. Contrasting intra-lineage phylogeographic patterns suggest differences in adaptation and responses to Plio-Pleistocene climatic and vegetation changes. The role of ecological factors in driving speciation in the group needs further investigation.


Drug Discovery for Kinetoplastid Diseases: Future Directions.
Kinetoplastid parasites have caused human disease for millennia. Significant achievements have been made toward developing new treatments for leishmaniasis (particularly on the Indian subcontinent) and for human African trypanosomiasis (HAT). Moreover, the sustained decrease in the incidence of HAT has made the prospect of elimination a tantalizing reality. Despite the gains, no new chemical or biological entities to treat kinetoplastid diseases have been registered in more than three decades, and more work is needed to discover safe and effective therapies for patients with Chagas disease and leishmaniasis. Advances in tools for drug discovery and novel insights into the biology of the host-parasite interaction may provide opportunities for accelerated progress. Here, we summarize the output from a gathering of scientists and physicians who met to discuss the current status and future directions in drug discovery for kinetoplastid diseases.


Kinetochore-independent chromosome poleward movement during anaphase of meiosis II in mouse eggs.
Kinetochores are considered to be the key structures that physically connect spindle microtubules to the chromosomes and play an important role in chromosome segregation during mitosis. Due to different mechanisms of spindle assembly between centrosome-containing mitotic cells and acentrosomal meiotic oocytes, it is unclear how a meiotic spindle generates the poleward forces to drive two rounds of meiotic chromosome segregation to achieve genome haploidization. We took advantage of the fact that DNA beads are able to induce bipolar spindle formation without kinetochores and studied the behavior of DNA beads in the induced spindle in mouse eggs during meiosis II. Interestingly, DNA beads underwent poleward movements that were similar in timing and speed to the meiotic chromosomes, although all the beads moved together to the same spindle pole. Disruption of dynein function abolished the poleward movements of DNA beads but not of the meiotic chromosomes, suggesting the existence of different dynein-dependent and dynein-independent force generation mechanisms for the chromosome poleward movement, and the latter may be dependent on the presence of kinetochores. Consistent with the observed DNA bead poleward movement, sperm haploid chromatin (which also induced bipolar spindle formation after injection to a metaphase egg without forming detectable kinetochore structures) also underwent similar poleward movement at anaphase as DNA beads. The results suggest that in the chromatin-induced meiotic spindles, kinetochore attachments to spindle microtubules are not absolutely required for chromatin poleward movements at anaphase.


Novel anti-melanoma immunotherapies: disarming tumor escape mechanisms.
The immune system fights cancer and sometimes temporarily eliminates it or reaches an equilibrium stage of tumor growth. However, continuous immunological pressure also selects poorly immunogenic tumor variants that eventually escape the immune control system. Here, we focus on metastatic melanoma, a highly immunogenic tumor, and on anti-melanoma immunotherapies, which recently, especially following the FDA approval of Ipilimumab, gained interest from drug development companies. We describe new immunomodulatory approaches currently in the development pipeline, focus on the novel CEACAM1 immune checkpoint, and compare its potential to the extensively described targets, CTLA4 and PD1. This paper combines multi-disciplinary approaches and describes anti-melanoma immunotherapies from molecular, medical, and business angles.


Genetically predicted testosterone and systemic inflammation in men: a separate-sample Mendelian randomization analysis in older Chinese men.
Observationally, testosterone is negatively associated with systemic inflammation, but this association is open to both residual confounding and reverse causality. Large-scale randomized controlled trials (RCTs), assessing exogenous effects, are presently unavailable. We examined the association of endogenous testosterone with well-established systemic inflammatory markers (white blood cell, granulocyte, lymphocyte and high-sensitivity C-reactive protein (hsCRP)) using a separate-sample Mendelian randomization analysis to minimize reverse causality. A genetic prediction rule for serum testosterone was developed in 289 young Chinese men with mean age of 21.0, using selected testosterone-related SNPs (rs10046, rs1008805 and rs1256031). Multivariable linear regression was used to examine the association of genetically predicted serum testosterone with inflammatory markers among 4,212 older Chinese men from the Guangzhou Biobank Cohort Study. Genetically predicted testosterone was unrelated to white blood cell count (-0.01 109/L per nmol/L testosterone, 95% confidence interval (CI) -0.05 to 0.04), granulocyte count (-0.02 109/L, 95% CI -0.06 to 0.02), lymphocyte count (0.005 109/L, 95% CI -0.01 to 0.02) and hsCRP (-0.05 mg/L, 95% CI -0.15 to 0.06). Our findings did not corroborate any anti-inflammatory effects of testosterone or corresponding potentially protective effects of testosterone on chronic diseases resulting from reduced low-grade systemic inflammation.


Treatment of an acquired Factor XIII inhibitor in an adolescent with systemic lupus erythematosus and renal failure.
Factor (F)XIII deficiency is a rare inherited bleeding disorder, but can also be acquired due to the development of inhibitors. A 17-year-old female with systemic lupus erythematosus and end-stage kidney disease secondary to Class IV lupus nephritis developed spontaneous subcutaneous and muscular hematomas and delayed major bleeding after invasive procedures. She had abnormal kaolin thromboelastography (kTEG; decreased maximal amplitude, representative of clot strength) initially attributed to thrombocytopenia and uremic platelet dysfunction, but her FXIII activity was undetectable, and a high-titer antibody against FXIII was identified. She had improvement in clinical bleeding and in kaolin thromboelastogram result and transient improvement in FXIII activity after each dose of plasma-derived FXIII concentrate (Corifact) or cryoprecipitate. Her inhibitor titers gradually improved with multiple immunosuppressive therapies and plasma exchange. While her FXIII activity level remained mildly decreased, she has not had additional significant bleeding. Treatment with either plasma-derived FXIII or cryoprecipitate is an effective treatment to normalize the kTEG variables and clinical bleeding diatheses associated with acquired FXIII inhibitors. Higher doses may be needed in patients with high-titer inhibitor.


The temporal advantage for individuating objects of expertise: perceptual expertise is an early riser.
The identification of faces has a temporal advantage over that of other object categories. The orientation-specific nature of this advantage suggests that it stems from our extensive experience and resulting expertise with upright faces. While experts can identify objects faster than novices, it is unclear exactly how the temporal dynamics of identification are changed by expertise and whether the nature of this temporal advantage is similar for face and non-face objects of expertise. Here, we titrated encoding time using a backward-masking paradigm with variable stimulus-mask onset-asynchronies and mapped the resulting effect on recognition for upright and inverted faces (Experiment 1) and for cars among car experts and car novices (Experiment 2). Performance for upright faces and cars among car experts rose above chance between 33 and 70 ms before that for inverted faces or cars among car novices. A shifted exponential function fitted to these data suggested that performance started to rise earlier for experts than for novices, but that additional encoding time increased performance at a similar rate. Experience influences the availability of information early in processing, possibly through the recruitment of more category-selective neurons, while the rate of perceptual processing may be less flexible and limited by inherent physiological constraints.


Regional variation in colorectal cancer testing and geographic availability of care in a publicly insured population.
Despite its demonstrated effectiveness, colorectal cancer (CRC) testing is suboptimal, particularly in vulnerable populations such as those who are publicly insured. Prior studies provide an incomplete picture of the importance of the intersection of multilevel factors affecting CRC testing across heterogeneous geographic regions where vulnerable populations live. We examined CRC testing across regions of North Carolina by using population-based Medicare and Medicaid claims data from disabled individuals who turned 50 years of age during 2003-2008. We estimated multilevel models to examine predictors of CRC testing, including distance to the nearest endoscopy facility, county-level endoscopy procedural rates, and demographic and community contextual factors. Less than 50% of eligible individuals had evidence of CRC testing; men, African-Americans, Medicaid beneficiaries, and those living furthest away from endoscopy facilities had significantly lower odds of CRC testing, with significant regional variation. These results can help prioritize intervention strategies to improve CRC testing among publicly insured, disabled populations.


Ethical issues in pediatric emergency mass critical care.
As a result of recent events, including natural disasters and pandemics, mass critical care planning has become a priority. In general, planning involves limiting the scope of disasters, increasing the supply of medical resources, and allocating scarce resources. Entities at varying levels have articulated ethical frameworks to inform policy development. In spite of this increased focus, children have received limited attention. Children require special attention because of their unique vulnerabilities and needs. In May 2008, the Task Force for Mass Critical Care published guidance on provision of mass critical care to adults. Acknowledging that the critical care needs of children during disasters were unaddressed by this effort, a 17-member Steering Committee, assembled by the Oak Ridge Institute for Science and Education with guidance from members of the American Academy of Pediatrics, convened in April 2009 to determine priority topic areas for pediatric emergency mass critical care recommendations.Steering Committee members established subgroups by topic area and performed literature reviews of MEDLINE and Ovid databases. Draft documents were subsequently developed and revised based on the feedback from the Task Force. The Pediatric Emergency Mass Critical Care Task Force, composed of 36 experts from diverse public health, medical, and disaster response fields, convened in Atlanta, GA, on March 29-30, 2010. This document reflects expert input from the Task Force in addition to the most current medical literature. The Ethics Subcommittee recommends that surge planning seek to provide resources for children in proportion to their percentage of the population or preferably, if data are available, the percentage of those affected by the disaster. Generally, scarce resources should be allocated on the basis of need, benefit, and the conservation of resources. Estimates of need, benefit, and resource utilization may be more subjective or objective. While the Subcommittee favors more objective methods, pediatrics lacks a simple, validated scoring system to predict benefit or resource utilization. The Subcommittee hesitantly recommends relying on expert opinion while pediatric triage tools are developed. If resources remain inadequate, they should then be allocated based on queuing or lottery. Choosing between these methods is based on ethical, psychological, and practical considerations upon which the Subcommittee could not reach consensus. The Subcommittee unanimously believes the proposal to favor individuals between 15 and 40 yrs of age is inappropriate. Other age-based criteria and criteria based on social role remain controversial. The Subcommittee recommends continued work to engage all stakeholders, especially the public, in deliberation about these issues.


Binding of azobenzene and p-diaminoazobenzene to the human voltage-gated sodium channel Nav1.4.
The activity of voltage-gated ion channels can be controlled by the binding of photoswitches inside their internal cavity and subsequent light irradiation. We investigated the binding of azobenzene and p-diaminoazobenzene to the human Nav1.4 channel in the inactivated state by means of Gaussian accelerated molecular dynamics simulations and free-energy computations. Three stable binding pockets were identified for each of the two photoswitches. In all the cases, the binding is controlled by the balance between the favorable hydrophobic interactions of the ligands with the nonpolar residues of the protein and the unfavorable polar solvation energy. In addition, electrostatic interactions between the ligand and the polar aminoacids are also relevant for p-diaminoazobenzene due to the presence of the amino groups on the benzene moieties. These groups participate in hydrogen bonding in the most favorable binding pocket and in long-range electrostatic interactions in the other pockets. The thermodinamically preferred binding sites found for both photoswitches are close to the selectivity filter of the channel. Therefore, it is very likely that the binding of these ligands will induce alterations in the ion conduction through the channel.