Genetic Analysis of Association Between Calcium Signaling and Hippocampal Activation, Memory Performance in the Young and Old, and Risk for Sporadic Alzheimer Disease.
Human episodic memory performance is linked to the function of specific brain regions, including the hippocampus; declines as a result of increasing age; and is markedly disturbed in Alzheimer disease (AD), an age-associated neurodegenerative disorder that primarily affects the hippocampus. Exploring the molecular underpinnings of human episodic memory is key to the understanding of hippocampus-dependent cognitive physiology and pathophysiology. To determine whether biologically defined groups of genes are enriched in episodic memory performance across age, memory encoding-related brain activity, and AD. In this multicenter collaborative study, which began in August 2008 and is ongoing, gene set enrichment analysis was done by using primary and meta-analysis data from 57 968 participants. The Swiss cohorts consisted of 3043 healthy young adults assessed for episodic memory performance. In a subgroup (n = 1119) of one of these cohorts, functional magnetic resonance imaging was used to identify gene set-dependent differences in brain activity related to episodic memory. The German Study on Aging, Cognition, and Dementia in Primary Care Patients cohort consisted of 763 elderly participants without dementia who were assessed for episodic memory performance. The International Genomics of Alzheimer's Project case-control sample consisted of 54 162 participants (17 008 patients with sporadic AD and 37 154 control participants). Analyses were conducted between January 2014 and June 2015. Gene set enrichment analysis in all samples was done using genome-wide single-nucleotide polymorphism data. Episodic memory performance in the Swiss cohort and German Study on Aging, Cognition, and Dementia in Primary Care Patients cohort was quantified by picture and verbal delayed free recall tasks. In the functional magnetic resonance imaging experiment, activation of the hippocampus during encoding of pictures served as the phenotype of interest. In the International Genomics of Alzheimer's Project sample, diagnosis of sporadic AD served as the phenotype of interest. In the discovery sample, we detected significant enrichment for genes constituting the calcium signaling pathway, especially those related to the elevation of cytosolic calcium (P = 2 × 10-4). This enrichment was replicated in 2 additional samples of healthy young individuals (P = .02 and .04, respectively) and a sample of healthy elderly participants (P = .004). Hippocampal activation (P = 4 × 10-4) and the risk for sporadic AD (P = .01) were also significantly enriched for genes related to the elevation of cytosolic calcium. By detecting consistent significant enrichment in independent cohorts of young and elderly participants, this study identified that calcium signaling plays a central role in hippocampus-dependent human memory processes in cognitive health and disease, contributing to the understanding and potential treatment of hippocampus-dependent cognitive pathology.


Impaired bactericidal activity of PMN from two brothers with necrotizing ulcerative gingivo-periodontitis.
The purpose of this study was to investigate the pathogenesis of necrotizing ulcerative gingivo-periodontitis (ANUP) diagnosed in two brothers, age 9 (ANUP1) and 14 (ANUP2) from rural Egypt. Complete blood count, differential and blood chemistry were within normal limits for both brothers and they were not malnourished. The phagocytosis and killing function of their polymorphonuclear leukocytes (PMN) towards four bacterial species were assessed using a fluorochrome microassay. The selection of bacterial species was based on preliminary microbiological results in early onset periodontitis in Egypt. Fluorochrome-labeled Prevotella intermedia, Peptostreptococcus micros, Campylobacter rectus, and Porphyromonas gingivalis were pre-opsonized with ANUP serum and added to PMN from both ANUP patients, as well as PMN from three sex-matched and two sex- and age-matched healthy Egyptian control (CTL) subjects. We found significant depressions (P < 0.05) in PMN phagocytosis and killing of C. rectus and P. intermedia by ANUP1 and ANUP2, when compared to all CTL PMN. An assessment of the Gram-negative subgingival microflora present in both ANUP patients (in colony forming unit percent of total CFU recovered) (CFU %) revealed the presence of P. intermedia (ANUP1, 41.7 CFU %; ANUP2, 14.8 CFU %), Fusobacterium nucleatum (ANUP1, 3.6 CFU %; ANUP2, 48.1 CFU %), and Veillonella spp. (ANUP1, 18.2 CFU %; ANUP2, 18.5 CFU %). Spirochetes were also observed in cytocentrifuged, Gram-stained plaque from both ANUP patients. The predominant Gram-positive bacterial species recovered from both NUG1 and NUG2 was Streptococcus morbillorum.


Na+,K(+)-ATPase of human placenta during gestational hypertension: a biochemical-biophysical study.
1. Na+,K(+)-ATPase is the membrane enzyme catalysing the active transport of Na+ and K+ across the plasma membrane of animal cells. A reduced activity of Na+,K(+)-ATPase has been described in gestational hypertension in a variety of cell types, in agreement with the hypothesis that gestational hypertension can induce membrane transport modifications similar to those reported for essential hypertension. The causes of the reduced Na+,K(+)-ATPase activity are still debated. 2. The aim of the present work was to investigate the molecular mechanism of the reduced enzymic activity in gestational hypertension using as a model Na+,K(+)-ATPase purified from human placenta. Na+,K(+)-ATPase obtained from term placentas of eight healthy pregnant women and eight age-matched women with gestational hypertension was purified as previously described. 3. We observed in gestational hypertension: (i) a significant increase in the activation energies above transition temperature; (ii) a significant decrease in the fluorescence polarization of 1-(4-trimethylaminophenyl)-6-phenyl-1,3,5-hexatriene (i.e. increased fluidity) and an increase in the mean lifetime (modified hydrophobicity); (iii) a lower Kq, suggesting an enzymic structural modification; and (iv) an increased mean lifetime and rotational relaxation time of pyrene isothiocyanate, indicating a modified ATP binding site.


Lysosomal dysfunction increases exosome-mediated alpha-synuclein release and transmission.
Alpha-synuclein aggregation plays a central role in Parkinson's disease pathology. Direct transmission of alpha-synuclein from pathologically affected to healthy unaffected neurons may be important in the anatomical spread of the disease through the nervous system. We have demonstrated that exosomes released from alpha-synuclein over-expressing SH-SY5Y cells contained alpha-synuclein and these exosomes were capable of efficiently transferring alpha-synuclein protein to normal SH-SY5Y cells. Moreover, the incubation of cells with ammonium chloride or bafilomycin A1 to produce the lysosomal dysfunction recently reported in Parkinson's disease led to an increase in the release of alpha-synuclein in exosomes and a concomitant increase in alpha-synuclein transmission to recipient cells. This study clearly demonstrates the importance of exosomes in both the release of alpha synuclein and its transmission between cells and suggests that factors associated with PD pathology accelerate this process. These mechanisms may play an important role in PD pathology and provide a suitable target for therapeutic intervention.


The Public Goods Hypothesis for the evolution of life on Earth.
It is becoming increasingly difficult to reconcile the observed extent of horizontal gene transfers with the central metaphor of a great tree uniting all evolving entities on the planet. In this manuscript we describe the Public Goods Hypothesis and show that it is appropriate in order to describe biological evolution on the planet. According to this hypothesis, nucleotide sequences (genes, promoters, exons, etc.) are simply seen as goods, passed from organism to organism through both vertical and horizontal transfer. Public goods sequences are defined by having the properties of being largely non-excludable (no organism can be effectively prevented from accessing these sequences) and non-rival (while such a sequence is being used by one organism it is also available for use by another organism). The universal nature of genetic systems ensures that such non-excludable sequences exist and non-excludability explains why we see a myriad of genes in different combinations in sequenced genomes. There are three features of the public goods hypothesis. Firstly, segments of DNA are seen as public goods, available for all organisms to integrate into their genomes. Secondly, we expect the evolution of mechanisms for DNA sharing and of defense mechanisms against DNA intrusion in genomes. Thirdly, we expect that we do not see a global tree-like pattern. Instead, we expect local tree-like patterns to emerge from the combination of a commonage of genes and vertical inheritance of genomes by cell division. Indeed, while genes are theoretically public goods, in reality, some genes are excludable, particularly, though not only, when they have variant genetic codes or behave as coalition or club goods, available for all organisms of a coalition to integrate into their genomes, and non-rival within the club. We view the Tree of Life hypothesis as a regionalized instance of the Public Goods hypothesis, just like classical mechanics and euclidean geometry are seen as regionalized instances of quantum mechanics and Riemannian geometry respectively. We argue for this change using an axiomatic approach that shows that the Public Goods hypothesis is a better accommodation of the observed data than the Tree of Life hypothesis.


Creation and validation of a ligation-independent cloning (LIC) retroviral vector for stable gene transduction in mammalian cells.
Cloning vectors capable of retroviral transduction have enabled stable gene overexpression in numerous mitotic cell lines. However, the relatively small number of feasible restriction enzyme sequences in their cloning sites can hinder successful generation of overexpression constructs if these sequences are also present in the target cDNA insert. Utilizing ligation-independent cloning (LIC) technology, we have modified the highly efficient retroviral transduction vector, pBABE, to eliminate reliance on restriction enzymes for cloning. Instead, the modified plasmid, pBLIC, utilizes random 12/13-base overhangs generated by T4 DNA polymerase 3' exonuclease activity. PCR-based introduction of the complementary sequence into any cDNA of interest enables universal cloning into pBLIC. Here we describe creation of the pBLIC plasmid, and demonstrate successful cloning and protein overexpression from three different cDNAs, Bax, catalase, and p53 through transduction into the human prostate cancer cell line, LNCaP or the human lung cancer line, H358. Our results show that pBLIC vector retains the high transduction efficiency of the original pBABE while eliminating the requirement for checking individual cDNA inserts for internal restriction sites. Thus it comprises an effective retroviral cloning system for laboratory-scale stable gene overexpression or for high-throughput applications such as creation of retroviral cDNA libraries. To our knowledge, pBLIC is the first LIC vector for retroviral transduction-mediated stable gene expression in mammalian cells.


Bone-strengthening effects and safety of compound peptides from skin of Chiloscyllium plagiosum and Mustelus griseus.
Fish processing produces a lot of by-products highly containing large amount of proteins which mainly consist of collagen, implying great potential value for application as nutraceutical ingredients. In present study, two kinds of sharks, Chiloscyllium plagiosum and Mustelus griseus, were used as raw material to gain three kinds of "compound peptides" (CPs) by enzymolysis, FCP (CPs from the flesh of C. plagiosum), SCP (CPs from the skin of C. plagiosum), and SMG (CPs from the skin of M. griseus). According to a series of constituent analysis, the molecule weights of FCP, SCP, and SMG were under 800 Da; amino acids composition analysis of FCP, SCP, and SMG showed that there were high glycine, proline, and hydroxyproline and low cysteine contents in SCP and SMG, which is the characteristic of collagen peptides; their total protein contents were 87.500%, 91.875%, and 95.625%, respectively; and heavy metal contents of CPs were all beneath national standards. After three kinds of CPs were administrated intragastrically to C57BL/6 mice at a total dosage of 15 g/kg, bone-strengthening effects of SCP and SMG were manifested by osteoblasts activity promotion, bone mineral density (BMD) increase, and marrow adipocyte number decrease, yet nonsignificant effects were shown in FCP group. No index showed toxicity of SCP and SMG in subacute toxicology trial, indicating their safety as functional foods. Herein, industrial application foundation of the skins from these two sharks was explored but more efforts should subsequently be implemented for further exploitation.


[A survey on urinary incontinence among middle aged and older people].
Studies in Western countries have revealed that urinary incontinence, non-intentional loss of urine, is a common condition in aged populations, and even younger individuals may suffer from urinary incontinence. However, in Japan, the evidence for community residents on this topic is limited. The aim of this study was to estimate the prevalence of urinary incontinence among middle aged using a structured questionnaire and older people and to provide useful information including frequency, voided volume, relation to parity as a risk factor and persons to consult for this condition. The study subjects consisted of 985 residents, 350 males (mean age 62.5 +/- 11.2 years)and 635 females (64.3 +/- 11.4), who participated in annual health check-ups and answered a self-reported questionnaire on urinary incontinence. The questionnaire included questions on frequency, voided volume, condition-specific QOL score, self-diagnostic item (above four from Scored International Consultation on Incontinence Questionnaire-Short Form Japanese version), person to consult for this condition and parity (only for females). The proportion of those with urinary incontinence was 11.4% in males and 34.5% in females, and the proportion increased with age (P for trend <0.01). In females, the proportion was high, even in their forties (30.4%). In this study, parity was associated with urinary incontinence: compared to females with no childbirth experience, those giving birth to 4 or more children showed an odds ratio of 4.26 (95% CI: 1.13-16.10). In females, an increase in frequency of urinary incontinence negatively affected the QOL. When asked who they would consult, the majority of males answered either a medical institution (54.2%) or family (34.0%). In females, 39.6% reported a medical institution, 22.6% reported family, 16.5% reported no one, 10.6% reported health nurses other than in medical institutions and 9.5% reported friends. The study results showed that urinary incontinence is a common condition in this population. Particularly, a large proportion of females suffer from this condition, even in their forties. The study also revealed that urinary incontinence might negatively affect the QOL and that there are some individuals who do not consult (or intend to consult) anyone about their problem. This information might be useful for planning health policy on the topic in the future.


Duration of HIV-1 viral suppression on cessation of antiretroviral therapy in primary infection correlates with time on therapy.
A minority of HIV-1 positive individuals treated with antiretroviral therapy (ART) in primary HIV-1 infection (PHI) maintain viral suppression on stopping. Whether this is related to ART duration has not been explored. And Methods: Using SPARTAC trial data from individuals recruited within 6 months of seroconversion, we present an observational analysis investigating whether duration of ART was associated with post-treatment viraemic control. Kaplan-Meier estimates, logistic regression and Cox models were used. 165 participants reached plasma viral loads (VL) <400 copies/ml at the time of stopping therapy (ART stop). After ART stop, 159 experienced confirmed VL ≥400 copies/ml during median (IQR) follow-up of 167 (108,199) weeks. Most participants experienced VL rebound within 12 weeks from ART stop, however, there was a suggestion of a higher probability of remaining <400 copies/ml for those on ART >12 weeks compared to ≤12 weeks (p=0.061). Cumulative probabilities of remaining <400 copies/ml at 12, 52 and 104 weeks after ART stop were 21% (95%CI=13,30), 4% (1,9), and 4% (1,9) for ≤12 weeks ART, and 32% (22,42), 14% (7,22), and 5% (2,11) for >12 weeks. In multivariable regression, ART for >12 weeks was independently associated with a lower probability of being ≥400 copies/ml within 12 weeks of ART stop (OR=0.11 (95%CI=0.03,0.34), p<0.001)). In Cox models of time to VL ≥400 after 12 weeks, we only found an association with female sex (OR=0.2, p=0.001). Longer ART duration in PHI was associated with a higher probability of viral control after ART stop. Controlled-Trials.com 76742797 http://www.controlled-trials.com/ISRCTN76742797.


Peptide vaccination against multiple myeloma using peptides derived from anti-apoptotic proteins: a phase I trial.
The B-cell lymphoma-2 (Bcl-2) family of proteins play a crucial role in multiple myeloma (MM), contributing to lacking apoptosis which is a hallmark of the disease. This makes the Bcl-2 proteins interesting targets for therapeutic peptide vaccination. We report a phase I trial of therapeutic vaccination with peptides from the proteins Bcl-2, Bcl-XL and Mcl-1 in patients with relapsed MM. Vaccines were given concomitant with bortezomib. Out of 7 enrolled patients, 4 received the full course of 8 vaccinations. The remaining 3 patients received fewer vaccinations due to progression, clinical decision of lacking effect and development of hypercalcemia, respectively. There were no signs of toxicity other than what was to be expected from bortezomib. Immune responses to the peptides were seen in all 6 patients receiving more than 2 vaccinations. Three patients had increased immune responses after vaccination. Vaccination against Bcl-2 was well tolerated and was able to induce immune responses in patients with relapsed MM.


Understanding the role of the gut in undernutrition: what can technology tell us?
Gut function remains largely underinvestigated in undernutrition, despite its critical role in essential nutrient digestion, absorption and assimilation. In areas of high enteropathogen burden, alterations in gut barrier function and subsequent inflammatory effects are observable but remain poorly characterised. Environmental enteropathy (EE)-a condition that affects both gut morphology and function and is characterised by blunted villi, inflammation and increased permeability-is thought to play a role in impaired linear growth (stunting) and severe acute malnutrition. However, the lack of tools to quantitatively characterise gut functional capacity has hampered both our understanding of gut pathogenesis in undernutrition and evaluation of gut-targeted therapies to accelerate nutritional recovery. Here we survey the technology landscape for potential solutions to improve assessment of gut function, focussing on devices that could be deployed at point-of-care in low-income and middle-income countries (LMICs). We assess the potential for technological innovation to assess gut morphology, function, barrier integrity and immune response in undernutrition, and highlight the approaches that are currently most suitable for deployment and development. This article focuses on EE and undernutrition in LMICs, but many of these technologies may also become useful in monitoring of other gut pathologies.


Vitamin D3 alters microglia immune activation by an IL-10 dependent SOCS3 mechanism.
Microglia become activated immune cells during infection or disease in the central nervous system (CNS). However, the mechanisms that downregulate activated microglia to prevent immune-mediated damage are not completely understood. Vitamin D3 has been suggested to have immunomodulatory affects, and high levels of vitamin D3 have been correlated with a decreased risk for developing some neurological diseases. Recent studies have demonstrated the synthesis of active vitamin D3, 1,25-dihydroxyvitamin D3, within the CNS, but its cellular source and neuroprotective actions remain unknown. Therefore, we wanted to determine whether microglia can respond to vitamin D3 and whether vitamin D3 alters immune activation of microglia. We have previously shown that microglia become activated by IFNγ or LPS or by infection with virus to express pro-inflammatory cytokines, chemokines, and effector molecules. In this study, activated microglia increased the expression of the vitamin D receptor and Cyp27b1, which encodes the enzyme for converting vitamin D3 into its active form, thereby enhancing their responsiveness to vitamin D3. Most importantly, the activated microglia exposed to vitamin D3 had reduced expression of pro-inflammatory cytokines, IL-6, IL-12, and TNFα, and increased expression of IL-10. The reduction in pro-inflammatory cytokines was dependent on IL-10 induction of suppressor of cytokine signaling-3 (SOCS3). Therefore, vitamin D3 increases the expression of IL-10 creating a feedback loop via SOCS3 that downregulates the pro-inflammatory immune response by activated microglia which would likewise prevent immune mediated damage in the CNS.


Blood culture and stimulation conditions for the diagnosis of tuberculosis in cervids by the Cervigam assay.
Mitogen- and antigen-induced interferon-gamma (IFN-gamma) responses of peripheral blood leucocytes from cervids were evaluated by a commercial whole-blood assay. The assay was applied to Mycobacterium bovis-infected white-tailed deer and reindeer, M bovis BCG-vaccinated white-tailed deer and elk, and unvaccinated, uninfected white-tailed deer, fallow deer, elk and reindeer. The responses of the M bovis-infected white-tailed deer to pokeweed mitogen (PWM) varied with time and between individuals. The responses of the M bovis-infected reindeer to PWM and M bovis purified protein derivative (PPD) were positively associated. Samples from tuberculosis-free captive herds in various parts of the USA were also evaluated. Four per cent of fallow deer, 20 per cent of elk, 44 per cent of white-tailed deer, and 91 per cent of reindeer had responses to PWM exceeding 0.25 Delta optical density, that is, PWM stimulation minus no stimulation. The specificity of the responses to M bovis PPD and a Mycobacterium tuberculosis complex-specific antigen rESAT-6:CFP-10, excluding animals not responding to PWM, ranged from 78 per cent to 100 per cent and was dependent upon the species and the positive response cut-off value. The results show that the commercial assay is valid for the detection of TB in reindeer; however, further development of the assay will be required before it is used in surveillance programmes for white-tailed deer, fallow deer, and elk.


Genetic epidemiology of colon cancer in the cotton-top tamarin (Saguinus oedipus).
Colon cancer is known to be heritable in humans, but the opportunity to investigate the genetic epidemiology of cancer in nonhuman primates has been limited by the size of available populations. The cotton-top tamarin (Saguinus oedipus) colony at the Oak Ridge Associated Universities (ORAU) Marmoset Research Center is a large population with a high rate of spontaneous colon cancer that has been monitored over several years, thus allowing investigation of the genetic basis for colon cancer in this colony. The presence of colon cancer at death was scored in 392 necropsies at the colony. Genealogical and demographic data for these animals were obtained from colony records. The heritability of the liability to colon cancer was estimated using maximum-likelihood-based pedigree analyses after evaluating the effects of gender, origin (wild-born or laboratory-born), and age at death on cancer experience. Cancer rates were not significantly different between males and females or between wild- and laboratory-born animals. Differences in age at death were also statistically insignificant for both laboratory- and wild-born animals. The heritability estimate for the liability to contract colon cancer is 17% for the ORAU cotton-top tamarins. This heritability estimate is not significantly different from zero, indicating no evidence for heritable variation in cancer experience in this population. If genetic factors affect cotton-top tamarin colon cancer, they are fixed or nearly fixed in this population.


Predictors of negative beliefs toward the sexual rights and perceived sexual healthcare needs of people with physical disabilities in South Africa.
Background: Although sexuality is a ubiquitous human need, recent empirical research has shown that people without disabilities attribute fewer sexual rights and perceive sexual healthcare to benefit fewer people with disabilities, compared to non-disabled people. Within a global context, such misperceptions have tangible, deleterious consequences for people with disabilities (e.g., exclusion from sexual healthcare), creating an urgent need for effective strategies to change misperceptions.Methods: To lay the groundwork for developing such strategies, we examined predictors of the recognition of sexual rights of people with physical disabilities within the South African context, derived from three key social psychological literatures (prejudice, social dominance orientation and intergroup contact), as well as the relationship between sexual rights and beliefs about sexual healthcare. Data were obtained through a cross-sectional survey, given to non-disabled South Africans (N = 1989).Results: Findings indicated that lack of recognition of the sexual rights for physically disabled people predicted less positive beliefs about the benefits of sexual healthcare. In turn, high levels of prejudice (both cognitive and affective) toward disabled sexuality predicted less recognition of their sexual rights, while prejudice (both forms) was predicted by prior contact with disabled people and possessing a social dominance orientation (cognitive prejudice only). Evidence was also obtained for an indirect relationship of contact and social dominance orientation on sexual healthcare beliefs through prejudice, although these effects were extremely small.Conclusion: Results are discussed in terms of their implications for rehabilitation, as well as national-level strategies to tackle negative perceptions of disabled sexuality, particularly in contexts affected by HIV.Implications for rehabilitationFindings demonstrate an empirical link between prejudice toward disabled sexuality, lack of recognition of sexual rights and viewing sexual healthcare of less benefit for disabled people.Consequently, there is need for increased attention to these dimensions within the rehabilitative context.Contact with disabled people, including dedicated interventions, is unlikely to meaningfully impact beliefs about the benefits of sexual healthcare.


Flexible surge capacity - public health, public education, and disaster management.
Background: Failed attempts to improve the delivery of healthcare to communities show distinct flaws that have a higher impact during a major incident or disaster (MID). This study evaluates the concept of surge capacity, which intends to achieve a balance between the needs and resources in affected areas by providing staff, stuff, structure, and system. Methods: A systematic literature review was performed according to the PRISMA statement and by using PubMed, Scopus, and Google Scholar, and related keywords. Results: There were limited publications about flexible surge capacity (FSC). However, the sum of data obtained indicated the need for flexibility in expanding major incidents or disasters, demanding new resources, which may neither be available on time nor reachable due to infrastructural damage. Conclusion: FSC is a novel concept based on international guidelines. It refers to the extra and adjustable human and material resources that can be mobilized by activating nonprofessional but educated staff and different but accepted facilities in a fast, smooth, and productive way. Public health and public education play an essential role in obtaining such flexibility.


The Role of Transnasal Esophagoscopy in ENT Office: A Prospective, Multicenter Study in Korea.
The purpose of study was to report the current role of transnasal esophagoscopy (TNE) in Korea. One hundred thirty-seven patients who underwent TNE at Soonchunhyang University Bucheon Hospital (n=69) and Korea University Anam Hospital (n=68) from July 2007 to February 2009 were prospectively analyzed. Laryngopharyngeal reflux disease (LPRD) patients without any response to proton-pump inhibitor (n=102), and patients with complaints that require esophagoscopy as part of their evaluation (n=35) were included in this study; investigation of metachronous lesions or routine follow-up screening of head and neck cancer patients, n=17; dysphagia, n=9; blood tinged saliva, n=4; to determine the cause of vocal fold paralysis as screening tool, n=4; suspicious esophageal foreign body, n=1. Fifty-three patients (38.7%) had positive findings on TNE. Positive finding ratio was highest in group of dysphagia (7 among 9 patients, 78%). Forty-two patients (41.1%) were found to have pathology (esophagitis, n=41; esophageal diverticulum, n=1) during the screening examination for LPRD. There were no significant complications in any of the patients. TNE is a high-yield diagnostic and therapeutic modality available to otolaryngologists for use on awake patients in the office setting.


China's online parrot trade: Generation length and body mass determine sales volume via price.
The wildlife trade threatens global biodiversity and animal welfare, where parrots are among the taxa most frequently traded, supplying exotic pets and captive breeders worldwide. Using phylogenetic path analysis, we examine how biological factors interact with price to influence online protected parrot trade volumes in China, using transactions recorded for 46 species (n = 5862 individuals). Trade was greatest in smaller, faster breeding species that commanded a lower price. This price effect followed the economic law of demand, with Relatively Inelastic Demand (-0.758), outweighing indicators of 'quality' such as body coloration, and conservation status. We identify two areas of concern: those larger, slower-breeding, rarer species, even though sold at lower numbers, may be at conservation risk if harvested from the wild. In contrast, the sheer numbers (over 90% of the individuals were under median generation length, body mass and/or price) and ready availability of smaller and more common species comprises a substantial overall animal welfare issue, given that the capture, importation, or captive breeding of many parrot species in China is illegal and thus unregulated. Our investigation highlights the importance of properly understanding the internal relations among drivers of wildlife trade to inform appropriate management.


Intrauterine growth discordance across gestation and birthweight discordance in dichorionic twins.
Although intertwin size difference is an important measure of fetal growth, the appropriate cut point to define discordance is unclear. Few studies have assessed intertwin differences in estimated fetal weight longitudinally or in relation to size differences at birth. The objectives of the study were to estimate the magnitude of percentage differences in estimated fetal weight across gestation in dichorionic twins in relation to a fixed discordance cut point and compare classification of aberrant fetal growth by different measures (estimated fetal weight differences, birthweight discordance, small for gestational age). Women aged 18-45 years from 8 US centers with dichorionic twin pregnancies at 8 weeks 0 days to 13 weeks 6 days gestation planning to deliver in participating hospitals were recruited into the Eunice Kennedy Shriver National Institute of Child Health and Human Development Fetal Growth Studies-Dichorionic Twins study and followed through delivery (n = 140; 2012-2013). Ultrasounds were conducted at 6 targeted study visits to obtain fetal biometrics and calculate estimated fetal weight. Percent estimated fetal weight and birthweight differences were calculated: ([weightlarger - weightsmaller]/weightlarger)*100; discordance was defined as ≥18% for illustration. Birth sizes for gestational age (both, 1, or neither small for gestational age) were determined; twins were categorized into combined birthweight plus small for gestational age groups: birthweight discordance ≥18% (yes, no) with both, 1, or neither small for gestational age. Linear mixed-models estimated percentiles of estimated fetal weight percent differences across gestation and compared estimated fetal weight differences between combined birthweight discordance and small for gestational age groups. A Fisher exact test compared birthweight discordance and small for gestational age classifications. Median estimated fetal weight percentage difference increased across gestation (5.9% at 15.0, 8.4% at 38.0 weeks), with greater disparities at higher percentiles (eg, 90th percentile: 15.6% at 15.0, 26.3% at 38.0 weeks). As gestation advanced, an increasing percentage of pregnancies were classified as discordant using a fixed cut point: 10% at 27.0, 15% at 34.0, and 20% at 38.0 weeks. Birthweight discordance and small for gestational age classifications differed (P = .002); for birthweight discordance ≥18% vs <18%: 44% vs 71% had neither small for gestational age; 56% vs 18% had 1 small for gestational age; no cases (0%) vs 11% had both small for gestational age, respectively. Estimated fetal weight percent difference varied across gestation by birthweight discordance plus small for gestational age classification (P = .040). Estimated fetal weight percentage difference increased with birthweight discordance ≥18% (neither small for gestational age: 0.46%/week [95% confidence interval, 0.08-0.84]; 1 small for gestational age: 0.57%/week [95% confidence interval, 0.25-0.90]) but less so without birthweight discordance (neither small for gestational age: 0.17%/week [95% confidence interval, 0.06-0.28]; 1 small for gestational age: 0.03%/week [95% confidence interval, -0.17 to 0.24]); both small for gestational age: 0.10%/week [95% confidence interval, -0.15 to 0.36]). The percentage of dichorionic pregnancies exceeding a fixed discordance cut point increased over gestation. A fixed cut point for defining twin discordance would identify an increasing percentage of twins as discordant as gestation advances. Small for gestational age and percentage weight differences assess distinct aspects of dichorionic twin growth. A percentile cut point may be more clinically useful for defining discordance, although further study is required to assess whether any specific percentile cut point correlates to adverse outcomes.


Pathophysiology of shock and adult respiratory distress syndrome.
The respiratory failure that develops in surgical patients is usually caused by a surgical problem--shock, trauma, sepsis, pulmonary contusion, aspiration, pulmonary emboli or pain, with its attendant ventilatory compromise. Although the underlying pathophysiology for the respiratory failure in these conditions is not precisely known, the means for prevention are well known. Patients subjected to trauma should be aggressively resuscitated from shock. They should have the chance of being cared for in a facility where an operation can be performed promptly. The respiratory failure of sepsis is best treated by seeking out foci of pus or devitalized tissue and surgically ablating these foci when found. Adherence to these basic surgical principles--aggressive resuscitation of patients in shock and prompt attention to their surgical problems--will alleviate much of the respiratory distress of surgical patients, no matter what the pathophysiology or etiology may be.


'Experts', 'partners' and 'fools': exploring agency in HIV treatment seeking among African migrants in London.
In an attempt to promote patient agency and foster more egalitarian relationships between patients and doctors, discourse concerning health and wellbeing in the UK has increasingly centred around the notion of informed and 'expert' patients who are able to effectively input into the direction and management of their own health care and treatment. While the relationship between a patient and their doctor can play a vital role in influencing the treatment decisions and health-related outcomes of people living with long term illness, little is known about the ways in which people living with HIV actually perceive their relationship with their doctors, nor the implications this may have for the types of treatment they may seek to use and the related information that they share. Drawing on 11 focus group discussions and 20 repeat interviews undertaken in 2008-2009 with HIV-positive adult migrants from Zambia, Zimbabwe and South Africa living in the UK, this paper argues that patient-doctor relationships can be heavily influenced by the perceived legitimacy of different forms of medical knowledge and treatments and by culturally influenced ideas regarding health, wellbeing and agency. Despite a desire amongst some migrants to use 'traditional' medicines from southern Africa as well as other non-biomedical treatments and therapies, the research found that the perceived lack of legitimacy associated with these treatments in the UK rendered their use a largely clandestine activity. At the same time, many patients made clear distinctions concerning issues affecting their immediate health and factors influencing their more general wellbeing, which in turn, impacted upon the information that they chose to share with, or conceal from, their doctors. Such findings challenge assumptions underpinning policy promoting patient agency and have significant and, in cases, potentially adverse implications for the safety and effective administration and management of HIV treatments in African migrant populations and possibly more generally.


A gene-expression profiling score for prediction of outcome in patients with follicular lymphoma: a retrospective training and validation analysis in three international cohorts.
Patients with follicular lymphoma have heterogeneous outcomes. Predictor models to distinguish, at diagnosis, between patients at high and low risk of progression are needed. The objective of this study was to use gene-expression profiling data to build and validate a predictive model of outcome for patients treated in the rituximab era. A training set of fresh-frozen tumour biopsies was prospectively obtained from 160 untreated patients with high-tumour-burden follicular lymphoma enrolled in the phase 3 randomised PRIMA trial, in which rituximab maintenance was evaluated after rituximab plus chemotherapy induction (median follow-up 6·6 years [IQR 6·0-7·0]). RNA of sufficient quality was obtained for 149 of 160 cases, and Affymetrix U133 Plus 2.0 microarrays were used for gene-expression profiling. We did a multivariate Cox regression analysis to identify genes with expression levels associated with progression-free survival independently of maintenance treatment in a subgroup of 134 randomised patients. Expression levels from 95 curated genes were then determined by digital expression profiling (NanoString technology) in 53 formalin-fixed paraffin-embedded samples of the training set to compare the technical reproducibility of expression levels for each gene between technologies. Genes with high correlation (>0·75) were included in an L2-penalised Cox model adjusted on rituximab maintenance to build a predictive score for progression-free survival. The model was validated using NanoString technology to digitally quantify gene expression in 488 formalin-fixed, paraffin-embedded samples from three independent international patient cohorts from the PRIMA trial (n=178; distinct from the training cohort), the University of Iowa/Mayo Clinic Lymphoma SPORE project (n=201), and the Barcelona Hospital Clinic (n=109). All tissue samples consisted of pretreatment diagnostic biopsies and were confirmed as follicular lymphoma grade 1-3a. The patients were all treated with regimens containing rituximab and chemotherapy, possibly followed by either rituximab maintenance or ibritumomab-tiuxetan consolidation. We determined an optimum threshold on the score to predict patients at low risk and high risk of progression. The model, including the multigene score and the threshold, was initially evaluated in the three validation cohorts separately. The sensitivity and specificity of the score for the prediction of the risk of lymphoma progression at 2 years were assessed on the combined validation cohorts. In the training cohort, the expression levels of 395 genes were associated with a risk of progression. 23 genes reflecting both B-cell biology and tumour microenvironment with correlation coefficients greater than 0·75 between the two technologies and sample types were retained to build a predictive model that identified a population at an increased risk of progression (p<0·0001). In a multivariate Cox model for progression-free survival adjusted on rituximab maintenance treatment and Follicular Lymphoma International Prognostic Index 1 (FLIPI-1) score, this predictor independently predicted progression (adjusted hazard ratio [aHR] of the high-risk group compared with the low-risk group 3·68, 95% CI 2·19-6·17 [p<0·0001]). The 5-year progression-free survival was 26% (95% CI 16-43) in the high-risk group and 73% (64-83) in the low-risk group. The predictor performances were confirmed in each of the individual validation cohorts (aHR comparing high-risk to low-risk groups 2·57 [95% CI 1·65-4·01] in cohort 1; 2·12 [1·32-3·39] in cohort 2; and 2·11 [1·01-4·41] in cohort 3). In the combined validation cohort, the median progression-free survival was 3·1 years (95% CI 2·4-4·8) in the high-risk group and 10·8 years (10·1-not reached) in the low-risk group (p<0·0001). The risk of lymphoma progression at 2 years was 38% (95% CI 29-46) in the high-risk group and 19% (15-24) in the low-risk group. In a multivariate analysis, the score predicted progression-free survival independently of anti-CD20 maintenance treatment and of the FLIPI score (aHR for the combined cohort 2·30, 95% CI 1·72-3·07). We developed and validated a robust 23-gene expression-based predictor of progression-free survival that is applicable to routinely available formalin-fixed, paraffin-embedded tumour biopsies from patients with follicular lymphoma at time of diagnosis. Applying this score could allow individualised therapy for patients according to their risk category. Roche, SIRIC Lyric, LYSARC, National Institutes of Health, the Henry J Predolin Foundation, and the Spanish Plan Nacional de Investigacion.


Highly selective vagotomy and duodenal ulcers that fail to respond to H2 receptor antagonists.
A study was conducted to see whether patients with duodenal ulcers that failed to heal in response to H2 receptor antagonists had a higher incidence of recurrent ulceration after highly selective vagotomy than patients whose ulcers healed with these drugs. Between 1977 and 1983, 157 patients had a highly selective vagotomy for uncomplicated duodenal ulcer; in 57 patients the ulcer had failed to heal despite treatment with H2 receptor antagonists (refractory group), 19 patients had developed recurrent ulceration while receiving maintenance treatment, 67 patients had remained healed while taking H2 receptor antagonists but suffered frequent relapses when treatment was stopped, and 14 patients had not been given these drugs before operation. The overall incidence of recurrent ulceration was 6% after two years and 11% after five years of follow up. In the refractory group, however, the incidence of recurrent ulceration was 18% at two years and 34% after five years, whereas the incidence of recurrence was only 1.5% at two years and 3% after five years in patients whose ulcers had healed with H2 receptor antagonists. Resistance to H2 receptor antagonists was not related to preoperative basal or peak acid output but was related to cigarette smoking. Factors associated with recurrent ulceration after highly selective vagotomy were basal acid outputs before and after operation, cigarette smoking, and the surgeon who performed the operation. Duodenal ulcers that fail to respond to H2 receptor antagonists represent a more severe ulcer diathesis, for which highly selective vagotomy is less effective.


The Modulatory Role of Orexin 1 Receptor in CA1 on Orofacial Pain-induced Learning and Memory Deficits in Rats.
Cognitive impairment is commonly associated with pain. The modulatory role of orexin 1 receptor (OX1R) in pain pathways as well as learning and memory processes is reported in several studies. The current study was designed to investigate the possible role of CA1-hippocampal OX1R on spatial learning and memory of rats following capsaicin-induced orofacial pain. Orofacial pain was induced by subcutaneous intra lip injection of capsaicin (100 μg). CA1 administration of orexin A and its selective antagonist (SB-334867-A) were performed 20 minutes prior to capsaicin injection. Learning and spatial memory performances were assessed by Morris Water Maze (MWM) task. Capsaicin treated rats showed impairment in spatial learning and memory. In addition, pretreatment with orexin A (20 and 40 nM/rat) significantly attenuated learning and memory impairment in capsaicin-treated rats. Conversely, blockage of OX1R via SB-334867-A (40 and 80 nM/rat) significantly exaggerated learning and memory loss in capsaicin-treated rats. The obtained results indicated that CA1 OX1R may be involved in modulation of capsaicin -induced spatial learning and memory impairment.


Preventing Smoking Progression in Young Adults: the Concept of Prevescalation.
As adolescents cross the threshold to young adulthood, they encounter more opportunities to engage in or accelerate previously discouraged or prohibited behaviors. Young adults, therefore, are more apt to initiate cigarette smoking and, more importantly, to accelerate their use if they tried and experimented as an adolescent. Preventing the escalation and entrenchment of smoking in the young adult years is critically important to reducing tobacco's long-term health toll. However, traditional interventions for youth have focused on preventing smoking initiation, and interventions for adults have focused on smoking cessation; both have failed to address the needs of young adults. We introduce the concept of "prevescalation" to capture the need and opportunity to prevent the escalation of risk behaviors that typically occur during young adulthood, with a focus on the example of cigarette smoking. Prevescalation negates the notion that prevention has failed if tobacco experimentation occurs during adolescence and focuses on understanding and interrupting transitions between experimentation with tobacco products and established tobacco use that largely occur during young adulthood. However, since risk behaviors often co-occur in young people, the core concept of prevescalation may apply to other behaviors that co-occur and become harder to change in later adulthood. We present a new framework for conceptualizing, developing, and evaluating interventions that better fit the unique behavioral, psychosocial, and socio-environmental characteristics of the young adult years. We discuss the need to target this transitional phase, what we know about behavioral pathways and predictors of cigarette smoking, potential intervention considerations, and research challenges.


Exclusion of erythrocyte-specific membrane proteins from clathrin-coated pits during differentiation of human erythroleukemic cells.
When human erythroleukemic cells are induced to differentiate, they produce globin and redistribute glycophorin and spectrin to one pole of the cell. This process was accompanied by an alteration in the clathrin-coated pits at the cell surface. In nondifferentiating cells, receptors for Concanavalin A have been shown, using electron microscopy, to be concentrated into coated pits and rapidly internalized. Glycophorin was also internalized via coated pits, but was not greatly concentrated into these portions of the surface membrane. Ligands attached to glycophorin were, therefore, cleared from the cell surface more slowly than Concanavalin A. In nondifferentiating cells, immunoelectron microscopy showed that spectrin is largely excluded from coated pits. After erythroid differentiation proceeded for several days, glycophorin was totally excluded from the coated pits along with spectrin. This did not reflect a general cessation of endocytosis, however, because Concanavalin A receptors continued to be internalized. It is possible that the specific exclusion of glycophorin from coated pits is part of the remodeling process that occurs when the precursor cell membrane differentiates into that of the mature erythrocyte.


Gross motor performance in children prenatally exposed to alcohol and living in remote Australia.
This study aimed to determine the gross motor (GM) performance of Aboriginal children living in remote Australia. The relationship between GM skills, prenatal alcohol exposure (PAE) and fetal alcohol spectrum disorders (FASD) was explored. A population-based observation study was conducted in 2011 to assess motor performance in children living in the Fitzroy Valley, Western Australia, using the Bruininks-Oseretsky Test of Motor Proficiency (BOT-2). BOT-2 data were retrospectively analysed using recently developed software enabling separation of fine and GM outcomes. A total of 108 children (98.1% Aboriginal; 53% male, mean age: 8.7 years) were assessed. Half (52.2%) were exposed to at least 'risky' levels of PAE, and 21 (19%) were diagnosed with an FASD. The mean GM composite score of the cohort (47.0 ± 8.4) approached the BOT-2 normative mean (50.0 ± 10) and was similar between children with and without PAE (P = 0.27). This mean score, however, was significantly lower in children with FASD than without (mean difference: -5.5 ± 20.6; P = 0.006). Compared with children without FASD, children with FASD had significant impairment in subtests for running speed and agility (mean difference ± standard deviation (SD): -2.4 ± 8.1; P = 0.003) and strength (mean difference ± SD:-2.8 ± 9.9; P = 0.004) and (ii) a higher proportion than expected had overall GM impairment (≤2 SD: 9.5%; ≤1 SD: 23.8%). In groups with PAE, no PAE and no FASD, GM function approached expected population norms. A higher than expected proportion of children with FASD had GM scores that indicated impairment and need for therapy. Evaluation of GM performance should routinely be included in FASD assessment to determine strategies to optimise child development.


Production of a human-tissue-equivalent MRI phantom: optimization of material heating.
We conceived a 2-stage heating method to dissolve the ingredients of magnetic resonance (MR) imaging phantoms to overcome issues of uneven quality in conventional MR imaging phantoms, and we evaluated uniformity and the reproducibility of our method. We used a 3-liter capacity, column-shaped, enamel-coated porcelain container to produce a muscle-equivalent phantom (diameter, 160 mm; height, 100 mm; volume, 2 liters). The phantom contained: 1) carrageenan as a gelling agent; 2) agarose as a T2 modifier; 3) GdCl3 as a T1 modifier; 4) NaN3 as an antiseptic; and 5) distilled water. We applied both direct heating and 2-stage heating of pre-soaked materials. We placed powdered materials directly into hot water for direct heating but soaked them in water one day before use (post-swelling) in 2-stage heating. The materials in the container were melted in a silicone oil bath of 120 or 140 degrees C under various conditions, then allowed to gel by natural cooling. We observed the resulting gel phantoms macroscopically using a CCD camera and evaluated their uniformity by microscopy and MR imaging. We found it necessary to raise the temperature inside the phantom to 100.0 degrees C, to produce a uniform gel with stable homogeneity and few bubbles. Use of an enamel-coated porcelain container required setting the temperature of the oil bath at 140 degrees C. A uniform and reproducible human tissue-equivalent phantom with few bubbles can be manufactured using our 2-stage heating method, which employs pre-soaking in a silicone oil bath at 140 degrees C for 30 min. We then added the swollen carrageenan to the agarose solution, which heating the temperature to 140 degrees C for 30 min while continuously stirring at 120 rpm, following with natural cooling.


Decellularized Versus Standard Pulmonary Allografts in the Ross Procedure: Propensity-Matched Analysis.
It is hypothesized that decellularization of allografts used for right ventricular outflow tract reconstruction may result in decreased valve deterioration. This study compared the durability of fresh decellularized pulmonary allografts with standard cryopreserved pulmonary allografts in patients undergoing the Ross procedure. The Ross procedure was performed in 144 patients with decellularized allografts (DA) from 2005 to 2014 and in 619 with standard cryopreserved allografts (SCA) from 1990 to 2014. Propensity score matching was used to compare early and midterm clinical outcome and echocardiographic allograft function over time between the two groups. We matched 94 DA patients (79.3% male; median age, 34.0 years; mean follow-up, 2.4 ± 1.9 years) to 94 SCA patients (78.3% male; median age, 35.0 years; mean follow-up, 9.4 ± 4.2 years). There were no significant differences in baseline characteristics after matching. The matched DA vs SCA groups, respectively, were comparable in actuarial 5-year freedom from allograft dysfunction (85.6% [95% confidence interval {CI}, 53.9% to 96.2%] vs 93.3% [95% CI, 85.7% to 96.9%], p = 0.892), freedom from allograft reintervention (98.8% [95% CI, 91.7% to 99.8%] vs 95.5% [95% CI, 88.5% to 98.3%], p = 0.383), survival (95.3% [95% CI, 87.8% to 98.2%] vs 97.7% [95% CI, 91.3% to 99.4%], p = 0.323), and event-free survival (83.5% [95% CI, 70.6% to 91.1%] vs 84.5% [95% CI, 75.2% to 90.5%], p = 0.515). Longitudinal echocardiographic analyses showed a similarly modest increase in allograft gradient and regurgitation grades over time in both groups, although direct statistical comparison was not possible. Up to 5 years of follow-up, DA and SCA used for right ventricular outflow tract reconstruction in the Ross procedure are associated with comparably excellent clinical and hemodynamic outcome. Longer follow-up and dedicated echocardiographic studies will shed light on the long-term performance of DAs.


Pharmacogenetics of Ketamine-Induced Emergence Phenomena: A Pilot Study.
Up to 55% of patients who are administered ketamine experience an emergence phenomena (EP) that closely mimics schizophrenia and increases their risk of injury; however, to date, no studies have investigated genetic association of ketamine-induced EP in healthy patients. The aim of the study was to investigate the feasibility and sample sizes required to explore the relationship between CYP2B6*6 and GRIN2B single-nucleotide polymorphisms and ketamine-induced EP. This cross-sectional, pharmacogenetic candidate, gene pilot study recruited 75 patients having minor elective outpatient surgeries. EP was measured with the Clinician Administered Dissociative State Scale. Genetic association of CYP2B6*6 and GRIN2B (rs1019385 and rs1806191) single-nucleotide polymorphisms and ketamine-induced EP occurrence and severity were tested using logistic and linear regression. Forty-seven patients (63%) received ketamine and were genotyped, and 40% of them experienced EP. Occurrence and severity of EP were not associated with CYP2B6*6 or GRIN2B (p > .10). Exploratory analysis of nongenotype models containing age, ketamine dose, duration of anesthesia, and time from ketamine administration to assessment for EP significantly predicted EP occurrence (p = .001) and severity (p = .007). This pilot study demonstrates feasibility for implementing a pharmacogenetic study in a clinical setting, and we estimate that between 380 and 570 cases will be needed to adequately power future genetic association studies. Younger age, higher dose, and longer duration of anesthesia significantly predicted EP occurrence and severity among our pilot sample. Although the small sample size limited our ability to demonstrate significant genotype differences, we generated effect sizes, sample size estimates, and nongenetic covariates information in order to support future pharmacogenetic study design for evaluating this adverse event.


Platelet: transporter of vascular endothelial growth factor.
In animal models, growth of tumors and their metastases is dependent on factors that stimulate vessel formation (angiogenesis). Most clinical studies confirm the importance of angiogenesis for cancer growth in patients. Recent studies on circulating angiogenic factors in patients have focused on serum vascular endothelial growth factor (VEGF) levels in a variety of cancer types. We measured serum VEGF concentrations and blood counts in 27 breast cancer patients during each of 6 cycles of chemotherapy with doxorubicin and cyclophosphamide supported by granulocyte macrophage colony-stimulating factor. Serum VEGF concentrations highly correlated with platelet counts during chemotherapy (r = 0.8; P < 0.01). In particular, during the first treatment cycle, after an initial episode of thrombocytopenia, a strong platelet rebound coincided closely with a serum VEGF peak (r = 0.9; P < 0.01). In addition, plasma VEGF concentrations from 15 other cancer patients and 30 healthy volunteers were 5- to 8-fold lower than their corresponding serum VEGF concentrations (P < 0.001). Activation of platelets increased the VEGF content 8-10 times. These findings demonstrate that VEGF is released by platelets during serum preparation. In this study, we found evidence for VEGF transport by platelets, indicating that serum VEGF concentrations reflect mainly platelet counts rather than tumor burden in cancer patients, as reported earlier. Platelets, known to be important for wound healing, have also been reported to contribute to metastasis formation and tumor growth in animal models. Indeed, tumors can be regarded as never-healing wounds. Our data suggest that platelets may have a stimulating role on angiogenesis-dependent tumor growth through their function as transporters of VEGF.


Stereotactic radiosurgery planning of vestibular schwannomas: Is MRI at 3 Tesla geometrically accurate?
MRI is a mandatory requirement to accurately plan Stereotactic Radiosurgery (SRS) for Vestibular Schwannomas. However, MRI may be distorted due not only to inhomogeneity of the static magnetic field and gradients but also due to susceptibility-induced effects, which are more prominent at higher magnetic fields. We assess geometrical distortions around air spaces and consider MRI protocol requirements for SRS planning at 3 T. Hardware-related distortion and the effect of incorrect shimming were investigated with structured test objects. The magnetic field was mapped over the head on five volunteers to assess susceptibility-related distortion in the naso-oro-pharyngeal cavities (NOPC) and around the internal ear canal (IAC). Hardware-related geometric displacements were found to be less than 0.45 mm within the head volume, after distortion correction. Shimming errors can lead to displacements of up to 4 mm, but errors of this magnitude are unlikely to arise in practice. Susceptibility-related field inhomogeneity was under 3.4 ppm, 2.8 ppm, and 2.7 ppm for the head, NOPC region and IAC region, respectively. For the SRS planning protocol (890 Hz/pixel, approximately 1 mm3 isotropic), susceptibility-related displacements were less than 0.5 mm (head), and 0.4 mm (IAC and NOPC). Large displacements are possible in MRI examinations undertaken with lower receiver bandwidth values, commonly used in clinical MRI. Higher receiver bandwidth makes the protocol less vulnerable to sub-optimal shimming. The shimming volume and the CT-MR co-registration must be considered jointly. Geometric displacements can be kept under 1 mm in the vicinity of air spaces within the head at 3 T with appropriate setting of the receiver bandwidth, correct shimming and employing distortion correction.


Detection of markers predictive of macrolide and fluoroquinolone resistance in Mycoplasma genitalium from patients attending sexual health services in England.
Resistance to both macrolides and fluoroquinolones has been reported in Mycoplasma genitalium; however, due to limited diagnostics, studies are often small and confined to specific geographical areas. This study sought to determine the rate of predicted resistance in M. genitalium-positive specimens referred for diagnostic testing. Seventy-four M. genitalium-positive specimens, referred to the national reference laboratory (2010-2013) from 19 centres across England, were blinded and anonymised. Specimens were examined for markers predictive of resistance to macrolides and fluoroquinolones using PCR followed by sequence analysis of 23S rRNA gene, or gyrA and parC, respectively. 23S rRNA gene PCR sequencing revealed that 82.4% (61/74) of specimens harboured a single nucleotide polymorphism (SNP) associated with macrolide resistance. Differences were observed between the rates of predicted macrolide resistance in male (95.1% (58/61)) and female (23.1% (3/13)) patients (P = <0.001). By contrast, all specimens for which sequencing data were available (73/74) yielded wild-type gyrA sequences; and 58/61 (95.1%) had wild-type parC genes. Three specimens (3/61 4.9%) had SNPs in the parC gene associated with fluoroquinolone treatment failure, and all three also had predicted resistance to macrolides. Eighty-two per cent and 4.9% of M. genitalium specimens had SNPs associated with macrolide and fluoroquinolone resistance, respectively. Due to lack of widespread availability of testing for M. genitalium in the UK, this study sample was likely to be sourced from patients who may have already failed first-line macrolide therapy. Nevertheless, this study highlights the need for both greater access to M. genitalium diagnostics and genetic antimicrobial resistance testing.


Brain glucose sensors play a significant role in the regulation of pancreatic glucose-stimulated insulin secretion.
As patients decline from health to type 2 diabetes, glucose-stimulated insulin secretion (GSIS) typically becomes impaired. Although GSIS is driven predominantly by direct sensing of a rise in blood glucose by pancreatic β-cells, there is growing evidence that hypothalamic neurons control other aspects of peripheral glucose metabolism. Here we investigated the role of the brain in the modulation of GSIS. To examine the effects of increasing or decreasing hypothalamic glucose sensing on glucose tolerance and insulin secretion, glucose or inhibitors of glucokinase, respectively, were infused into the third ventricle during intravenous glucose tolerance tests (IVGTTs). Glucose-infused rats displayed improved glucose handling, particularly within the first few minutes of the IVGTT, with a significantly lower area under the excursion curve within the first 10 min (AUC0-10). This was explained by increased insulin secretion. In contrast, infusion of the glucokinase inhibitors glucosamine or mannoheptulose worsened glucose tolerance and decreased GSIS in the first few minutes of IVGTT. Our data suggest a role for brain glucose sensors in the regulation of GSIS, particularly during the early phase. We propose that pharmacological agents targeting hypothalamic glucose-sensing pathways may represent novel therapeutic strategies for enhancing early phase insulin secretion in type 2 diabetes.


Diagnostic value of medical thoracoscopy in malignant pleural effusion.
Medical thoracoscopy has been shown to be an efficacious procedure in diagnosing unexplained exudative pleural effusions with excellent safety. This study aimed to assess the diagnostic significance of thoracoscopy in the management of patients with malignant pleural effusion (MPE). Consecutive patients with malignant pleural effusion were retrospectively reviewed, and their demographic, radiographic, thoracoscopic and histological data were collected. Between July 2005 and June 2014, 342 of 833 patients undergoing thoracoscopy were finally confirmed to suffer from MPE. The top three frequent causes of MPE were metastatic carcinoma (79.5%), malignant mesothelioma (10.2%), and lymphoma (2.9%). Among metastatic malignancies, the most common cancer was lung cancer (85.2%), followed by breast cancer (4.4%), ovarian cancer (2.2%), pancreatic cancer (1.8%), etc. No serious adverse events associated with thoracoscopy were recorded. Medical thoracoscopy is a valuable and safe tool in diagnosing malignant pleural effusion with minimal complication rates.


Phospho-Bcl-xL(Ser62) influences spindle assembly and chromosome segregation during mitosis.
Functional analysis of a series of phosphorylation mutants reveals that Bcl-xL(Ser62Ala) influences cell entry into anaphase and mitotic exit in taxol-exposed cells compared with cells expressing wild-type Bcl-xL or a series of other phosphorylation mutants, an effect that appears to be independent of its anti-apoptotic activity. During normal mitosis progression, Bcl-xL(Ser62) is strongly phosphorylated by PLK1 and MAPK14/SAPKp38α at the prometaphase, metaphase, and the anaphase boundaries, while it is de-phosphorylated at telophase and cytokinesis. Phospho-Bcl-xL(Ser62) localizes in centrosomes with γ-tubulin and in the mitotic cytosol with some spindle-assembly checkpoint signaling components, including PLK1, BubR1, and Mad2. In taxol- and nocodazole-exposed cells, phospho-Bcl-xL(Ser62) also binds to Cdc20- Mad2-, BubR1-, and Bub3-bound complexes, while Bcl-xL(Ser62Ala) does not. Silencing Bcl-xL expression and expressing the phosphorylation mutant Bcl-xL(Ser62Ala) lead to an increased number of cells harboring mitotic spindle defects including multipolar spindle, chromosome lagging and bridging, aneuploidy with micro-, bi-, or multi-nucleated cells, and cells that fail to resolve undergo mitosis within 6 h. Together, the data indicate that during mitosis, Bcl-xL(Ser62) phosphorylation impacts on spindle assembly and chromosome segregation, influencing chromosome stability. Observations of mitotic cells harboring aneuploidy with micro-, bi-, or multi-nucleated cells, and cells that fail to resolve undergo mitosis within 6 h were also made with cells expressing the phosphorylation mutant Bcl-xL(Ser49Ala) and dual mutant Bcl-xL(Ser49/62Ala).


Preclinical and clinical evidence of antioxidant effects of antidepressant agents: implications for the pathophysiology of major depressive disorder.
Major depressive disorder (MDD) is a common mental disorder associated with a significant negative impact on quality of life, morbidity/mortality, and cognitive function. Individuals who suffer with MDD display lower serum/plasmatic total antioxidant potentials and reduced brain GSH levels. Also, F2-isoprostanes circulatory levels are increased in MDD subjects and are correlated with the severity of depressive symptoms. Urinary excretion of 8-OHdG seems to be higher in patients with MDD compared to healthy controls. Despite the fact that antidepressant drugs have been used for more than 50 years, their mechanism of action is still not fully understood. This paper examines preclinical (in vitro and animal model) and clinical literature on oxidative/antioxidant effects associated with antidepressant agents and discusses their potential antioxidant-related effects in the treatment of MDD. Substantial data support that MDD seems to be accompanied by elevated levels of oxidative stress and that antidepressant treatments may reduce oxidative stress. These studies suggest that augmentation of antioxidant defences may be one of the mechanisms underlying the neuroprotective effects of antidepressants in the treatment of MDD.


Genetic, biochemical, and molecular characterization of the polypeptide transport-associated domain of Escherichia coli BamA.
The BamA protein of Escherichia coli plays a central role in the assembly of β-barrel outer membrane proteins (OMPs). The C-terminal domain of BamA folds into an integral outer membrane β-barrel, and the N terminus forms a periplasmic polypeptide transport-associated (POTRA) domain for OMP reception and assembly. We show here that BamA misfolding, caused by the deletion of the R44 residue from the α2 helix of the POTRA 1 domain (ΔR44), can be overcome by the insertion of alanine 2 residues upstream or downstream from the ΔR44 site. This highlights the importance of the side chain orientation of the α2 helix residues for normal POTRA 1 activity. The ΔR44-mediated POTRA folding defect and its correction by the insertion of alanine were further demonstrated by using a construct expressing just the soluble POTRA domain. Besides misfolding, the expression of BamA(ΔR44) from a low-copy-number plasmid confers a severe drug hypersensitivity phenotype. A spontaneous drug-resistant revertant of BamA(ΔR44) was found to carry an A18S substitution in the α1 helix of POTRA 1. In the BamA(ΔR44, A18S) background, OMP biogenesis improved dramatically, and this correlated with improved BamA folding, BamA-SurA interactions, and LptD (lipopolysaccharide transporter) biogenesis. The presence of the A18S substitution in the wild-type BamA protein did not affect the activity of BamA. The discovery of the A18S substitution in the α1 helix of the POTRA 1 domain as a suppressor of the folding defect caused by ΔR44 underscores the importance of the helix 1 and 2 regions in BamA folding.


Characterizing metastable states beyond energies and lifetimes: Dyson orbitals and transition dipole moments.
The theoretical description of electronic resonances is extended beyond calculations of energies and lifetimes. We present the formalism for calculating Dyson orbitals and transition dipole moments within the equation-of-motion coupled-cluster singles and doubles method for electron-attached states augmented by a complex absorbing potential (CAP-EOM-EA-CCSD). The capabilities of the new methodology are illustrated by calculations of Dyson orbitals of various transient anions. We also present calculations of transition dipole moments between transient and stable anionic states as well as between different transient states. Dyson orbitals characterize the differences between the initial neutral and final electron-attached states without invoking the mean-field approximation. By extending the molecular-orbital description to correlated many-electron wave functions, they deliver qualitative insights into the character of resonance states. Dyson orbitals and transition moments are also needed for calculating experimental observables such as spectra and cross sections. Physically meaningful results for those quantities are obtained only in the framework of non-Hermitian quantum mechanics, e.g., in the presence of a complex absorbing potential (CAP), when studying resonances. We investigate the dependence of Dyson orbitals and transition moments on the CAP strength and illustrate how Dyson orbitals help understand the properties of metastable species and how they are affected by replacing the usual scalar product by the so-called c-product.


Ketamine influences CLOCK:BMAL1 function leading to altered circadian gene expression.
Major mood disorders have been linked to abnormalities in circadian rhythms, leading to disturbances in sleep, mood, temperature, and hormonal levels. We provide evidence that ketamine, a drug with rapid antidepressant effects, influences the function of the circadian molecular machinery. Ketamine modulates CLOCK:BMAL1-mediated transcriptional activation when these regulators are ectopically expressed in NG108-15 neuronal cells. Inhibition occurs in a dose-dependent manner and is attenuated after treatment with the GSK3β antagonist SB21673. We analyzed the effect of ketamine on circadian gene expression and observed a dose-dependent reduction in the amplitude of circadian transcription of the Bmal1, Per2, and Cry1 genes. Finally, chromatin-immunoprecipitation analyses revealed that ketamine altered the recruitment of the CLOCK:BMAL1 complex on circadian promoters in a time-dependent manner. Our results reveal a yet unsuspected molecular mode of action of ketamine and thereby may suggest possible pharmacological antidepressant strategies.


Magnetization transfer effects on T1-weighted three-dimensional gradient-echo MR images of a phantom simulating enhancing brain lesions.
To develop a simple tissue phantom to study the effects of various imaging parameters and gadolinium concentrations on magnetization transfer (MT) and lesion-to-background ratios. A commercial egg product was doped with gadolinium in concentrations of 0.0 to 1.0 mmol/L and cooked. The T1 and T2 values were determined for the phantom materials and for the white and gray matter of a healthy volunteer subject. The gadolinium-doped egg phantom and human brain were studied using a short-repetition-time three-dimensional gradient-echo MT sequence with various effective MT powers, frequency offsets, and section-select flip angles. The normalized signal intensities, MT ratios (MTRs), and simulated lesion-to-background normal white matter contrast ratios were determined for a variety of experimental conditions. The MTR and lesion-to-background contrast ratios for all materials were greatest at the highest effective MT power (270 Hz, root-mean-square of amplitude) and the narrowest MT pulse frequency offset (1000 Hz). There was an inverse relationship between gadolinium concentration and MTR, and a positive relationship between the gadolinium concentration and lesion-to-background contrast. MTR was greatest at low flip angles, where there was little T1 weighting. The simulated lesion-to-background contrast showed a complex, gadolinium concentration-dependent relationship with section excitation flip angle. The tissue phantom has relaxation properties and MT behavior close to that expected for enhancing brain lesions, allowing a rigorous analysis of simulated lesion-to-background contrast for high MT power, short-repetition-time, three-dimensional gradient-echo sequences.


Does humor moderate the effects of experimentally-induced stress?
This study attempted to determine whether humor production moderates mood and physiological responses to stress of subjects high and low in trait humor. Forty subjects who were high and 40 subjects who were low in trait humor were selected. Half of each group was randomly assigned to one of two conditions. In one condition they generated a humorous monologue and in the other condition they generated a serious monologue to a silent stressful film. Heart rate, skin conductance level, and skin temperature were taken continuously for the fifteen minutes before, during, and fifteen minutes after the film. Pre- and post-stress mood and tension ratings were also recorded. Analyses of covariance were conducted with baseline mood and tension as covariates. Compared to the production of a serious narrative, humor production led to lower negative affect, lower tension, and reduced psychophysiological reactivity for both high and low trait-humor groups. These results suggest that humor production may be an effective coping strategy, even for individuals who do not typically use humor to cope with stress.


The effects of camera lenses and dental specialties on the perception of smile esthetics.
The purpose of this study was to investigate whether different camera lenses and dental specialties can affect the perception of smile esthetics. In the first phase of this study, 40 female smile photographs (taken from dental students) were evaluated by six orthodontists, three specialists in restorative dentistry, and three prosthodontists to select the most beautiful smiles. The 20 students with the best smile ranks were again photographed in standard conditions, but this time with two different lenses: Regular and then macro lenses. Each referee evaluated the beauty of the smiles on a visual analog scale. The referees were blinded of the type of lenses, and the images were all coded. The data were analyzed using two-way analysis of variance (ANOVA), Kruskal-Wallis and Mann-Whitney U-tests (alpha = 0.05, alpha = 0.0167). The lenses led to similar scores of beauty perception (Mann-Whitney P = 0.8). There was no difference between subjective beauty perception of specialties (Kruskal-Wallis P = 0.6). Two-way ANOVA indicated no significant role for lenses (P = 0.1750), specialties (P = 0.7677), or their interaction (P = 0.7852). The photographs taken by a regular lens and then digitally magnified can be as appealing as close-up photographs taken by a macro lens. Experts in different specialties (orthodontics, prosthodontics, and restorative dentistry) showed similar subjective judgments of smile beauty.


Ab initio studies on the photophysics of guanine tautomers: out-of-plane deformation and NH dissociation pathways to conical intersections.
The radiationless decay mechanisms of the S1 excited states of the 7H-keto-amino, 7H-enol-amino, and 7H-keto-imino tautomers of guanine have been investigated with the CASPT2//CASSCF method. Out-of-plane deformation of the six-membered ring or the imino group as well as dissociation of NH bonds have been considered as photochemical pathways leading to conical intersections with the electronic ground state. It has been found that all three tautomers can reach S0-S1 conical intersections by out-of-plane deformation. However, only in the 7H-keto-amino tautomer the reaction path leading to the conical intersection is barrierless. This tautomer also has the lowest energy barrier for hydrogen detachment via the (1)pi sigma* state, whose potential energy surface intersects that of the (1)pi pi* state as well as that of the ground state. The other tautomers of guanine exhibit substantial energy barriers on their S1 potential energy surfaces with respect to both reaction mechanisms. These findings suggest that the 7H-keto-amino tautomer exhibits the shortest excited-state lifetime of the three tautomers due to particularly fast nonradiative deactivation processes through S0-S1 conical intersections. The computational results explain the remarkable observation that the energetically most stable 7H-keto-amino tautomer is missing in the resonant two-photon ionization spectrum of guanine in a supersonic jet. The results also explain that the energetically less stable 7H-enol-amino and 7H-keto-imino tautomers have longer excited-state lifetimes and are thus detectable by resonant two-photon ionization.


Immunohistochemical evidence of seizure-induced activation of trkB receptors in the mossy fiber pathway of adult mouse hippocampus.
Genetic and pharmacological perturbations suggest that tyrosine receptor kinase B (trkB) receptor activation promotes limbic epileptogenesis, but whether or where trkB activation occurs during epileptogenesis is uncertain. Because activation of trk receptors involves phosphorylation of specific tyrosine residues (Segal et al., 1996), the availability of antibodies that selectively recognize the phosphorylated form of trk receptors at the Shc site permits an immunohistochemical assessment of trk receptor activation. We reported previously increased phospho-specific trk (p-trk) immunoreactivity in the mossy fiber pathway of the hippocampus during epileptogenesis in rats (Binder et al., 1999b). Because the p-trk antibody does not distinguish among trkA, trkB, and trkC, the identity of the neurotrophin receptor(s) undergoing phosphorylation was uncertain. The development of mice carrying a point mutation of the Shc binding site (Y515F) in the trkB gene (trkB(shc)) provided an opportunity to test the hypothesis that trkB is the neurotrophin receptor undergoing phosphorylation. Epileptogenesis in wild-type (WT) mice was associated with increased p-trk immunoreactivity in both the mossy fiber pathway and CA3 stratum oriens of hippocampus. In contrast, the epileptogenesis-associated increase of p-trk immunoreactivity was reduced in trkB(shc) mutant mice. The development of epileptogenesis as measured by electrophysiological and behavioral indices did not differ between trkB(shc) mutant and WT mice. These data demonstrate that the neurotrophin receptor trkB undergoes phosphorylation in the mossy fiber pathway and CA3 stratum oriens of the hippocampus during limbic epileptogenesis. In addition, the signaling pathways activated by the Shc site of trkB exert no detectable regulatory effects on limbic epileptogenesis.


Estimating traffic noise over a large urban area: An evaluation of methods.
Unlike air pollution, traffic-related noise remains unregulated and has been under-studied despite evidence of its deleterious health impacts. To characterize population exposure to traffic noise, both acoustic-based numerical models and data-driven statistical approaches can generate estimates over large urban areas. The aim of this work is to formally compare the performances of the most common traffic noise models by evaluating their estimates for different categories of roads and validating them against a unique dataset of measured noise in Long Beach, California. Specifically, a statistical land use regression model, an extreme gradient boosting machine learning model (XGB), and three numerical/acoustic traffic noise models: the US Noise Model (FHWA-TNM2.5), a commercial noise model (CadnaA), and an open-source European model (Harmonoise) were optimized and compared. The results demonstrate that XGB and CadnaA were the most effective models for estimating traffic noise, and they are particularly adept at differentiating noise levels on different categories of road.


The Adverse Survival Implications of Bland Thrombus in Renal Cell Carcinoma With Venous Tumor Thrombus.
To characterize the presence of bland (nontumor) thrombus in advanced renal cell carcinoma and assess the impact of this finding on cancer-specific survival. A multi-institutional database of patients treated with nephrectomy with caval thrombectomy for locally-advanced renal tumors was assembled from 5 tertiary care medical centers. Using clinicopathologic variables including patient age, body mass index, Eastern Cooperative Oncology Group performance status, tumor stage, grade, nodal status and histology, and nearest-neighbor and multiple-matching propensity score matched cohorts of bland thrombus vs nonbland thrombus patients were assessed. Multivariable analysis for predictors of cancer-specific survival was performed. From an initial cohort of 579 patients, 446 met inclusion criteria (174 with bland thrombus, 272 without). At baseline, patients with bland thrombus had significantly worse performance status, higher tumor stage, higher prevalence of regional nodal metastases and higher nuclear grade (P < .01 for all). In both nearest-neighbor and multiple-matching propensity score matched cohorts, the presence of bland thrombus presence was associated with inferior median cancer-specific survival (28.1 months vs 156.8 months, and 28.1 months vs 76.7 months, P < .001 for both). The presence of bland thrombus remained independently associated with an increased risk of cancer-specific mortality on multivariable analysis (hazard ratio 4.33, 95% confidence interval 2.79-6.73, P < .001). Presence of bland thrombus is associated with adverse survival outcomes in patients treated surgically for renal tumors with venous tumor thrombus. These findings may have important implications in patient counseling, selection for surgery and inclusion in clinical trials.


Two-wavelength interferometry that uses a fourier-transform method.
Two-wavelength interferometry that is based on a Fourier-transform method has been investigated. A phase profile at a synthetic wavelength has been measured from a two-wavelength interferogram with two spatial carrier frequencies. A phase error caused by the difference between modulation intensities at two wavelengths has been theoretically and numerically analyzed. A phase map without the error can be obtained from a power-spectrum adjustment in the two-wavelength interferogram.


Future therapeutic trends in osteoarthritis.
Since cartilage contains no nerve endings, symptoms of osteoarthritis (OA) are indirect. Therapy of OA, to date, has been directed at the symptoms of pain, signs of inflammation and loss of function. A major advance has been surgical joint replacement. This benefit however, is often limited by the joint area involved and to the survival of the endoprosthesis. Orthopedic new approaches to therapy of OA include removal of abnormal tissue to stimulate repair (e.g., burring, abrasion) and grafting (e.g., osteochondral grafts, perichondrium, periosteum) to the subchondral bone. Controlled activity (e.g., passive motion) has been studied alone and with the above. Can a medication retard or reverse the degradative process of OA? Several medications are being examined for potential "chondroprotective" characteristics. Some of these agents are not new: oversulfated glycosaminoglycans (Arteparon) derived from cartilage and glycosaminoglycan peptides (Rumalon) derived from cartilage and bone marrow extracts may be prototypes of this approach to therapy. Other agents demonstrating potential benefit in retarding cartilage degradation may include non-steroidal anti-inflammatory agents, tiaprofenic acid, sodium pentosan sulfate and low dose corticosteroids. This concept of "chondroprotection" provides us a new approach to a disease in need of a new approach.


[Design of the general population study NEMESIS-2: Netherlands Mental Health Survey and Incidence Study-2].
The longitudinal epidemiological population study NEMESIS-2 (Netherlands Mental Health Survey and Incidence Study-2) replicates the first study conducted from 1996 to 1999, and expands it by adding new subjects such as impulse-control disorders. To describe the aims and design of nemesis-2, particularly of its first round of measurements, to provide up-to-date figures on prevalence, incidence, course and consequences of mental disorders and associated factors, and to study trends in the mental health of the population aged 18-64 years and the use these people make of psychiatric services. Face-to-face interviews were conducted (November 2007-July 2009) by means of the Composite International Diagnostic Interview 3.0. The response was 65.1% (n = 6646). Respondents were reasonably representative for the population, but young persons were somewhat underrepresented. Two follow-up rounds of measurements are planned with three-year intervals between the rounds. The second round of measurements began in November 2010. A qualitatively good dataset was built up. This will allow several mental health topics to be studied in the future.


Vocal development through morphological computation.
The vocal behavior of infants changes dramatically during early life. Whether or not such a change results from the growth of the body during development-as opposed to solely neural changes-has rarely been investigated. In this study of vocal development in marmoset monkeys, we tested the putative causal relationship between bodily growth and vocal development. During the first two months of life, the spontaneous vocalizations of marmosets undergo (1) a gradual disappearance of context-inappropriate call types and (2) an elongation in the duration of context-appropriate contact calls. We hypothesized that both changes are the natural consequences of lung growth and do not require any changes at the neural level. To test this idea, we first present a central pattern generator model of marmoset vocal production to demonstrate that lung growth can affect the temporal and oscillatory dynamics of neural circuits via sensory feedback from the lungs. Lung growth qualitatively shifted vocal behavior in the direction observed in real marmoset monkey vocal development. We then empirically tested this hypothesis by placing the marmoset infants in a helium-oxygen (heliox) environment in which air is much lighter. This simulated a reversal in development by decreasing the effort required to respire, thus increasing the respiration rate (as though the lungs were smaller). The heliox manipulation increased the proportions of inappropriate call types and decreased the duration of contact calls, consistent with a brief reversal of vocal development. These results suggest that bodily growth alone can play a major role in shaping the development of vocal behavior.


Immunoreactivity of androgen receptor protein in sexually dimorphic spinal motonucleus in neonatal male rats.
The spinal motonucleus of the genitofemoral nerve regulating scrotal temperature can also be related to prenatal and neonatal testicular descent by gubernacular change in rats, and a sexually dimorphic-like bulbocavernosus/dorsolateral motonucleus. There is a hypothesis that neonatal androgen affects these motonuclei, and induces development of sexual organs through neural stimulation. Until now, the accumulation of isotope-labelled androgen and the immuno-reactivity of androgen receptor protein in each sexually-dimorphic spinal motonucleus have been revealed in adult rats but they have not been established in rats during neonatal periods. To investigate the presence of the androgen receptor in spinal sexually-dimorphic motonuclei in the neonatal period, we evaluated the androgen receptor immunoreactivity of these motonuclei. In Sprague-Dawley male rats, the lumbar spinal cords were resected at postnatal days 3, 10 and 30, and stained immunohistochemically using polyclonal antibody of androgen receptor protein. The immunoreactivity of androgen receptor protein was observed in the cells of the genitofemoral motonucleus from the 13th thoracic to the 2nd lumbar spinal cord and the bulbocavernosus/dorsolateral motonucleus was observed from the 4th to 5th lumbar spinal cord in all age groups. The proportional areas of both motonuclei at days 3 and 10 on cross-section were larger than at day 30. The motonuclei at days 3 and 10 were similar in all age groups. With the above results, the presence of androgen receptor protein was confirmed in the genitofemoral and bulbocavernosus/dorsolateral motonucleus from neonate to day 30. The larger proportional area of these motonuclei in neonates may indicate an active role for these motonuclei during the neonatal period. Although the immunoreactivity does not directly imply the presence of a functional receptor, neonatal androgen could be responsible for the development of sexual organs through the spinal motonucleus.


Immune parameters and outcomes during Ebola virus disease.
The West African Ebola virus epidemic from 2014-2016 highlighted the lack of knowledge about the pathogenicity of the virus and the factors responsible for outcome. A performant and rapid diagnosis is of crucial importance, as is overcoming the difficulty of providing high-quality patient management during such an extensive outbreak. Here, we propose to study the role of the immune mediators during Ebola virus disease and to define some molecules of importance in the outcome. Plasma from Guinean patients sampled during the outbreak were analyzed using RT-qPCR, magnetic bead assay, ELISA, and high-quality statistical analyses. We also performed a transcriptomic analysis in leukocytes samples. Therefore, we deeply characterized the immune responses involved in Ebola virus disease. We evaluated the immune patterns depending on the outcome of the disease. Survivors presented an efficient and well-balanced immune response, whereas fatalities were characterized by an intense inflammatory response, overexpression of multiple cytokines, and a "chemokine storm." The plasma concentration of most of the parameters tested increased until death. Statistical analyses also allowed us to define a panel of markers highly predictive of outcome. The immune response observed in fatalities was highly similar to that characterizing septic shock syndrome. Our results suggest that immune responses can play a major pathogenic role during severe Ebola virus infection and argue in favor of therapeutic approaches that act on both viral replication and the induction of shock syndrome. French Ministry of Foreign Affairs, the Agence Française de Développement, and the Institut Pasteur.


pH-dependent localization of Btn1p in the yeast model for Batten disease.
Btn1p the yeast homolog of human CLN3, which is associated with juvenile Batten disease has been implicated in several cellular pathways. Yeast cells lacking BTN1 are unable to couple ATP hydrolysis and proton pumping activities by the vacuolar ATPase (V-ATPase). In this work, we demonstrate that changes in extracellular pH result in altered transcription of BTN1, as well as a change in the glycosylation state and localization of Btn1p. At high pH, Btn1p expression was increased and the protein was mainly located in vacuolar membranes. However, low pH decreased Btn1p expression and changed its location to undefined punctate membranes. Moreover, our results suggest that differential Btn1p localization may be regulated by its glycosylation state. Underlying pathogenic implications for Batten disease of altered cellular distribution of CLN3 are discussed.


Electrophysiological Changes During Early Steps of Retinitis Pigmentosa.
The rhodopsin mutation P23H is responsible for a significant portion of autosomal-dominant retinitis pigmentosa, a disorder characterized by rod photoreceptor death. The mechanisms of toxicity remain unclear; previous studies implicate destabilization of P23H rhodopsin during light exposure, causing decreased endoplasmic reticulum (ER) exit and ER stress responses. Here, we probed phototransduction in Xenopus laevis rods expressing bovine P23H rhodopsin, in which retinal degeneration is inducible by light exposure, in order to examine early physiological changes that occur during retinal degeneration. We recorded single-cell and whole-retina responses to light stimuli using electrophysiology. Moreover, we monitored morphologic changes in rods after different periods of light exposure. Initially, P23H rods had almost normal photoresponses, but following a brief light exposure varying from 4 to 32 photoisomerizations per disc, photoresponses became irreversibly prolonged. In intact retinas, rods began to shed OS fragments after a rod-saturating exposure of 12 minutes, corresponding to approximately 10 to 100 times more photoisomerizations. Our results indicate that in P23H rods light-induced degeneration occurs in at least two stages, the first involving impairment of phototransduction and the second involving initiation of morphologic changes.


Insulin gene therapy for type 1 diabetes mellitus.
Type 1 diabetes mellitus is an autoimmune disease resulting from the destruction of pancreatic β cells. Current treatments for patients with type 1 diabetes mellitus include daily insulin injections or whole pancreas transplant, each of which are associated with profound drawbacks. Insulin gene therapy, which has shown great efficacy in correcting hyperglycemia in animal models, holds great promise as an alternative strategy to treat type 1 diabetes mellitus in humans. Insulin gene therapy refers to the targeted expression of insulin in non-β cells, with hepatocytes emerging as the primary therapeutic target. In this review, we present an overview of the current state of insulin gene therapy to treat type 1 diabetes mellitus, including the need for an alternative therapy, important features dictating the success of the therapy, and current obstacles preventing the translation of this treatment option to a clinical setting. In so doing, we hope to shed light on insulin gene therapy as a viable option to treat type 1 diabetes mellitus.


Conceptions of learning and approaches to studying among White and ethnic minority students in distance education.
The attainment of White students at UK institutions of higher education tends to be higher than that of students from other ethnic groups, but the causes of this are unclear. This study compared White students and students from other ethnic groups in their conceptions of learning, their approaches to studying, and their academic attainment. A stratified sample of 1,146 White students and 1,146 students from other ethnic groups taking courses by distance learning with the UK Open University. The Mental Models section of the Inventory of Learning Styles and the Revised Approaches to Studying Inventory were administered in a postal survey. The students' questionnaire scores were contaminated by response bias, which varied across different ethnic groups. When adjusted to control for response bias, the scores on the two questionnaires shared 37.2% of their variance and made a significant contribution to predicting the students' attainment. White students were more likely to exhibit a meaning-directed learning pattern, whereas Asian and Black students were more likely to exhibit a reproduction-directed learning pattern. However, the variation in attainment across different ethnic groups remained significant when their questionnaire scores and prior qualifications were taken into account. There is a strong relationship between students' conceptions of learning and their approaches to studying, and variations in conceptions of learning in different ethnic groups give rise to variations in approaches to studying. However, factors other than prior qualifications and conceptions of learning are responsible for variation in attainment across different ethnic groups.