The feasibility of applying item response theory to measures of migraine impact: a re-analysis of three clinical studies.
Item response theory (IRT) is a powerful framework for analyzing multiitem scales and is central to the implementation of computerized adaptive testing. To explain the use of IRT to examine measurement properties and to apply IRT to a questionnaire for measuring migraine impact--the Migraine Specific Questionnaire (MSQ). Data from three clinical studies that employed the MSQ-version 1 were analyzed by confirmatory factor analysis for categorical data and by IRT modeling. Confirmatory factor analyses showed very high correlations between the factors hypothesized by the original test constructions. Further, high item loadings on one common factor suggest that migraine impact may be adequately assessed by only one score. IRT analyses of the MSQ were feasible and provided several suggestions as to how to improve the items and in particular the response choices. Out of 15 items, 13 showed adequate fit to the IRT model. In general, IRT scores were strongly associated with the scores proposed by the original test developers and with the total item sum score. Analysis of response consistency showed that more than 90% of the patients answered consistently according to a unidimensional IRT model. For the remaining patients, scores on the dimension of emotional function were less strongly related to the overall IRT scores that mainly reflected role limitations. Such response patterns can be detected easily using response consistency indices. Analysis of test precision across score levels revealed that the MSQ was most precise at one standard deviation worse than the mean impact level for migraine patients that are not in treatment. Thus, gains in test precision can be achieved by developing items aimed at less severe levels of migraine impact. IRT proved useful for analyzing the MSQ. The approach warrants further testing in a more comprehensive item pool for headache impact that would enable computerized adaptive testing.


Treatment of uncomplicated multidrug-resistant falciparum malaria with artesunate-atovaquone-proguanil.
In an open-label trial carried out on the northwest border of Thailand, 1596 patients with uncomplicated multidrug-resistant falciparum malaria were randomly assigned to receive atovaquone-proguanil, atovaquone-proguanil-artesunate, or artesunate-mefloquine and were followed up for 42 days. All 3 regimens were highly effective and well tolerated. Fever duration and parasite clearance times were significantly shorter among patients who received artesunate (P<.001). Polymerase chain reaction genotyping confirmed that recrudescence occurred in 13 patients who received artesunate-mefloquine (2.4%), 5 who received atovaquone-proguanil-artesunate (0.9%), and 15 who received atovaquone-proguanil (2.8%). Adding artesunate to atovaquone-proguanil reduced the risk of failure 3-fold (95% confidence interval [CI], 1.1-8.2) and subsequent gametocyte carriage 21-fold (95% CI, 14-30). Gastrointestinal complaints in the first 48 h after initiation of treatment were more common among artesunate recipients, but after day 2, dizziness, sleep disturbance, nausea, vomiting, and anorexia were more common among mefloquine recipients (P< or =.014). Artesunate-atovaquone-proguanil is a highly effective and well-tolerated treatment for multidrug-resistant falciparum malaria.


Clonal evolution and therapeutic resistance in solid tumors.
Tumors frequently arise as a result of an acquired genomic instability and the subsequent evolution of neoplastic populations with variable genomes. A barrier to the study of the somatic genetics of human solid tumors in vivo is the presence of admixtures of non-neoplastic cells with normal genomes in patient samples. These can obscure the presence of somatic aberrations including mutations, homozygous deletions, and breakpoints in biopsies of interest. Furthermore, clinical samples frequently contain multiple neoplastic populations that cannot be distinguished by morphology. Consequently, it is difficult to determine whether mutations detected in a sample of interest are concurrent in a single clonal population or if they occur in distinct cell populations in the same sample. The advent of targeted therapies increases the selection for preexisting populations. However the asymmetric distribution of therapeutic targets in clonal populations provides a mechanism for the rapid evolution of resistant disease. Thus, there is a need to not only isolate tumor from normal cells, but to also enrich distinct populations of clonal neoplastic cells in order to apply genome technologies to identify clinically relevant genomic aberrations that drive disease in patients in vivo. To address this we have applied single and multiparameter DNA content based flow assays to the study of solid tumors. Our work has identified examples of clonal resistance to effective therapies. This includes androgen withdrawal in advanced prostate cancer. In addition we demonstrate examples of co-existing clonal populations with highly aberrant genomes and ploidies in a wide variety of solid tumors. We propose that clonal analysis of tumors, based on flow cytometry and high resolution genome analyses of purified neoplastic populations, provides a unique approach to the study of therapeutic responses and the evolution of resistance.


Ontogeny of the electric organ discharge and of the papillae of the electrocytes in the weakly electric fish Campylomormyrus rhynchophorus (Teleostei: Mormyridae).
The electric organ of the mormyrid weakly electric fish, Campylomormyrus rhynchophorus (Boulenger, 1898), undergoes changes in both the electric organ discharge (EOD) and the light and electron microscopic morphology as the fish mature from the juvenile to the adult form. Of particular interest was the appearance of papillae, surface specializations of the uninnervated anterior face of the electrocyte, which have been hypothesized to increase the duration of the EOD. In a 24.5 mm long juvenile the adult electric organ (EO) was not yet functional, and the electrocytes lacked papillae. A 40 mm long juvenile, which produced a short biphasic EOD of 1.3 ms duration, shows small papillae (average area 136 μm2 ). In contrast, the EOD of a 79 mm long juvenile was triphasic. The large increase in duration of the EOD to 23.2 ms was accompanied by a small change in size of the papillae (average area 159 μm2 ). Similarly, a 150 mm long adult produced a triphasic EOD of comparable duration to the younger stage (24.7 ms) but featured a prominent increase in size of the papillae (average area 402 μm2 ). Thus, there was no linear correlation between EOD duration and papillary size. The most prominent ultrastructural change was at the level of the myofilaments, which regularly extended into the papillae, only in the oldest specimen-probably serving a supporting function. Physiological mechanisms, like gene expression levels, as demonstrated in some Campylomormyrus species, might be more important concerning the duration of the EOD.


Relative survival after hospitalisation for hip fracture in older people in New South Wales, Australia.
Survival after hospitalisation for hip fracture by age group and sex relative to survival in the general population was assessed in people aged 65+. Men had double the risk of death compared with women to 1 year, but age effects lasted only to 3 months. Clinical outcomes need to be improved. We assessed the relative survival of hospitalised fall-related hip fracture patients aged 65+ years leaving hospital in New South Wales, Australia, between July 2000 and December 2003. We carried out a population-based study of all hospital separations for NSW residents with a principal diagnosis of hip fracture (ICD-10-AM S72.0 to S72.2) and first external cause of fall (ICD-10-AM codes W00 to W19), linked to NSW death data. A total of 16,836 cases were included. Relative survival 3 to 36 months post-admission by 10-year age groups and sex was calculated, using NSW life tables for 2002-2004. Relative excess risk was modelled using a generalised linear model with Poisson error structure, using the life table data. One-year cumulative relative survival in 65- to 74-year-olds was 82% (men), 90% (women); in 85+-year-olds 65% (men), 80% (women). Men have a relative excess risk of death of 2.2 (95% CI 2.03-2.38) times that of women. Only 21% of deaths mention the hip fracture as contributing to death. There is a need to reduce the number of hip fractures and improve clinical outcomes for older people hospitalised with hip fractures.


Idiosyncratic responses to climate-driven forest fragmentation and marine incursions in reed frogs from Central Africa and the Gulf of Guinea Islands.
Organismal traits interact with environmental variation to mediate how species respond to shared landscapes. Thus, differences in traits related to dispersal ability or physiological tolerance may result in phylogeographic discordance among co-distributed taxa, even when they are responding to common barriers. We quantified climatic suitability and stability, and phylogeographic divergence within three reed frog species complexes across the Guineo-Congolian forests and Gulf of Guinea archipelago of Central Africa to investigate how they responded to a shared climatic and geological history. Our species-specific estimates of climatic suitability through time are consistent with temporal and spatial heterogeneity in diversification among the species complexes, indicating that differences in ecological breadth may partly explain these idiosyncratic patterns. Likewise, we demonstrated that fluctuating sea levels periodically exposed a land bridge connecting Bioko Island with the mainland Guineo-Congolian forest and that habitats across the exposed land bridge likely enabled dispersal in some species, but not in others. We did not find evidence that rivers are biogeographic barriers across any of the species complexes. Despite marked differences in the geographic extent of stable climates and temporal estimates of divergence among the species complexes, we recovered a shared pattern of intermittent climatic suitability with recent population connectivity and demographic expansion across the Congo Basin. This pattern supports the hypothesis that genetic exchange across the Congo Basin during humid periods, followed by vicariance during arid periods, has shaped regional diversity. Finally, we identified many distinct lineages among our focal taxa, some of which may reflect incipient or unrecognized species.


Overriding "doing wrong" and "not doing right": validation of the Dispositional Self-Control Scale (DSC).
We present the Dispositional Self-Control (DSC) Scale, which reflects individuals' tendency to override 2 types of temptations, termed doing wrong and not doing right. We report a series of 5 studies designed to test the reliability and validity of the scale. As hypothesized, high DSC predicts distant future orientation and low DSC predicts deviant behaviors such as aggression, alcohol misuse, and aberrant driving. DSC also predicts task performance among resource-depleted participants. Taken together, these findings suggest that the DSC Scale could be a useful tool toward further understanding the role of personality in overcoming self-control challenges.


Chinese version of the Global Youth Tobacco Survey: cross-cultural instrument adaptation.
Tobacco smoking poses public health concerns because of its high risk for many chronic diseases. Most smokers begin using tobacco in their teens and recent reports indicate that smoking prevalence is climbing among youth. The Global Youth Tobacco Survey (GYTS) is a worldwide, school-based, tobacco-specific survey, but cross-cultural differences limit its effectiveness in international studies. Specifically, the GYTS assesses not only the prevalence of smoking, but also tobacco-related attitudes, school curricula, and advertisements, which are culturally influenced. Therefore, we conducted this study to develop a Chinese version of the GYTS for both national surveillance and international comparison. The original English GYTS was translated and back translated using a cross-cultural adaptation process. The comprehensiveness and feasibility of using the Chinese-version GYTS were reviewed by a panel of 6 tobacco-control experts. The understandability and cultural relevance of the Chinese-version GYTS were discussed in a focus group of 5 schoolteachers and 8 students. The expert and focus group feedback was incorporated into a final Chinese version of the GYTS, which was administered to 382 students throughout Taiwan by multi-stage sampling from 10 randomly selected schools. The internal consistency (Cronbach's alpha) for the GYTS subscales (smoking susceptibility, attitude toward smoking, and media messages about smoking) ranged from 0.70 to 0.94. The internal logical agreement of responses ranged from 85.3 to 99.2%. The Chinese version of the GYTS has good reliability and validity and can serve as the foundation for international comparison and tobacco control in Chinese-speaking communities.


Cardiovascular and renal manifestations of hyperthyroidism.
In the simplest terms, hyperthyroidism is the clinical syndrome that results from an excess of thyroid hormones. This review considers the effects of hyperthyroidism on the cardiovascular and renal systems by reviewing the available literature on the clinical manifestations of this syndrome in the cat and also considering experimental studies and experience in other species, including human beings.


Ploidy and Size at Multiple Scales in the Arabidopsis Sepal.
Ploidy and size phenomena are observed to be correlated across several biological scales, from subcellular to organismal. Two kinds of ploidy change can affect plants. Whole-genome multiplication increases ploidy in whole plants and is broadly associated with increases in cell and organism size. Endoreduplication increases ploidy in individual cells. Ploidy increase is strongly correlated with increased cell size and nuclear volume. Here, we investigate scaling relationships between ploidy and size by simultaneously quantifying nuclear size, cell size, and organ size in sepals from an isogenic series of diploid, tetraploid, and octoploid Arabidopsis thaliana plants, each of which contains an internal endopolyploidy series. We find that pavement cell size and transcriptome size increase linearly with whole-organism ploidy, but organ area increases more modestly due to a compensatory decrease in cell number. We observe that cell size and nuclear size are maintained at a constant ratio; the value of this constant is similar in diploid and tetraploid plants and slightly lower in octoploid plants. However, cell size is maintained in a mutant with reduced nuclear size, indicating that cell size is scaled to cell ploidy rather than to nuclear size. These results shed light on how size is regulated in plants and how cells and organisms of differing sizes are generated by ploidy change.


Dietary supplements and hypertension: potential benefits and precautions.
Dietary supplements (DSs) are used extensively in the general population and many are promoted for the natural treatment and management of hypertension. Patients with hypertension often choose to use these products either in addition to or instead of pharmacologic antihypertensive agents. Because of the frequent use of DS, both consumers and health care providers should be aware of the considerable issues surrounding these products and factors influencing both efficacy and safety. In this review of the many DSs promoted for the management of hypertension, 4 products with evidence of possible benefits (coenzyme Q10, fish oil, garlic, vitamin C) and 4 that were consistently associated with increasing blood pressure were found (ephedra, Siberian ginseng, bitter orange, licorice). The goals and objectives of this review are to discuss the regulation of DS, evaluate the efficacy of particular DS in the treatment of hypertension, and highlight DS that may potentially increase blood pressure.


The effects of seasons and light therapy on G protein levels in mononuclear leukocytes of patients with seasonal affective disorder.
Information-transducing heterotrimeric G proteins have been implicated previously in the mechanism of action of mood stabilizers and in the pathophysiology of mood disorders. Mononuclear leukocytes of patients with unipolar and bipolar depression have been characterized by reduced measures of the stimulatory and inhibitory G proteins. In this study, patients with seasonal affective disorder (SAD) were measured for mononuclear leukocyte G protein levels while depressed during the winter, following light therapy, and in remission during the summer. Twenty-six patients with SAD and 28 healthy subjects were assessed in the study. The immunoreactivities of Gs alpha, Gi alpha, and Gbeta subunit proteins were determined by Western blot analysis of mononuclear leukocyte membranes with selective polyclonal antibodies for the various G subunit proteins, followed by densitometric quantitation using an image analysis system. Untreated patients with SAD and winter, atypical-type depression showed significantly reduced mononuclear leukocyte immunoreactive levels of Gs alpha and Gi alpha proteins, similar to previous observations in patients with nonseasonal major depression. The reduced G protein levels were normalized with 2 weeks of light therapy. The same patients while in remission during the summer had G protein levels that were similar to those of healthy subjects. G protein-immunoreactive measures in patients with SAD are suggested as a state marker for winter depression, which is normalized by light treatment and during the summer. We speculate that light may exert its effects via normalization of transducin (Gt protein) levels, which are thought to be reduced in winter depression.


Expanded analysis of high-grade astrocytoma with piloid features identifies an epigenetically and clinically distinct subtype associated with neurofibromatosis type 1.
High-grade astrocytoma with piloid features (HGAP) is a recently recognized glioma type whose classification is dependent on its global epigenetic signature. HGAP is characterized by alterations in the mitogen-activated protein kinase (MAPK) pathway, often co-occurring with CDKN2A/B homozygous deletion and/or ATRX mutation. Experience with HGAP is limited and to better understand this tumor type, we evaluated an expanded cohort of patients (n = 144) with these tumors, as defined by DNA methylation array testing, with a subset additionally evaluated by next-generation sequencing (NGS). Among evaluable cases, we confirmed the high prevalence CDKN2A/B homozygous deletion, and/or ATRX mutations/loss in this tumor type, along with a subset showing NF1 alterations. Five of 93 (5.4%) cases sequenced harbored TP53 mutations and RNA fusion analysis identified a single tumor containing an NTRK2 gene fusion, neither of which have been previously reported in HGAP. Clustering analysis revealed the presence of three distinct HGAP subtypes (or groups = g) based on whole-genome DNA methylation patterns, which we provisionally designated as gNF1 (n = 18), g1 (n = 72), and g2 (n = 54) (median ages 43.5 years, 47 years, and 32 years, respectively). Subtype gNF1 is notable for enrichment with patients with Neurofibromatosis Type 1 (33.3%, p = 0.0008), confinement to the posterior fossa, hypermethylation in the NF1 enhancer region, a trend towards decreased progression-free survival (p = 0.0579), RNA processing pathway dysregulation, and elevated non-neoplastic glia and neuron cell content (p < 0.0001 and p < 0.0001, respectively). Overall, our expanded cohort broadens the genetic, epigenetic, and clinical phenotype of HGAP and provides evidence for distinct epigenetic subtypes in this tumor type.


The outcome of renal ischemia-reperfusion injury is unchanged in AMPK-β1 deficient mice.
Activation of the master energy-regulator AMP-activated protein kinase (AMPK) in the heart reduces the severity of ischemia-reperfusion injury (IRI) but the role of AMPK in renal IRI is not known. The aim of this study was to determine whether activation of AMPK by acute renal ischemia influences the severity of renal IRI. AMPK expression and activation and the severity of renal IRI was studied in mice lacking the AMPK β1 subunit and compared to wild type (WT) mice. Basal expression of activated AMPK, phosphorylayed at αThr¹⁷², was markedly reduced by 96% in AMPK-β1⁻/⁻ mice. Acute renal ischaemia caused a 3.2-fold increase in α1-AMPK activity and a 2.5-fold increase in α2-AMPK activity (P<0.001) that was associated with an increase in AMPK phosphorylation of the AMPK-α subunit at Thr¹⁷² and Ser⁴⁸⁵, and increased inhibitory phosphorylation of the AMPK substrate acetyl-CoA carboxylase. After acute renal ischemia AMPK activity was reduced by 66% in AMPK-β1⁻/⁻ mice compared with WT. There was no difference, however, in the severity of renal IRI at 24-hours between AMPK-β1⁻/⁻ and WT mice, as measured by serum urea and creatinine and histological injury score. In the heart, macrophage migration inhibitory factor (MIF) released during IRI contributes to AMPK activation and protects from injury. In the kidney, however, no difference in AMPK activation by acute ischemia was observed between MIF⁻/⁻ and WT mice. Compared with the heart, expression of the MIF receptor CD74 was found to be reduced in the kidney. The failure of AMPK activation to influence the outcome of IRI in the kidney contrasts with what is reported in the heart. This difference might be due to a lack of effect of MIF on AMPK activation and lower CD74 expression in the kidney.


Notch signaling via Hes1 transcription factor maintains survival of melanoblasts and melanocyte stem cells.
Melanoblasts (Mbs) are thought to be strictly regulated by cell-cell interactions with epidermal keratinocytes, although the precise molecular mechanism of the regulation has been elusive. Notch signaling, whose activation is mediated by cell-cell interactions, is implicated in a broad range of developmental processes. We demonstrate the vital role of Notch signaling in the maintenance of Mbs, as well as melanocyte stem cells (MSCs). Conditional ablation of Notch signaling in the melanocyte lineage leads to a severe defect in hair pigmentation, followed by intensive hair graying. The defect is caused by a dramatic elimination of Mbs and MSCs. Furthermore, targeted overexpression of Hes1 is sufficient to protect Mbs from the elimination by apoptosis. Thus, these data provide evidence that Notch signaling, acting through Hes1, plays a crucial role in the survival of immature Mbs by preventing initiation of apoptosis.


Factors associated with early sexual initiation among preparatory and high school youths in Woldia town, northeast Ethiopia: a cross-sectional study.
Early initiation of sexual activity affects the sexual and reproductive health of the young population. The youth are at a high risk of risky sexual behaviours, including multiple partners and inconsistent condom use. There has been limited research on the level and determinants of early sexual initiation in Woldia town. Thus, this study aimed to assess the prevalence of early sexual initiation and associated factors among preparatory and high school students in Woldia town, northeast Ethiopia. An institution based cross-sectional study was conducted on 723 students selected by the simple random sampling technique on March 7, 2016. A pre-tested and structured self-administered questionnaire was used for data collection. Descriptive statistics, bivariate and multivariable logistic regression were computed. Adjusted odds ratio (AOR) with a 95% confidence interval (CI) was calculated to examine the strength of association. In the multivariable analysis, a p-value < 0.05 was considered as statistically significant. The prevalence of early sexual initiation among preparatory and high school students in Woldia town was 18.4% (95% CI:15.50,21.30%). Not attending religious programs (AOR = 3.2, 95% CI:1.84,5.44), peer pressure (AOR = 1.9, 95% CI:1.14,3.25), cigarette smoking (AOR = 2.3, 95% CI:1.06,4.85), poor parental monitoring (AOR = 2.8, 95% CI:1.77,4.53), and exposure to pornographic materials (AOR = 2.7, 95% CI:1.68,4.40) were significantly associated with early sexual initiation. A large number of students initiated sexual activity at an early age. The practiced is associated with sexual and reproductive health problems. Therefore, raising awareness of students about the risk factors for and implication of early sexual initiation through teachers, religious leaders, and parents is highly recommended.


Influence of inflammatory polyarthritis on cancer incidence and survival: results from a community-based prospective study.
To investigate whether the incidence of cancer is increased and whether the rate of cancer survival is reduced in patients following the onset of inflammatory polyarthritis. Between 1990 and 1999, we recruited 2,105 patients to a large primary care-based register of new-onset inflammatory polyarthritis. Subsequent cancers were ascertained by linkage to hospital and death records and were confirmed by the regional cancer register. Cancer incidence, both all-site and site-specific, was compared with regional rates, adjusting for age, sex, and calendar year. Overall cancer survival, adjusted for site, was compared with regional data using Kaplan-Meier curves and Cox regression. There were 123 incident cases of cancer in the cohort of patients with inflammatory polyarthritis. The overall incidence of cancer among this cohort of patients with inflammatory polyarthritis was not increased compared with that in the regional population. Among cancers of all major organ systems, only the incidence of hematopoietic cancers (including lymphoma) was increased. Five-year cancer survival was reduced in patients with inflammatory polyarthritis compared with patients without inflammatory polyarthritis. After adjusting for diagnosis, age, sex, and tumor type, mortality in patients with inflammatory polyarthritis and cancer was significantly increased (hazard ratio 1.4, 95% confidence interval 1.1-1.7). This is the first investigation of overall cancer survival in patients with inflammatory polyarthritis. Compared with an increased incidence of cancer, reduced cancer survival might be a greater contributor to the increased cancer mortality observed in some rheumatoid arthritis populations.


Molecular cloning and functional expression of the mouse gap junction gene connexin-57 in human HeLa cells.
A new mouse connexin gene has been isolated that codes for a connexin protein of 505 amino acid residues. Based on the predicted molecular mass of 57.115 kDa, it has been designated connexin-57. Similar to most other mouse connexin genes, the coding region of connexin-57 is not interrupted by introns and exists in the mouse genome as a single-copy gene. Within the connexin family, this new gene shows highest sequence identity to porcine connexin-60 in the alpha group of connexins. The connexin-57 gene was mapped to a position on mouse chromosome 4, 30 centimorgans proximal to a cluster of previously mapped connexin genes. Low levels of connexin-57 mRNA were detected in skin, heart, kidney, testis, ovary, intestine, and in the mouse embryo after 8 days post coitum, but expression was not detected in brain, sciatic nerve or liver. In order to analyze gene function, the connexin-57 coding region was expressed by transfection in human HeLa cells, where it restored homotypic intercellular transfer of microinjected neurobiotin. Heterotypic transfer was observed between HeLa connexin-57 transfectants and HeLa cells, expressing murine connexin-43, -37, or -30.3. Double whole-cell voltage clamp analyses revealed that HeLa-connexin-57 transfectants expressed about 10 times more channels than parental HeLa cells. Voltage gating by transjunctional and transmembrane voltages as well as unitary conductance ( approximately 27 picosiemens) were different from intrinsic connexin channels in parental HeLa cells.


Effects of systemic opioid receptor ligands on ethanol- and sucrose seeking and drinking in alcohol-preferring (P) and Long Evans rats.
The endogenous opioid system has been implicated in mediating the reinforcing effects of ethanol (EtOH). Naltrexone (NTX), an opioid antagonist with concentration-dependent selectivity for the mu receptor, naltrindole (NTI), a selective delta receptor antagonist, and U50,488H, a selective kappa receptor agonist were examined in both alcohol-preferring (P) and nonselected (Long Evans (LE)) rats to determine whether they differentially affected the seeking and consumption of EtOH and sucrose. Using the sipper-tube model, rats reinforced with either 2% sucrose or 10% EtOH were injected with vehicle and either NTI (2.5, 5.0, or 10.0 mg/kg), U50 (2.5, 5.0, or 10.0 mg/kg), low-dose NTX (0.1, 0.3, or 1.0 mg/kg), or high-dose NTX (1.0, 3.0, or 10.0 mg/kg). Subsequent intakes (consummatory) or lever responses (seeking) were assessed. Overall, NTI, U50, and NTX attenuated intake and responding for sucrose and EtOH, with EtOH-reinforced P rats being the most sensitive to the effects of NTI on intake and seeking. U50 treatment decreased intake and seeking in both P and LE rats but did not selectively reduce EtOH intake or seeking in either line. P rats were more sensitive than LE rats to lower doses of NTX, and these doses more selectively attenuated responding for EtOH than sucrose. Higher doses of NTX suppressed intake and responding across both lines and reinforcers. These results suggest that drugs selective for the opioid receptors may be good pharmacotherapeutic targets, particularly in those with an underlying genetic predisposition for greater EtOH preference/intake.


Volumetric Parameterization of the Placenta to a Flattened Template.
We present a volumetric mesh-based algorithm for parameterizing the placenta to a flattened template to enable effective visualization of local anatomy and function. MRI shows potential as a research tool as it provides signals directly related to placental function. However, due to the curved and highly variable in vivo shape of the placenta, interpreting and visualizing these images is difficult. We address interpretation challenges by mapping the placenta so that it resembles the familiar ex vivo shape. We formulate the parameterization as an optimization problem for mapping the placental shape represented by a volumetric mesh to a flattened template. We employ the symmetric Dirichlet energy to control local distortion throughout the volume. Local injectivity in the mapping is enforced by a constrained line search during the gradient descent optimization. We validate our method using a research study of 111 placental shapes extracted from BOLD MRI images. Our mapping achieves sub-voxel accuracy in matching the template while maintaining low distortion throughout the volume. We demonstrate how the resulting flattening of the placenta improves visualization of anatomy and function. Our code is freely available at https://github.com/mabulnaga/placenta-flattening.


c-fos induction in the subnucleus caudalis following noxious mechanical stimulation of the oral mucous membrane.
c-fos expression in response to noxious mechanical stimulation of the peripheral receptive field was used to study the somatotopic representation of the oral mucous membrane and trigeminal cutaneous receptive fields in the trigeminal subnucleus caudalis and the cervical spinal dorsal horn. Fos-neurons (neurons with c-fos protein-like immunoreactivity) following stimulation of the cutaneous receptive field were found in laminae I and II of the first and second cervical segments of the spinal cord ipsilateral to the stimulation and exhibited a clear somatotopic segregation; i.e., the fos-neurons responding to receptive fields in the mandibular, maxillary, and ophthalmic divisions were arranged in a mediolateral sequence. On the other hand, fos-neurons responding to the oral mucous membrane were found in the similar laminae of the rostral pole of subnucleus caudalis bilaterally. They were all found in the dorsalmost part of the subnucleus without segregation; e.g., topographic distributions of fos-neurons resulting from the mandibular and maxillary gingival stimulations were indistinguishable. The central mechanism of trigeminal nociception is discussed with respect to the difference between intra- and extraoral receptive fields.


Comparison of overlapping peptide sets for detection of antiviral CD8 and CD4 T cell responses.
Increasing efforts are directed towards the development of effective vaccines through induction of virus-specific T cell responses. Although emerging data indicate a significant role of these cells in determining viral set point in infections such as HIV, there is as yet no consensus as to the best methods for assaying the breadth of these responses. In this study, we used sensitive interferon gamma-based intracellular cytokine staining (ICS) and Elispot assays to determine the optimal overlapping peptide set to screen for these responses. Twenty persons with established HIV infection were studied, focusing on responses to the highly immunogenic Nef protein. Six different HIV-1 Nef peptide sets were used, ranging in length from 15 to 20 amino acids (aa), in overlap from 10 to 11 amino acids, and derived from two different B clade sequences. A total of 54 CD8 T cell responses to Nef peptides were found in this cohort, of which only 12 were detected using previously defined Nef optimal epitopes. No single peptide set detected all responses. Though there was a trend of the shorter peptides detecting more CD8 T cell responses than the 20 amino acid long peptides and longer peptides detecting more CD4 T cell responses, neither was statistically significant. There was no difference between an overlap of 10 or 11 amino acids. All responses detected with the six different sets of overlapping peptides were towards the more highly conserved regions of Nef. We conclude that peptides ranging from 15 to 20 amino acids yield similar results in IFN-gamma-based Elispot and ICS assays, and that all are likely to underestimate the true breadth of responses to a given reference strain of virus.


Hepatoprotective effects of Liv-52 and its indirect influence on the regulation of thyroid hormones in rat liver toxicity induced by carbon tetrachloride.
This study was undertaken to investigate the protective effect of Liv-52, a herbal formulation, on various serum and liver marker enzymes, lipid peroxidation and histological changes in the liver of male albino rats suffering long-term carbon tetrachloride (CCl4) poisoning. It was observed that the activities of serum marker enzymes, hepatic enzymes and NADPH-dependent lipid peroxidation were significantly elevated after treatment with CCl4. However, in rats given Liv-52 at the same time as CCl4, the levels of all the marker enzymes were closer to those found in control animals. A similar trend was seen in the case of lipid peroxidation after Liv-52 treatment. CCl4 alone caused severe liver damage, but when Liv-52 was simultaneously given, there was much less effect on the structure of the organ. Circulating T3 and T4 concentrations were also determined after 6 weeks of simultaneous treatment with Liv-52 and CCl4. Concentrations of T3 were significantly lowered after CCl4 treatment alone, but Liv-52 administration together with CCl4 resulted in maintenance of the T3 activity within normal limits, thus suggesting indirect beneficial effects of Liv-52 on the regulation of thyroid hormone concentrations.


Reproducibility of serum 25-hydroxyvitamin d and vitamin D-binding protein levels over time in a prospective cohort study of black and white adults.
Prospective epidemiologic studies generally rely on 1 baseline biologic sample from participants for measurement of prediagnostic biomarkers, assuming that 1 measurement adequately represents the participant's "typical" level. The body of work assessing the reproducibility of circulating serum 25-hydroxyvitamin D (25(OH)D) levels over time focuses almost exclusively on populations of European descent, and data for vitamin D-binding protein (VDBP) are virtually nonexistent. Thus, the authors measured levels of serum 25(OH)D and VDBP twice in samples collected between 2005 and 2008 from 225 participants (155 black, 70 white) in the Southern Community Cohort Study. Reproducibility for 25(OH)D was uniformly high, with adjusted intraclass correlation coefficients (ICCs) of 0.84 (95% confidence interval (CI): 0.79, 0.88) for blacks and 0.92 (95% CI: 0.87, 0.95) for whites, and there was substantial agreement for assignment of 25(OH)D quartile (κ = 0.83, 95% CI: 0.78, 0.87) and vitamin D adequacy status (κ = 0.76, 95% CI: 0.69, 0.83). VDBP levels were highly stable over time, with adjusted ICCs of 0.97 (95% CI: 0.96, 0.98) for blacks and 0.96 (95% CI: 0.93, 0.97) for whites. These findings suggest that single, baseline 25(OH)D and VDBP serum measurements provide reasonably representative measures of these compounds for both white and black adults, demonstrating their utility as epidemiologic biomarkers in prospective studies.


Dissociation between wanting and liking for alcohol and caffeine: A test of the Incentive Sensitisation Theory.
Limited human studies have directly tested the dissociation between wanting and liking with human substance users, a core tenet of the Incentive Sensitisation Theory (IST). The aim of this study is to test the dissociation between wanting and liking in humans across two commonly used licit substances, alcohol and caffeine. The STRAP-R (Sensitivity To Reinforcement of Addictive and other Primary Rewards) questionnaire was administered to 285 alcohol users (mean age=33.30, SD= 8.83) and 134 coffee users (mean age=33.05, SD=8.10) ranging in their levels of substance use to assess wanting and liking. Findings showed that in high risk alcohol users wanting may drive alcohol consumption more so than liking, compared with low risk alcohol users. However, wanting and liking did not significantly dissociate as alcohol consumption increased. These findings partially support IST. Additionally, IST was not supported in coffee users. It is possible that caffeine functions differently at the neurological level compared with alcohol, perhaps explaining the lack of dissociation emerging in coffee users as caffeine use increased. Nevertheless, the current study makes several contributions to IST research. Future studies should focus on utilising the STRAP-R with a clinically dependent sample to test the dissociation between wanting and liking.


Topical application of L-arginine blocks advanced glycation by ascorbic acid in the lens of hSVCT2 transgenic mice.
Previous experiments from our laboratory showed that the oral intake of selected guanidino compounds could block the formation of crystallin-bound advanced ascorbylation products. Here we tested whether these were also active when applied as eye drops. Two month old hSVCT2 transgenic mice (n=10) were treated twice daily with one drop of 0.1% L-arginine, γ-guanidinobutyric acid (GBA), penicillamine (PA) or N-acetylcysteine (NAC) in one eye and vehicle only in the other eye. After seven months, lens crystallins were isolated, dialyzed, and proteolytically digested to determine the protein-bound fluorescence at 335/385 and 370/440 nm excitation/emission and the advanced glycation/ascorbylation endproducts carboxymethyl-lysine (CML), carboxyethyl-lysine (CEL), glucosepane, glyoxal, and methylglyoxal hydroimidazolones G-H1 and MG-H1. The topical uptake of L-arginine and NAC was also evaluated in vitro and in vivo in rabbit lens. In hSVCT2 mice, L-arginine decreased 335/385 and 370/440 nm fluorescence by 40% (p<0.001), CML, CEL, and glucosepane crystallin crosslinks by 35% (p<0.05), 30% (p<0.05), and 37% (p<0.05), respectively, without affecting MG-H1 and G-H1. NAC decreased 335/385 nm fluorescence by 50% (p<0.001) but, like PA and GBA, had no effect on other modifications. L-Arginine uptake into rabbit eyes treated topically reached identical lenticular plateau levels (~400 nmol/g wet weight) at 0.5% and 2.0% but levels remained three times higher at 5 h at 2% versus 0.5% concentration, respectively. In vitro studies showed a 100 fold higher L-arginine level than NAC levels, implicating high affinity uptake of the former. L-Arginine when applied both orally and topically is a potent and broad suppressor of advanced ascorbylation in the lens. Its uptake in rabbit lens upon topical application suggests transcorneal uptake into the human lens should be feasible for testing its potential anticataract properties in clinical trials.


The Impact of Image Quality and Trachomatous Inflammation on Using Photography for Trachoma Prevalence Surveys.
Graded images can be used for trachoma prevalence surveys, but there is concern for mismatch between image and field grades of the upper tarsal conjunctiva. We aimed to determine if poor photograph quality and/or inflammation may contribute to differential grading of trachomatous inflammation-follicular (TF) between field and photograph graders. We developed a simplified and expanded image quality grading tool. Agreement was assessed using kappa statistic. We included 5417 eyes with both field and image grades for TF. Eyes where the field and adjudicated photograph TF grades did not match were identified (mismatched) and assigned an image quality (IQ) score and a potential mismatch reason. We also assigned IQ scores to a stratified random sample of 60 eyes with matching field and photograph TF grades (matched). There were 5240 eyes that had matching grades, whereas 177 eyes (3.3%) were mismatched. Overall quality was high, even in mismatched eyes. There was no difference in overall or specific IQ metrics between eyes with matching grades and eyes with mismatched grades (P = 0.59). Mismatched eyes had worse inflammation compared to matched eyes (P = 0.048). The primary reason for calling TF in the field but not in the photographs appeared to be the number of follicles observed. Image quality did not explain mismatch between field grades and image grades from this prevalence survey. Inflammation made mismatch more likely. Our quality grading scheme rapidly identifies image quality issues for training. Standardizing TF grading in the presence of inflammation will improve field and photograph grading.


Resistivity of Rotated Graphite-Graphene Contacts.
Robust electrical contact of bulk conductors to two-dimensional (2D) material, such as graphene, is critical to the use of these 2D materials in practical electronic devices. Typical metallic contacts to graphene, whether edge or areal, yield a resistivity of no better than 100 Ω μm but are typically >10 kΩ μm. In this Letter, we employ single-crystal graphite for the bulk contact to graphene instead of conventional metals. The graphite contacts exhibit a transfer length up to four-times longer than in conventional metallic contacts. Furthermore, we are able to drive the contact resistivity to as little as 6.6 Ω μm(2) by tuning the relative orientation of the graphite and graphene crystals. We find that the contact resistivity exhibits a 60° periodicity corresponding to crystal symmetry with additional sharp decreases around 22° and 39°, which are among the commensurate angles of twisted bilayer graphene.


Self-determination and substance use: is effortful control a mediator?
Alcohol and other drug use among college students are highly common in the United States. This study examined the relationships between 2 motivational orientations (i.e., autonomy and controlled orientations) and substance use and related problems among college students. It also examined whether effortful control mediated the relationship between these motivational orientations and substance use. Study participants were 644 undergraduate students (67.2% female; 87.2% Caucasian) who completed a series of online questionnaires as a part of a larger longitudinal study on sleep and substance use. The mean age of participants was 23.58 (SD = 6.861). Students with a higher autonomy orientation were more likely than their counterparts to report that they did not drink in the last 6 months. In contrast, students with a higher controlled orientation were less likely to report that they did not drink. Among those who drank in the last 6 months, effortful control significantly mediated the effects of autonomy orientation and controlled orientation on frequency of alcohol use within that time frame. Autonomy orientation positively predicted effortful control, which was associated with a decrease in the expected frequency of drinking. In contrast, controlled orientation negatively predicted effortful control, which was associated with an increase in the expected frequency of drinking. Controlled orientation also significantly predicted the presence of alcohol-related problems and illicit drug use. Intervention and prevention programs on college drinking could incorporate education about strategies for self-control, including strategies for withstanding peer pressure and diverting one's attention to activities unrelated to substance use. Focusing on strategies of self-control may be a useful starting point for a more in-depth discussion about the motivations, values, and psychological needs satisfaction that are associated with drinking and other drug use.


Bayesian basecalling for DNA sequence analysis using hidden Markov models.
It has been shown that electropherograms of DNA sequences can be modeled with hidden Markov models. Basecalling, the procedure that determines the sequence of bases from the given eletropherogram, can then be performed using the Viterbi algorithm. A training step is required prior to basecalling in order to estimate the HMM parameters. In this paper, we propose a Bayesian approach which employs the Markov chain Monte Carlo (MCMC) method to perform basecalling. Such an approach not only allows one to naturally encode the prior biological knowledge into the basecalling algorithm, it also exploits both the training data and the basecalling data in estimating the HMM parameters, leading to more accurate estimates. Using the recently sequenced genome of the organism Legionella pneumophila we show that the MCMC basecaller outperforms the state-of-the-art basecalling algorithm in terms of total errors while requiring much less training than other proposed statistical basecallers.


Lymph node staging by positron emission tomography in cervical cancer: relationship to prognosis.
PURPOSE A previous retrospective study demonstrated that positron emission tomography with [(18)F]fluorodeoxyglucose (FDG-PET) was more sensitive than computed tomography for lymph node staging in patients with cervical cancer; the findings on FDG-PET were strongly associated with progression-free survival. Therefore, a prospective cohort study was initiated to evaluate FDG-PET lymph node staging in a larger patient population. PATIENTS AND METHODS The study was conducted between July 2000 and March 2009. All 560 patients with cervical cancer underwent pretreatment FDG-PET lymph node staging. Treatment included surgery alone, surgery and postoperative radiation therapy, and definitive radiation or combination radiation and chemotherapy. PET findings were correlated with the risk of disease progression and with survival. Results Overall, 47% of patients had lymph node involvement by FDG-PET at diagnosis. The frequency of lymph node metastasis increased with clinical stage and was similar to that in historical surgical series. Within a stage, patients with PET-positive lymph nodes had significantly worse disease-specific survival than those with PET-negative lymph nodes (P < .001). Disease-specific survival was stratified into distinct groups based on the most distant level of PET-detected nodal disease (none, pelvic, para-aortic, or supraclavicular; P < .001). The hazard ratios for disease recurrence increased incrementally based on the most distant level of nodal disease: pelvic 2.40 (95% CI, 1.63 to 3.52), para-aortic 5.88 (95% CI, 3.80 to 9.09), and supraclavicular 30.27 (95% CI 16.56 to 55.34). CONCLUSION Nodal involvement detected by FDG-PET in cervical cancer relates to clinical stage, is comparable to historical data, and stratifies patient recurrence and survival outcomes.


Satisfaction with Social Contacts of Older Europeans.
This paper analyses the determinants of an important component of well-being among individuals aged 50 years or older in eleven European countries: satisfaction with social contacts. We use data from the Survey of Health, Ageing and Retirement in Europe and anchoring vignettes to correct for potential differences in responses scales across countries and socio-demographic groups. On average, older Europeans report being satisfied with their social contacts, but there exist substantial differences across countries: respondents from Northern countries tend to be more satisfied than individuals from Central or Mediterranean countries. Our analysis shows that correcting for response scale differentials alters the country ranking for of satisfaction with social contacts, while it has much less effect on the estimates of what drives within country determinants.


Present state and future prospects: a review of cooperative groups' adjuvant and neoadjuvant trials in breast cancer.
In patients with operable breast cancer, adjuvant hormonal therapy and adjuvant chemotherapy result in significant and long-term reductions in the rates of disease recurrence and death. These reductions are evident in both patients with node-negative as well as in those with node-positive disease. However, several issues in the adjuvant treatment of breast cancer still remain unresolved. These issues were recently considered at the 2000 National Institutes of Health (NIH) Consensus Development Conference, which reviewed the current state of knowledge on adjuvant therapy and outlined strategies for future research. In the area of adjuvant hormonal therapy, tamoxifen is still the gold standard, and present evidence supports the use of tamoxifen for patients with estrogen receptor (ER)-positive tumors irrespective of age, menopausal status, nodal status, or tumor size. Optimal duration of tamoxifen therapy is about 5 years. Future research directions include evaluating the benefit of extending tamoxifen beyond 5 years, the contribution of ovarian ablation, and the role of hormonal manipulations involving selective ER modulators and aromatase inhibitors instead of or in addition to tamoxifen. In the area of adjuvant chemotherapy, polychemotherapy regimens have been consistently found to be superior to single agents, and anthracycline-containing regimens produce a small but statistically significant improvement in survival when compared with regimens not containing an anthracycline. High-dose adjuvant chemotherapy with stem cell support has not been proven superior to standard regimens. Neoadjuvant therapy offers the possibility of testing in vivo the sensitivity of individual tumors to particular cytotoxic regimens and, hence, of improving ultimate disease control, as well as reducing the extent of local therapy. The contribution and optimal integration of taxanes in the adjuvant setting are yet to be established but are the subject of intense research effort. Similarly, novel targeted therapies such as trastuzumab and bisphosphonates are currently being evaluated in adjuvant studies


Learning separate visual representations of independently rotating objects.
Individual cells that respond preferentially to particular objects have been found in the ventral visual pathway. How the brain is able to develop neurons that exhibit these object selective responses poses a significant challenge for computational models of object recognition. Typically, many objects make up a complex natural scene and are never presented in isolation. Nonetheless, the visual system is able to build invariant object selective responses. In this paper, we present a model of the ventral visual stream, VisNet, which can solve the problem of learning object selective representations even when multiple objects are always present during training. Past research with the VisNet model has shown that the network can operate successfully in a similar training paradigm, but only when training comprises many different object pairs. Numerous pairings are required for statistical decoupling between objects. In this research, we show for the first time that VisNet is capable of utilizing the statistics inherent in independent rotation to form object selective representations when training with just two objects, always presented together. Crucially, our results show that in a dependent rotation paradigm, the model fails to build object selective representations and responds as if the two objects are in fact one. If the objects begin to rotate independently, the network forms representations for each object separately.


Immunodetection of human topoisomerase I-DNA covalent complexes.
A number of established and investigational anticancer drugs slow the religation step of DNA topoisomerase I (topo I). These agents induce cytotoxicity by stabilizing topo I-DNA covalent complexes, which in turn interact with advancing replication forks or transcription complexes to generate lethal lesions. Despite the importance of topo I-DNA covalent complexes, it has been difficult to detect these lesions within intact cells and tumors. Here, we report development of a monoclonal antibody that specifically recognizes covalent topo I-DNA complexes, but not free topo I or DNA, by immunoblotting, immunofluorescence or flow cytometry. Utilizing this antibody, we demonstrate readily detectable topo I-DNA covalent complexes after treatment with camptothecins, indenoisoquinolines and cisplatin but not nucleoside analogues. Topotecan-induced topo I-DNA complexes peak at 15-30 min after drug addition and then decrease, whereas indotecan-induced complexes persist for at least 4 h. Interestingly, simultaneous staining for covalent topo I-DNA complexes, phospho-H2AX and Rad51 suggests that topotecan-induced DNA double-strand breaks occur at sites distinct from stabilized topo I-DNA covalent complexes. These studies not only provide new insight into the action of topo I-directed agents, but also illustrate a strategy that can be applied to study additional topoisomerases and their inhibitors in vitro and in vivo.


A new case of spontaneous regression of inflammatory hepatic pseudotumor.
Introduction. Inflammatory pseudo-tumors (IPT) of the liver are rare and difficult to diagnose, because mimicking malignant tumors. Aim. We report a case of IPT of the liver wich diagnosis was made on clinical, radiological and evolutif features. Observation. A 15-year-old man had a 4-month history of abdominal pain in the right upper quadrant with fever and cought. Two successives ultrasonographies revealed a hypoechoic lesion occuping the segment VIII with 8 cm of diametre. Physical examination was normal. Laboratory investigation showed normal blood counts, liver function test and tumoral markers. Another ultrasonography was interpretated as normal. Tomodensitometry had showon a 3-cm lesion wich enhanced later after contrast injection. A second tomodensitometry done one mounth later described a 2-cm sub capsular heaptic lesion. Discussion. On routine activiy, pre operative diagnosis of IPT of the liver is difficut, and rarely made with certitude because mimicking a malignant tumor. In our cae report here, the analysis of previous history, of clinical, biological and radiological presentation, had permittes us to pose the diagnosis of PTI of the liver and this despite the absence of histological confirmation by percutaneous biopsy.


Idiopathic ulcerative laryngitis.
Idiopathic ulcerative laryngitis (IUL) is a distinct, clinical entity that presents after a prolonged upper respiratory infection with cough. It is characterized by the development of bilateral ulcerations of the mid-membranous vocal folds followed by a protracted course of healing. The purpose of this review was to characterize the typical patient presentation, clinical findings, and prognosis. Multi-institutional retrospective review Retrospective review of charts and videostroboscopic exams from patients with IUL at eight institutions. Fifteen cases met the criteria for IUL and were included in the study. The mean age of the patients was 49 years, and 93% were female. All patients were nonsmokers. Multiple medical interventions were employed by the treating otolaryngologist during the course of the disease, none of which resulted in acute resolution of the ulcerations. The average time from initial presentation to resolution of the disease was 3.3 months. All of the patients reported that their voice was improved after resolution of the disease process. However, in the majority of the patients (60%) there were persistent vibratory abnormalities after resolution of the ulcerations. This is the first multi-institutional study to define the complete disease course of IUL and to establish diagnostic criteria. IUL is a rare yet well-recognized clinical entity; however, there is no established etiology for this condition and no definitive treatments have emerged. Further study is needed to establish the etiology/risk factors of this condition and to determine optimal medical management.


Optical Projection Tomography Technique for Image Texture and Mass Transport Studies in Hydrogels Based on Gellan Gum.
The microstructure and permeability are crucial factors for the development of hydrogels for tissue engineering, since they influence cell nutrition, penetration, and proliferation. The currently available imaging methods able to characterize hydrogels have many limitations. They often require sample drying and other destructive processing, which can change hydrogel structure, or they have limited imaging penetration depth. In this work, we show for the first time an alternative nondestructive method, based on optical projection tomography (OPT) imaging, to characterize hydrated hydrogels without the need of sample processing. As proof of concept, we used gellan gum (GG) hydrogels obtained by several cross-linking methods. Transmission mode OPT was used to analyze image microtextures, and emission mode OPT to study mass transport. Differences in hydrogel structure related to different types of cross-linking and between modified and native GG were found through the acquired Haralick's image texture features followed by multiple discriminant analysis (MDA). In mass transport studies, the mobility of FITC-dextran (MW 20, 150, 2000 kDa) was analyzed through the macroscopic hydrogel. The FITC-dextran velocities were found to be inversely proportional to the size of the dextran as expected. Furthermore, the threshold size in which the transport is affected by the hydrogel mesh was found to be 150 kDa (Stokes' radii between 69 and 95 Å). On the other hand, the mass transport study allowed us to define an index of homogeneity to assess the cross-linking distribution, structure inside the hydrogel, and repeatability of hydrogel production. As a conclusion, we showed that the set of OPT imaging based material characterization methods presented here are useful for screening many characteristics of hydrogel compositions in relatively short time in an inexpensive manner, providing tools for improving the process of designing hydrogels for tissue engineering and drugs/cells delivery applications.


The effect of mechanical lymph drainage accompanied with heat on lymphedema.
Thermotherapy has been indicated by some researchers as a treatment for lymphedema. A study comparing temperatures demonstrated that a temperature of 40°C significantly increased the transportation of lymph compared to other temperatures assessed. The aim of this study was to evaluate the possible benefits of mechanical lymph drainage accompanied with heat in the treatment of lymphedema of the lower limbs. In a cross-over randomized study, the effect of heat on lymph drainage was evaluated in the treatment of leg lymphedema. The study, performed in the Godoy Clinic in São Jose do Rio Preto, Brazil, involved seven patients (two males and five females) with leg lymphedema. The patients' ages ranged from 18 to 79 years old with a mean of 48.5 years. The subjects underwent a total of 38 assessments including 19 evaluations of mechanical lymph drainage alone and 19 combined with thermotherapy. Heat was applied using an electric blanket which was wrapped around the legs of the patients. The volume of legs was evaluated by water plethysmography before and after treatment sessions. The paired t-test was used for statistical analysis with an alpha error of p = 0.05 being considered as acceptable. No statistically significant differences were evidenced between mechanical lymph drainage alone and lymph drainage combined with thermotherapy. There was no obvious synergic effect in the immediate post-treatment period when heat was combined with mechanical lymph drainage in the treatment of lymphedema.


Estimating seroprevalence of herpes simplex virus type 1 among different Middle East and North African male populations residing in Qatar.
HSV-1 epidemiology in the Middle East and North Africa (MENA) remains poorly understood. Our study aimed to measure HSV-1 antibody prevalence (seroprevalence) and its age-distribution among select MENA populations residing in Qatar. Sera were collected from male blood donors attending Hamad Medical Corporation 2013-2015. A total of 2,077 sera were tested for anti-HSV-1 antibodies using HerpeSelect® 1 ELISA IgG kits (Focus Diagnostics, Cypress, CA). Robust Poisson regression was conducted to estimate adjusted infection prevalence ratios. Country-specific HSV-1 seroprevalence was estimated for 10 national populations: 97.5% among Egyptians, 92.6% among Yemenis, 90.7% among Sudanese, 88.5% among Syrians, 86.5% among Jordanians, 82.3% among Qataris, 81.4% among Iranians, 81.4% among Lebanese, 80.5% among Palestinians, and 77.0% among Pakistanis. Age-specific HSV-1 seroprevalence was estimated for Egypt, the Fertile Crescent (Iraq, Jordan, Lebanon, Palestine, and Syria), and Qatar. Seroprevalence increased with age among Fertile Crescent and Qatari nationals. Seroprevalence increased from 70.0% among those aged ≤ 24 years up to 98.0% among those aged ≥55 years among Fertile Crescent nationals. Seroprevalence was consistently above 90% for all ages among Egyptians. HSV-1 seroprevalence is high in MENA, though with some variation across countries. The seroprevalence appears to have declined among current young age cohorts compared to its levels a few decades ago.


Lack of complete correlation between emetic and T-cell-stimulatory activities of staphylococcal enterotoxins.
This study examined the emetic activity of several staphylococcal enterotoxin type A and B (SEA and SEB, respectively) mutants that had either one or two amino acid residue substitutions. New sea gene mutations were constructed by site-directed mutagenesis; gene products were obtained with glycine residues at position 25, 47, 48, 81, 85, or 86 of mature SEA. Culture supernatants from Staphylococcus aureus RN4220, or derivatives containing either sea or a sea mutation, were analyzed for the ability to stimulate proliferation of murine splenocytes, as determined by incorporation of [3H]thymidine. Culture supernatants containing SEA-N25G (a SEA mutant with a substitution of glycine for the asparagine residue at position 25), SEA-F47G, or SEA-L48G did not stimulate T-cell proliferation, unlike supernatants containing the other substitution mutants. Purified preparations of SEA-N25G had weak activity and those of SEA-F47G and SEA-L48G had essentially no activity in the T-cell proliferation assay. All mutants except SEA-V85G, which was degraded by monkey stomach lavage fluid in vitro, were tested for emetic activity. SEA-C106A and two SEB mutants, SEB-D9N/N23D and SEB-F44S (previously referred to as BR-257 and BR-358, respectively), whose construction and altered immunological properties have been reported previously, were also tested in the emetic assay. Each mutant was initially administered intragastrically at doses of 75 to 100 micrograms per animal; if none of the animals responded, the dose was increased four-to fivefold. SEA-F47G, SEA-C106A, and SEB-D9N/N23D were the only mutants that did not induce vomiting at either dose tested; these three mutants had reduced immunological activity. However, there was not a perfect correlation between immunological and emetic activities; SEA-L48G and SEB-F44S retained emetic activity, although they had essentially no T-cell-stimulatory activity. These studies suggest that these two activities can be dissociated.


An automated method measures variability in P-glycoprotein and ABCG2 densities across brain regions and brain matter.
Changes in P-glycoprotein and ABCG2 densities may play a role in amyloid-beta accumulation in Alzheimer's disease. However, previous studies report conflicting results from different brain regions, without correcting for changes in vessel density. We developed an automated method to measure transporter density exclusively within the vascular space, thereby correcting for vessel density. We then examined variability in transporter density across brain regions, matter, and disease using two cohorts of post-mortem brains from Alzheimer's disease patients and age-matched controls. Changes in transporter density were also investigated in capillaries near plaques and on the mRNA level. P-glycoprotein density varied with brain region and matter, whereas ABCG2 density varied with brain matter. In temporal cortex, P-glycoprotein density was 53% lower in Alzheimer's disease samples than in controls, and was reduced by 35% in capillaries near plaque deposits within Alzheimer's disease samples. ABCG2 density was unaffected in Alzheimer's disease. No differences were detected at the transcript level. Our study indicates that region-specific changes in transporter densities can occur globally and locally near amyloid-beta deposits in Alzheimer's disease, providing an explanation for conflicting results in the literature. When differences in region and matter are accounted for, changes in density can be reproducibly measured using our automated method.


Metalloproteinase disintegrins ADAM8 and ADAM19 are highly regulated in human primary brain tumors and their expression levels and activities are associated with invasiveness.
Patients with primary brain tumors have bleak prognoses and there is an urgent desire to identify new markers for sensitive diagnosis and new therapeutic targets for effective treatment. A family of proteins, the disintegrin and metalloproteinases (ADAMs or adamalysins), are cell surface and extracellular multidomain proteins implicated in cell-cell signaling, cell adhesion, and cell migration. Their putative biological and pathological roles make them candidates for promoting tumor growth and malignancy. We investigated the expression levels of 12 cerebrally expressed ADAM genes in human primary brain tumors (astrocytoma WHO grade I-III, glioblastoma WHO grade IV, oligoastrocytoma WHO grade II and III, oligodendroglioma WHO grade II and III, ependymoma WHO grade II and III, and primitive neuroectodermal tumor WHO grade IV) using real-time PCR. The mRNAs of the five ADAMs 8, 12, 15, 17, and 19 were significantly upregulated. The ADAM8 and ADAM19 proteins were mainly located in tumor cells and in some tumors in endothelia of blood vessels. In brain tumor tissue, ADAM8 and ADAM19 undergo activation by prodomain removal resulting in active proteases. By using specific peptide substrates for ADAM8 and ADAM19, respectively, we demonstrated that the proteases exert enhanced proteolytic activity in those tumor specimens with the highest expression levels. In addition, expression levels and the protease activities of ADAM8 and ADAM19 correlated with invasive activity of glioma cells, indicating that ADAM8 and ADAM19 may play a significant role in tumor invasion that may be detrimental to patients survival.


The role of lysyl oxidase-like 1 DNA copy number variants in exfoliation glaucoma.
To investigate whether DNA copy number variants (CNVs) in the lysyl oxidase-like 1 (LOXL1) gene are associated with exfoliation glaucoma (XFG) in black South Africans. Black South African subjects with XFG and age-matched unaffected controls were recruited from the St. John Eye Hospital in Soweto (Johannesburg, South Africa) and East London Hospital Complex (Eastern Cape, South Africa) using standard clinical examination techniques. A customized array comparative genomic hybridization (aCGH) from Roche NimbleGen was designed to cover a 1.5 million base genomic region centered on the LOXL1 gene on chromosome 15. Twenty selected XFG cases were examined using this custom aCGH to identify common CNVs in the LOXL1 gene. The potential DNA copy number variants identified from aCGH were further validated using TaqMan probe-based CNV real-time PCR in a data set containing 91 XFG cases and 52 controls. The frequencies of CNVs in the LOXL1 region were compared between the XFG cases and the controls using Fisher's exact test. Several DNA CNV variants were identified in the LOXL1 genomic region using aCGH in the selected XFG cases. However, we were unable to validate these candidate CNVs using real-time PCR-based TaqMan CNV assays. There was no significant difference in the frequency of the DNA copy number variants in the LOXL1 region between the XFG cases and the controls. This represents the first DNA CNV study of LOXL1 in the black South African population with XFG. Our study did not identify any significant DNA copy number alterations in the genomic region containing the LOXL1 gene. This suggests that other as yet unknown causal variants of LOXL1 or variants in other genes in linkage disequilibrium with the LOXL1 locus contribute to the genetic risk of XFG in black South Africans.


A wide range of protein isoforms in serum and plasma uncovered by a quantitative intact protein analysis system.
We have implemented an orthogonal 3-D intact protein analysis system (IPAS) to quantitatively profile protein differences between human serum and plasma. Reference specimens consisting of pooled Caucasian-American serum, citrate-anticoagulated plasma, and EDTA-anticoagulated plasma were each depleted of six highly abundant proteins, concentrated, and labeled with a different Cy dye (Cy5, Cy3, or Cy2). A mixture consisting of each of the labeled samples was subjected to three dimensions of separation based on charge, hydrophobicity, and molecular mass. Differences in the abundance of proteins between each of the three samples were determined. More than 5000 bands were found to have greater than two-fold difference in intensity between any pair of labeled specimens by quantitative imaging. As expected, some of the differences in band intensities between serum and plasma were attributable to proteins related to coagulation. Interestingly, many proteins were identified in multiple fractions, each exhibiting different pI, hydrophobicity, or molecular mass. This is likely reflective of the expression of different protein isoforms or specific protein cleavage products, as illustrated by complement component 3 precursor and clusterin. IPAS provides a high resolution, high sensitivity, and quantitative approach for the analysis of serum and plasma proteins, and allows assessment of PTMs as a potential source of biomarkers.


Basic science of osteoarthritis.
Osteoarthritis (OA) is a prevalent, disabling disorder of the joints that affects a large population worldwide and for which there is no definitive cure. This review provides critical insights into the basic knowledge on OA that may lead to innovative end efficient new therapeutic regimens. While degradation of the articular cartilage is the hallmark of OA, with altered interactions between chondrocytes and compounds of the extracellular matrix, the subchondral bone has been also described as a key component of the disease, involving specific pathomechanisms controlling its initiation and progression. The identification of such events (and thus of possible targets for therapy) has been made possible by the availability of a number of animal models that aim at reproducing the human pathology, in particular large models of high tibial osteotomy (HTO). From a therapeutic point of view, mesenchymal stem cells (MSCs) represent a promising option for the treatment of OA and may be used concomitantly with functional substitutes integrating scaffolds and drugs/growth factors in tissue engineering setups. Altogether, these advances in the fundamental and experimental knowledge on OA may allow for the generation of improved, adapted therapeutic regimens to treat human OA.


Interneuron diversity in layers 2-3 of monkey prefrontal cortex.
The heterogeneity of gamma-aminobutyric acid interneurons in the rodent neocortex is well-established, but their classification into distinct subtypes remains a matter of debate. The classification of interneurons in the primate neocortex is further complicated by a less extensive database of the features of these neurons and by reported interspecies differences. Consequently, in this study we characterized 8 different morphological types of interneurons from monkey prefrontal cortex, 4 of which have not been previously classified. These interneuron types differed in their expression of molecular markers and clustered into 3 different electrophysiological classes. The first class consisted of fast-spiking parvalbumin-positive chandelier and linear arbor cells. The second class comprised 5 different morphological types of continuous-adapting calretinin- or calbindin-positive interneurons that had the lowest level of firing threshold. However, 2 of these morphological types had short spike duration, which is not typical for rodent adapting cells. Neurogliaform cells (NGFCs), which coexpressed calbindin and neuropeptide Y, formed the third class, characterized by strong initial adaptation. They did not exhibit the delayed spikes seen in rodent NGFCs. These results indicate that primate interneurons have some specific properties; consequently, direct translation of classification schemes developed from studies in rodents to primates might be inappropriate.


Electrical pacing counteracts intrinsic shortening of action potential duration of neonatal rat ventricular cells in culture.
Previous studies have demonstrated the relationship between the functional electrophysiological properties of cultured neonatal rat ventricular myocytes (NRVMs) and the ability of the substrate to induce and sustain arrhythmia. The goal of this study was to examine the effects of chronic pacing at a constant rate akin to that in vivo, on the functional electrophysiological properties of NRVM monolayers. Confluent NRVM monolayers grown on 20 mm diameter cover slips were left either unpaced or were stimulated at 3 Hz for the duration of the culture, and were optically mapped on days 4, 6, or 8. Action potential duration at 80% repolarization (APD80), conduction velocity (CV), and Kv4.3 (Ito) and NCX protein expression were measured. The effects of the excitation-contraction uncoupler 2,3-butadione monoxime (BDM) were also investigated. The 2 Hz APD80 of non-paced monolayers decreased significantly on days 6 (137.1+/-13.9 ms) and 8 (109.8+/-9.0 ms) compared with day 4 (197.0+/-11.8 ms), while that of paced monolayers did not (206.8+/-9.7, 209.1+/-9.2, and 210.6+/-9.9 ms, respectively). The 2 Hz CV of non-paced monolayers increased significantly on days 6 (26.0+/-1.6 cm/s) and 8 (26.5+/-1.0 cm/s) compared with day 4 (20.0+/-1.0 cm/s), while that of paced monolayers did not change significantly (26.0+/-2.0, 26.0+/-1.0, and 23.8+/-1.2 cm/s, respectively). The restitution curves of APD80 and CV of paced monolayers were also unchanging from days 4 through 8. Despite the unchanging APD80 and CV, a decrease in Kv4.3 expression and an increase in NCX expression were observed in paced compared with non-paced monolayers. Cessation of pacing or administration of BDM caused a reversal of phenotype back to that of non-paced monolayers. In summary, chronic electrical stimulation of confluent NRVM monolayers results in stabilization of APD80 and an advancement of the developmental rise of CV that is mediated by electromechanical coupling. These effects produce a steadier functional phenotype that may be beneficial for electrophysiological studies.


Racial disparities in the treatment of depression in low-income persons with diabetes.
Individuals with diabetes are at higher risk for depression than the general population. Although depression can be treated with antidepressant medications, patients with diabetes and comorbid depression often go untreated. The goal of this study was to examine racial disparities in the treatment of depression with antidepressant medication in the southeastern U.S. Cross-sectional data were collected at baseline from 69,068 participants (71% African American, 60% female, and 82% with incomes <$25,000) recruited from community health centers and enrolled in the Southern Cohort Community Study (SCCS). The SCCS is a prospective epidemiological cohort study designed to explore causes of health disparities in adults aged 40-79 years. Binary logistic regression was used to identify factors associated with antidepressant use among those with diabetes (n = 14,279). Individuals with diagnosed diabetes (14,279) were classified with no depressive symptoms (54.7%), or with mild (24.2%), moderate (12.8%), or severe depressive symptoms (8.3%). After controlling for sex, age, insurance, income, education, BMI, smoking status, alcohol consumption, and level of depression, African Americans with diabetes were much less likely to report taking antidepressant medication than whites (adjusted odds ratio 0.32 [95% CI 0.29-0.35], P < 0.0001). Antidepressant use is much less common among African Americans than among whites with diabetes. Reasons for racial disparities in treatment of depressive symptoms are unclear but may include a combination of differential diagnosis and treatment by health professionals as well as cultural differences in seeking help for emotional distress.


Do adult men and women in same-sex relationships have weaker ties to their parents?
Using a national sample of people in same-sex relationships (N = 843) and different-sex relationships (N = 510) in the Netherlands, we examine the frequently discussed but infrequently tested hypothesis of weaker intergenerational ties between parents and their adult daughters and sons in same-sex relationships. We also test hypotheses linking the strength of these ties to gender differences and the liberal or traditional views held by the parents when the child was growing up (reported retrospectively). Overall, we find few differences in the strength of the current parent-child relationship but clear differences in the process of leaving home. Our findings show that people who are in same-sex relationships in adulthood left home earlier and moved further away from their parents than those in different-sex relationships. In addition, they left more often due to conflicts at home and due to an unpleasant atmosphere in the community of origin, and less often to move in directly with a partner. In adulthood, people in same-sex relationships show many commonalities with people in different-sex relationships and only a few differences. Men in same-sex relationships have more ambivalent relationships with their mothers and weaker relationships with their fathers than men partnered with women. When the parental home was more traditional in terms of gendered role division in parenting, the current relationship of women in same-sex relationships with their father is on average weaker in adulthood. Women in same-sex relationships also have less frequent contact with both parents compared to women in different-sex relationships. (PsycInfo Database Record (c) 2021 APA, all rights reserved).


Labelling improves false belief understanding. A training study.
A total of 104 children aged between 41 and 47 months were selected to study the relationship between language and false belief understanding. Participants were assigned to four different training conditions: discourse, labelling, control (all with deceptive objects), and sentential complements (involving non-deceptive objects). Post-test results showed an improvement in children's false belief understanding in the discourse and the labelling conditions, but not in the sentential complements with non-deceptive objects or the control group. Furthermore, the most remarkable improvement in false belief understanding occurred in the labelling group. These results suggest that some types of linguistic experience promote the development of false belief understanding, provided that differing perspectives are confronted.


Navicular Stress Fracture Outcomes in Athletes: Analysis of 62 Injuries.
The optimal treatment modalities for navicular stress fractures in athletes is currently unknown for this season-ending injury. The present study evaluated factors that might be significant and affect healing outcomes, specifically focusing on the return to activity (RTA) time and a decreased desired activity (DDA) after treatment in athletes. Such considerations included previous navicular stress fractures, patient demographic data and type of sport, and initiation time of treatment. The data from 59 patients with 62 fractures were prospectively analyzed from May 2005 through July 2016. The results showed a significant correlation between a previous navicular stress fracture and decreased desired activity. The average duration of symptoms before receiving definitive treatment was 8.8 months. Computed tomography as the initial imaging modality correlated positively with a correct diagnosis (1.00). In contrast, magnetic resonance imaging, when used initially, was only 71% accurate. Runners constituted most of the cohort at 38 (61.3%). Ten other athletes were involved in jumping sports. Of the 62 injuries, 21 (33.9%) were in elite or professional athletes, all of whom were able to RTA, with 1 patient, a 38-year-old world record holding runner, having a DDA. Seven refractures (11.2%) occurred an average >5 years after the initial injury, predominantly in those aged <21 years, none with previous surgery. Eight patients (12.9%) developed postinjury arthrosis, including 1 with DDA. Patients who underwent open reduction and internal fixation had a RTA of 4.56 months compared with those who had undergone nonoperative treatment, who had an average RTA of 3.97 months. Seven patients (11.2%) underwent screw removal and required a longer RTA. Overall, of the 62 injuries, the patients with 57 of the injuries (91.9%) were able to RTA at their preinjury level.


Excess electron states in reduced bulk anatase TiO2: comparison of standard GGA, GGA+U, and hybrid DFT calculations.
The removal of lattice O atoms, as well as the addition of interstitial H atoms, in TiO(2) is known to cause the reduction in the material and the formation of "Ti(3+)" ions. By means of electronic structure calculations we have studied the nature of such oxygen vacancy and hydrogen impurity states in the bulk of the anatase polymorph of TiO(2). The spin polarized nature of these centers, the localized or delocalized character of the extra electrons, the presence of defect-induced states in the gap, and the polaronic distortion around the defect have been investigated with different theoretical methods: standard density functional theory (DFT) in the generalized-gradient approximation (GGA), GGA+U methods as a function of the U parameter, and two hybrid functionals with different admixtures of Hartree-Fock exchange. The results are found to be strongly dependent on the method used. Only GGA+U or hybrid functionals are able to reproduce the presence of states at about 1 eV below the conduction band, which are experimentally observed in reduced titania. The corresponding electronic states are localized on Ti 3d levels, but partly delocalized solutions are very close in energy. These findings show the limited predictive power of these theoretical methods to describe the electronic structure of reduced titania in the absence of accurate experimental data.


Physiologically relevant factors influence tau phosphorylation by leucine-rich repeat kinase 2.
Hyperphosphorylation and aggregation of tau are observed in multiple neurodegenerative diseases termed tauopathies. Tau has also been implicated in the pathogenesis of Parkinson's disease (PD) and parkinsonisms. Some PD patients with mutations in the leucine-rich repeat kinase 2 (LRRK2) gene exhibit tau pathology. Mutations in LRRK2 are a major risk factor for PD, but LRRK2 protein function remains unclear. The most common mutation, G2019S, is located in the kinase domain of LRRK2 and enhances kinase activity in vitro. This suggests that the kinase activity of LRRK2 may underlie its cellular toxicity. Recently, in vitro studies have suggested a direct interaction between tubulin-bound tau and LRRK2 that results in tau phosphorylation at one identified site. Here we present data suggesting that microtubules (MTs) enhance LRRK2-mediated tau phosphorylation at three different epitopes. We also explore the effect of divalent cations as catalytic cofactors for G2019S LRRK2-mediated tau phosphorylation and show that manganese does not support kinase activity but inhibits the efficient ability of magnesium to catalyze LRRK2-mediated phosphorylation of tau. These results suggest that cofactors such as MTs and cations in the cellular milieu have an important impact on LRRK2-tau interactions and resultant tau phosphorylation.


Spatiotopic buildup of saccade target representation depends on target size.
How we maintain spatial stability across saccade eye movements is an open question in visual neuroscience. A phenomenon that has received much attention in the field is our seemingly poor ability to discriminate the direction of transsaccadic target displacements. We have recently shown that discrimination performance increases the longer the saccade target has been previewed before saccade execution (Zimmermann, Morrone, & Burr, 2013). We have argued that the spatial representation of briefly presented stimuli is weak but that a strong representation is needed for transsaccadic, i.e., spatiotopic localization. Another factor that modulates the representation of saccade targets is stimulus size. The representation of spatially extended targets is more noisy than that of point-like targets. Here, I show that the increase in transsaccadic displacement discrimination as a function of saccade target preview duration depends on target size. This effect was found for spatially extended targets-thus replicating the results of Zimmermann et al. (2013)-but not for point-like targets. An analysis of saccade parameters revealed that the constant error for reaching the saccade target was bigger for spatially extended than for point-like targets, consistent with weaker representation of bigger targets. These results show that transsaccadic displacement discrimination becomes accurate when saccade targets are spatially extended and presented longer, thus resembling closer stimuli in real-world environments.


Maintaining and sustaining the On the CUSP: stop BSI model in Hawaii.
Hawaii joined the On the CUSP: Stop BSI national effort in the United States in 2009 (CUSP stands for Comprehensive Unit-based Safety Program). In the initial 18-month study evaluation, adult ICUs decreased central line-associated bloodstream infection (CLABSI) rates by 61%. The impact of a series of novel strategies/tools in reducing infections and sustaining the collaborative in ICUs and non-ICUs in Hawaii was assessed. This cohort collaborative consisted of 20 adult ICUs and 18 nonadult ICUs in 16 hospitals. Hawaii developed and implemented six tools between July 2010 and August 2011: a tool to investigate CLABSIs, a video to address cultural barriers, a standardized dressing change kit, a map of the cohort's journey, a 12-strategies leadership dashboard, and a geometric plot of consecutive infection-free days. The primary outcome measure was overall CLABSI rates (mean infections per 1,000 catheter-days). A comparison of baseline data from 28 ICUs with 12-quarter (36-month) postimplementation data indicated that the CLABSI rate decreased across the entire state: overall, 1.57 to 0.29 infections/1,000 catheter-days; adult ICUs, 1.49 to 0.25 infections/1,000 catheter-days; nonadult ICUs, 2.54 to 0.33 infections/1,000 catheter-days, non-ICUs (N= 14), 4.52 to 0.25 infections/1,000 catheter-days, and PICU/NICU (N = 4), 2.05 to 0.53 infections/1,000 catheter-days. Days between CLABSIs in the adult ICUs statewide increased from a median of 5 days in 2009 to 70 days in 2011. Hawaii successfully spread the program beyond adult ICUs and implemented a series of tools for maintenance and sustainment. Use of the tools shaped a culture around the continued belief that CLABSIs can be eradicated, and infections further reduced.


Protective effects of green and white tea against benzo(a)pyrene induced oxidative stress and DNA damage in murine model.
In the current investigation, the ameliorative effect of green tea (GT) and white tea (WT) against benzo(a)pyrene (BaP) induced oxidative stress and DNA damage has been studied in the livers and lungs of Balb/c mice. A single dose of BaP (125 mg/kg, b.w. orally) increased the levels of lipid peroxidation (LPO) and decreased endogenous antioxidants such as superoxide dismutase (SOD), glutahione reductase (GR), catalase (CAT), and glutathione (GSH) significantly. Pretreatment with GT and WT for 35 days before a single dose of BaP elevated the decreased activity of GR, SOD, and CAT in liver tissue and also tended to normalize the levels of GSH and LPO in both hepatic and pulmonary tissues. The percentage of DNA in comet tail and 8-hydroxy-2'-deoxyguanosine levels reflected the decreasing pattern of DNA damage from the BaP-treated group to the groups that received pretreatment with GT and WT. Our study concludes that both GT and WT are effective in combating BaP induced oxidative insult and DNA damage. However, WT was found to be more protective than GT with respect to CAT (only in the liver), percentage of DNA in comet tail (only in the lungs), GST activity, and GSH content in both the tissues.


Neuroendocrine dysfunction and insomniain in mild traumatic brain injury patients.
Mild traumatic brain injury (mTBI) has been a growing public health concern in the worldwide. To investigate the subjective and objective characteristics of insomnia following mTBI and the association between insomnia and hypothalamic-pituitary-adrenal (HPA) function of mTBI patients, 59 patients with mTBI (mTBI group) were compared with 50 healthy participants (control group) in the present study. The subjective and objective measures of insomnia were respectively obtained from Pittsburgh Sleep Quality (PSQI) and polysomnography (PSG). HPA function was measured with low-dose short synacthen test (LDSST). According to the comparative and correlation analysis of the two groups, for PSQI, the scores of sleep syndrome, sleep latency, sleep efficiency, overall sleep quality and daytime dysfunction of mTBI patients were all higher, however only sleep efficiency and daytime dysfunction of mTBI patients were related with peak cortisol on lDSST; while for PSG, sleep efficiency (SE) was lower and wake after sleep onset (WASO) was longer in mTBI patients, moreover SE and WASO of mTBI patients were correlated with peak cortisol on LDSTT; for HPA function indexes, only peak cortisol on LDSST was lower in mTBI patients. These findings suggested that mTBI patients experienced more serious subjective insomnia symptoms than objective measurement, which were associated with HPA dysfunction. This study may contribute to identifying better treatment for mTBI patients with insomnia.


Basic-level categorization of intermediate complexity fragments reveals top-down effects of expertise in visual perception.
Visual expertise is usually defined as the superior ability to distinguish between exemplars of a homogeneous category. Here, we ask how real-world expertise manifests at basic-level categorization and assess the contribution of stimulus-driven and top-down knowledge-based factors to this manifestation. Car experts and novices categorized computer-selected image fragments of cars, airplanes, and faces. Within each category, the fragments varied in their mutual information (MI), an objective quantifiable measure of feature diagnosticity. Categorization of face and airplane fragments was similar within and between groups, showing better performance with increasing MI levels. Novices categorized car fragments more slowly than face and airplane fragments, while experts categorized car fragments as fast as face and airplane fragments. The experts' advantage with car fragments was similar across MI levels, with similar functions relating RT with MI level for both groups. Accuracy was equal between groups for cars as well as faces and airplanes, but experts' response criteria were biased toward cars. These findings suggest that expertise does not entail only specific perceptual strategies. Rather, at the basic level, expertise manifests as a general processing advantage arguably involving application of top-down mechanisms, such as knowledge and attention, which helps experts to distinguish between object categories.


The structure of an integrin/talin complex reveals the basis of inside-out signal transduction.
Fundamental to cell adhesion and migration, integrins are large heterodimeric membrane proteins that uniquely mediate inside-out signal transduction, whereby adhesion to the extracellular matrix is activated from within the cell by direct binding of talin to the cytoplasmic tail of the beta integrin subunit. Here, we report the first structure of talin bound to an authentic full-length beta integrin tail. Using biophysical and whole cell measurements, we show that a specific ionic interaction between the talin F3 domain and the membrane-proximal helix of the beta tail disrupts an integrin alpha/beta salt bridge that helps maintain the integrin inactive state. Second, we identify a positively charged surface on the talin F2 domain that precisely orients talin to disrupt the heterodimeric integrin transmembrane (TM) complex. These results show key structural features that explain the ability of talin to mediate inside-out TM signalling.


Soluble Corn Fiber Increases Calcium Absorption Associated with Shifts in the Gut Microbiome: A Randomized Dose-Response Trial in Free-Living Pubertal Females.
Soluble corn fiber (SCF; 12 g fiber/d) is shown to increase calcium absorption efficiency, associated with shifts in the gut microbiota in adolescent males and females who participated in a controlled feeding study. We evaluated the dose response of 0, 10, and 20 g fiber/d delivered by PROMITOR SCF 85 (85% fiber) on calcium absorption, biochemical bone properties, and the fecal microbiome in free-living adolescents. Healthy adolescent females (n = 28; aged 11-14 y) randomly assigned into a 3-phase, double-blind, crossover study consumed SCF for 4 wk at each dose (0, 10, and 20 g fiber/d from SCF) alongside their habitual diet and were followed by 3-d clinical visits and 3-wk washout periods. Stable isotope ((44)Ca and (43)Ca) enrichment in pooled urine was measured by inductively coupled plasma mass spectrometry. Fecal microbial community composition was assessed by high-throughput sequencing (Illumina) of polymerase chain reaction-amplified 16S rRNA genes. Mixed model ANOVA and Friedman analysis were used to determine effects of SCF on calcium absorption and to compare mean microbial proportions, respectively. Calcium absorption increased significantly with 10 (13.3% ± 5.3%; P = 0.042) and 20 g fiber/d (12.9% ± 3.6%; P = 0.026) from SCF relative to control. Significant differences in fecal microbial community diversity were found after consuming SCF (operational taxonomic unit measures of 601.4 ± 83.5, 634.5 ± 83.8, and 649.6 ± 75.5 for 0, 10, and 20 g fiber/d, respectively; P < 0.05). Proportions of the genus Parabacteroides significantly increased with SCF dose (1.1% ± 0.8%, 2.1% ± 1.6%, and 3.0% ± 2.0% for 0, 10, and 20 g fiber/d from SCF, respectively; P < 0.05). Increases in calcium absorption positively correlated with increases in Clostridium (r = 0.44, P = 0.023) and unclassified Clostridiaceae (r = 0.40, P = 0.040). SCF, a nondigestible carbohydrate, increased calcium absorption in free-living adolescent females. Two groups of bacteria may be involved, one directly fermenting SCF and the second fermenting SCF metabolites further, thereby promoting increased calcium absorption. This trial was registered at clinicaltrials.gov as NCT01660503.


Dorsoventral axis formation in Drosophila depends on the correct dosage of the gene gurken.
The Drosophila gene gurken participates in a signaling process that occurs between the germ line and the somatic cells (follicle cells) of the ovary. This process is required for correct patterning of the dorsoventral axis of both the egg and the embryo. gurken produces a spatially localized transcript which encodes a TGF-alpha-like molecule (Neuman-Silberberg and Schupbach, Cell 75, 165-174, 1993). Mutations in gurken cause a ventralized phenotype in egg and embryo. To determine whether the gurken gene product plays an instructive role in dorsoventral patterning, we constructed females containing extra copies of a gurken transgene. Such females produce dorsalized eggs and embryos, which is expected if gurken acts as a limiting factor in the dorsoventral patterning process. In addition, the expression pattern of the gene rhomboid in the follicle cells is altered in ovaries of females containing extra copies of gurken. Our results indicate that changing gurken dosage in otherwise wild-type ovaries is sufficient to alter the number of somatic follicle cells directed to the dorsal fate. Therefore the gurken-torpedo signaling process plays an instructive role in oogenesis. It induces dorsal cell fates in the follicle cell epithelium and it controls the production of maternal components that will direct the embryonic dorsoventral pattern after fertilization.