Toxicogenomics discrimination of potential hepatocarcinogenicity of non-genotoxic compounds in rat liver.
Long-term carcinogenicity testing of a compound is exceedingly time-consuming and costly, and requires many test animals, whereas the Ames test, which is based on the assumption that any substance that is mutagenic may also exert carcinogenic potential, is useful as a short-term screening assay but has major drawbacks. Although, in fact, 90% of compounds that give a positive Ames test cause cancer in laboratory animals, a good proportion of compounds that give a negative Ames test are also carcinogens; that is, there is no good correlation between carcinogenicity and negative Ames test results. As an alternative to these two approaches, we have tried applying toxicogenomics to predict the carcinogenicity of a compound from the gene expression profile induced in vivo. To establish our model, male Sprague-Dawley rats were orally administered test compounds (12 hepatocarcinogens and 26 non-hepatocarcinogens) for 28 days. Analysis of liver gene expression data by Support Vector Machines (SVM) dividing compounds into 'for training' and 'for test' (20 cases assigned randomly) allowed a set of marker genes to be tested for prediction of hepatocarcinogenicity. The developed prediction model was then validated with reference to the concordance rate with training data and test data, and a good performance was obtained. We will have new gene expression data and continue the validation of our model.


Immunological definition of leukemic cell surface phenotypes.
Immunological phenotyping of blasts from over 200 children with acute lymphocytic leukemia (ALL) reveals both interpatient differences and phenotypic heterogeneity in the blast population from individual patients. A battery of five independent lymphocyte differentiation markers, erythrocyte-forming rosettes. T-cell antigens, Ia-like antigens, the common ALL antigen, and surface immunoglobulin, permit classification of all ALL specimens into four major marker groups. These are common, T-cell, B-cell, and undifferentiated ALL. Heterogeneity in the marker phenotypes within each of the major groups is observed. Within individual erythrocyte receptor-positive ALL specimens, phenotypic heterogeneity in the blast population is demonstrated. Sequential determinations of the blast phenotype during periods of active disease reveal a second example of intrapatient blast cell heterogeneity. Differences in phenotype of the dominant blast populations present prior to treatment and at relapse are observed in sequential studies of individual patients. These shifts in phenotype are nonrandom. They result most frequently from losses in single differentiation markers. A unifying hypothesis which explains these observations of phenotypic heterogeneity is that ALL blasts manifest limited lymphoid-like differentiation.


'Shape-Up', a Modified Cognitive-Behavioural Community Programme for Weight Management: Real-World Evaluation as an Approach for Delivering Public Health Goals.
Obesity is widespread, with serious health consequences; addressing it requires considerable effort at a public health level, incorporating prevention and management along with policies to support implementation. Behavioural weight-management programmes are widely used by public health bodies to address overweight and obesity. Shape-Up is an evidence-based programme combining a structured behavioural intervention (targeting nutrition and physical activity behaviours) within a peer-learning framework. This study was a service-evaluation of Shape-Up, as delivered in Rotherham by a local leisure provider, and included a secondary analysis of data collected in the community by service providers. The RE-AIM (Reach Effectiveness Adoption Implementation Maintenance) framework was used to explore programme effectiveness, implementation, and whom it reached. A total of 141 participants were included. Compared to local demographics, participants were older, at 48.9 (SD 14.47) years, with a lower employment rate (41% employed) and greater proportion female (67% female). Mean BMI was 38.0 (SD 7.54) kg/m2. Mean weight-change between baseline and endpoint (12 weeks, 10 group sessions) was -4.4 (SD 3.38) kg, and degree of weight change was associated with session attendance (F (9, 131) = 6.356, p < 0.0005). There were positive effects on participants' weight, health-related behaviours, and quality of life. The intervention content (including the focus of nutritional recommendations) and structure were adapted during implementation to better suit national guidelines and local population needs. RE-AIM was found to be a useful framework for evaluating and adapting an existing evidence-based weight management programme in line with local population needs. This could be a more cost-effective approach, compared to developing new programmes, for delivering public health goals relating to obesity, nutrition, and physical activity.


The application of bioturbators for aquatic bioremediation: Review and meta-analysis.
Human activities introduce significant contamination into aquatic systems that impact biodiversity and ecosystem function. Many contaminants accumulate, and remediation options are now required worldwide. One method for bioremediation involves the application of macrofauna to stimulate microbial ecosystem processes including contaminant removal. However, if we are to confidently apply such a technique, we need clarity on the effect of bioturbators on different contaminants and how these vary under different environmental scenarios. Here we used a systematic review and meta-analysis to analyse current knowledge on the activities of bioturbating macrofauna in contaminated sediments and quantify how bioturbation-bioremediation changes depend on the taxonomic group, the aquatic ecosystem and important environmental variables. Three common contaminant classes were reviewed and analysed: metals, nutrients (i.e. ammonia and phosphorous) and polycyclic aromatic hydrocarbons (PAH). In addition, meta-regressions were calculated to estimate the effect of environmental and experimental design variables on effect sizes. Meta-analytic results revealed that deeper burrowing and more active sediment surface animals (e.g. polychaetes) increased metal release from sediments, nutrients and oxygen uptake by microbial fractions in comparison to bioturbators that inhabit shallower depths in sediments. In addition, there was a different effect of bioturbators on response variables in different aquatic systems. Finally, bioturbator effects on nutrient and metal release appeared modulated by context-specific variables such as temperature, pH, sediment grain size, animal density and experimental duration. Our findings highlight critical knowledge gaps such as field applications, less studied macrobenthic fauna and the incorporation of molecular approaches. Our results provide the first quantitative synthesis of the effects of bioturbators on contaminant fate and the variables that need to be considered for the optimization of this method as a viable approach for sediment remediation and contaminant management in aquatic systems.


Orofacial pain: a guide for the headache physician.
Orofacial pain represents a significant burden in terms of morbidity and health service utilization. It includes very common disorders such as toothache and temporomandibular disorders, as well as rare orofacial pain syndromes. Many orofacial pain conditions have overlapping presentations, and diagnostic uncertainty is frequently encountered in clinical practice. This review provides a clinically orientated overview of common and uncommon orofacial pain presentations and diagnoses, with an emphasis on conditions that may be unfamiliar to the headache physician. A holistic approach to orofacial pain management is important, and the social, cultural, psychological and cognitive context of each patient needs to be considered in the process of diagnostic formulation, as well as in the development of a pain management plan according to the biopsychosocial model. Recognition of psychological comorbidities will assist in diagnosis and management planning.


Financial analysis of PA lifetime earnings and debt.
This economic analysis of physician assistant/associate (PA) career earnings sought to assess the increasing effect of student debt, its potential effect on job selection, and whether such financial obligations may influence graduates to select higher-paying specialties. The model was a 30-year-old newly graduated PA who begins working in family medicine. A simulation included wages, student debt, national household expenditures, and real estate statistics. The scenario consisted of a high and middle cost of living in two geographic areas, a family of four, and an average life expectancy. Using a validated economic program, a series of calculations produced the financial effect on moderateincome levels and expenditures based on median PA earnings. On the deficit side is education debt, loan repayment, financing a house, college for children, retirement, and discretionary spending. Weighted variables were used to maximize the sensitivity effect of the simulation. A Monte Carlo probabilistic program predicted the likely outcome of income, expenses, inflation, and investments. Furthermore, the lifetime earnings of a PA who retires at age 67 years and lives to age 85 years falls in the 75th percentile of income of all Americans. The conclusion is that a full-time PA career in any clinical role is as economically rewarding as it is satisfying.


Polygenic Scores for ADHD: A Meta-Analysis.
Attention-deficit/hyperactivity disorder (ADHD) is a highly heritable neurodevelopmental disorder that is known to have a polygenic (i.e., many genes of individually small effects) architecture. Polygenic scores (PGS), which characterize this polygenicity as a single score for a given individual, are considered the state-of-the-art in psychiatric genetics research. Despite the proliferation of ADHD studies adopting this approach and its clinical implications, remarkably little is known about the predictive utility of PGS in ADHD research to date, given that there have not yet been any systematic or meta-analytic reviews of this rapidly developing literature. We meta-analyzed 12 unique effect sizes from ADHD PGS studies, yielding an N = 40,088. These studies, which included a mixture of large population-based cohorts and case-control samples of predominantly European ancestry, yielded a pooled ADHD PGS effect size of rrandom = 0.201 (95% CI = [0.144, 0.288]) and an rfixed = 0.190 (95% CI = [0.180, 0.199]) in predicting ADHD. In other words, ADHD PGS reliably account for between 3.6% (in the fixed effects model) to 4.0% (in the random effects model) of the variance in broadly defined phenotypic ADHD. Findings provide important insights into the genetics of psychiatric outcomes and raise several key questions about the impact of PGS on psychiatric research moving forward. Our review concludes by providing recommendations for future research directions in the use of PGS, including new methods to account for comorbidities, integrating bioinformatics to elucidate biological pathways, and leveraging PGS to test mechanistic models of ADHD.


Neuroauditory toxicity of artemisinin combination therapies-have safety concerns been addressed?
Although artemisinin-based combination therapies (ACTs) are widely viewed as safe drugs with a wide therapeutic dose range, concerns about neuroauditory safety of artemisinins arose during their development. A decade ago, reviews of human data suggested a potential neuro-ototoxic effect, but the validity of these findings was questioned. With 5-10 years of programmatic use, emerging artemisinin-tolerant falciparum malaria in southeast Asia, and the first calls to consider an increased dose of artemisinins, we review neuroauditory safety data on ACTs to treat uncomplicated falciparum malaria. Fifteen studies reported a neurological or auditory assessment. The large heterogeneity of neuro-ototoxic end points and assessment methodologies and the descriptive nature of assessments hampered a formal meta-analysis and definitive conclusions, but they highlight the persistent lack of data from young children. This subgroup is potentially most vulnerable to any neuroauditory toxicity because of their development stage, increased malaria susceptibility, and repeated ACT exposure in settings lacking robust safety monitoring.


Placebo in nonalcoholic steatohepatitis: insight into natural history and implications for future clinical trials.
Changes in biochemical and histologic parameters related to nonalcoholic steatohepatitis (NASH) in placebo-treated patients may provide an insight into the natural history and help in defining treatment end points in NASH. The aim of our study was to assess the biochemical and histologic changes seen in the placebo arm of the randomized, placebo-controlled trials in adult patients with NASH. Medline was searched (through May 2008) for studies published in the English language. Randomized, placebo-controlled trials of at least 6 months' duration in patients with NASH that provided biochemical and/or histologic data of the placebo arm were included. One investigator performed the literature search and data extraction. Two investigators independently confirmed that the studies met prespecified criteria. Pooled estimates of biochemical and histologic parameters associated with NASH were calculated. Five randomized controlled trials met the predefined criteria and included 162 placebo-treated and 189 active-treatment patients. The mean serum alanine and aspartate aminotransferase levels decreased on placebo. A 1-point improvement in steatosis, ballooning degeneration, lobular inflammation, NASH fibrosis, and combined inflammation scores was seen in 31%, 15%, 33%, 22%, and 32% of patients, respectively. A 2-point improvement in NASH histologic scores is rarely seen. Serum alanine aminotransferase levels may decrease on placebo and is not a reliable measure of treatment response. Although a 1-point improvement is seen in a third of patients, a 2-point improvement in histologic parameters is rarely seen in the placebo arm and may be more reliable in assessing treatment response. These data may have important implications in designing future clinical trials in NASH.


Preschoolers' group bias in punishing selfishness in the Ultimatum Game.
Previous studies have shown that both adults and children tend to favor members of their own group and expect reciprocity of such in-group privilege. If a person is treated unfairly by an in-group member, a conflict arises between the tendency of in-group favoritism and the desire to punish violators of in-group norms. How do children solve the conflict at different points in development? We compared how preschoolers punished in-group and out-group members (marked by color preference) for selfishness in the Ultimatum Game. We found that (a) 3- to 6-year-old Chinese children rejected selfish allocations more often than fair ones, showing a robust preference for fairness; (b) 3- and 4-year-olds showed no group differences in their punishment behavior, suggesting that second-party punishment of selfishness is not biased during early childhood; (c) 5- and 6-year-old girls were more likely to punish selfishness of in-groups than of out-groups, illuminating an early sign of maintaining group-based fairness norms even at a personal cost; and (d) 5- and 6-year-old boys, however, punished in-groups and out-groups equally often and punished out-groups more often than did girls. These age and gender differences in children's punishment imply that socialization may play an important role in showing group bias when enforcing fairness norms.


Combinatorial chemoenzymatic synthesis and high-throughput screening of sialosides.
Although the vital roles of structures containing sialic acid in biomolecular recognition are well documented, limited information is available on how sialic acid structural modifications, sialyl linkages, and the underlying glycan structures affect the binding or the activity of sialic acid-recognizing proteins and related downstream biological processes. A novel combinatorial chemoenzymatic method has been developed for the highly efficient synthesis of biotinylated sialosides containing different sialic acid structures and different underlying glycans in 96-well plates from biotinylated sialyltransferase acceptors and sialic acid precursors. By transferring the reaction mixtures to NeutrAvidin-coated plates and assaying for the yields of enzymatic reactions using lectins recognizing sialyltransferase acceptors but not the sialylated products, the biotinylated sialoside products can be directly used, without purification, for high-throughput screening to quickly identify the ligand specificity of sialic acid-binding proteins. For a proof-of-principle experiment, 72 biotinylated alpha2,6-linked sialosides were synthesized in 96-well plates from 4 biotinylated sialyltransferase acceptors and 18 sialic acid precursors using a one-pot three-enzyme system. High-throughput screening assays performed in NeutrAvidin-coated microtiter plates show that whereas Sambucus nigra Lectin binds to alpha2,6-linked sialosides with high promiscuity, human Siglec-2 (CD22) is highly selective for a number of sialic acid structures and the underlying glycans in its sialoside ligands.


Comparing and transforming PROMIS utility values to the EQ-5D.
Summarizing patient-reported outcomes (PROs) on a quality-adjusted life year (QALY) scale is an essential component to any economic evaluation comparing alternative medical treatments. While multiple studies have compared PRO items and instruments based on their psychometric properties, no study has compared the preference-based summary of the EQ-5D-3L and Patient Reported Outcomes Measurement Information System (PROMIS-29) instruments. As part of this comparison, a major aim of this manuscript is to transform PROMIS-29 utility values to an EQ-5D-3L scale. A nationally representative survey of 2623 US adults completed the 29-item PROMIS health profile instrument (PROMIS-29) and the 3-level version of the EQ-5D instrument (EQ-5D-3L). Their responses were summarized on a health utility scale using published estimates. Using regression analysis, PROMIS-29 and EQ-5D-3L utility weights were compared with each other as well as with self-reported general health. PROMIS-29 utility weights were much lower than the EQ-5D-3L weights. However, a correlation coefficient of 0.769 between the utility values of the two instruments suggests that the main discordance is simply a difference in scale between the measures. It is also possible to map PROMIS-29 utility weights onto an EQ-5D-3L scale. EQ-5D-3L losses equal .1784 × (PROMIS-29 Losses).7286. The published estimates of the PROMIS-29 produce lower utility values than many other health instruments. Mapping the PROMIS-29 estimates to an EQ-5D-3L scale alleviates this issue and allows for a more straightforward comparison between the PROMIS-29 and other common health instruments.


Urinary schistosomiasis in rural communities of some local government areas in Plateau State, Nigeria: a preliminary parasitological and malacological survey.
A preliminary parasitological and malacological survey was effected in rural communities of some Local Government Areas (LGA) in Plateau State, Nigeria, to estimate the prevalence of urinary schistosomiasis and identify active transmission foci. Out of 2888 persons examined in six LGAs, 1381 (47.82%) were excreting eggs of Schistosoma haematobium in their urine. Prevalence rates did not vary significantly (P > 0.05) between the LGAs: Pankshin (62.4%), Shendam (40.2%), Qua'an-Pan (22.9%), Langtang South (45.4%), Langtang North (58.8%) and Wase (50.0%). Infection rates were significantly different (P < 0.001) between the sexes. Many water bodies in the study communities were colonized by infected Bulinus snails. Snail infection rates varied significantly (P < 0.001) between the dry and wet seasons. A positive correlation was observed between snail infection rates and the prevalence of S. haematobium.


Heterogeneous proliferative potential in regenerative adult newt cardiomyocytes.
Adult newt cardiomyocytes, in contrast to their mammalian counterparts, can proliferate after injury and contribute to the functional regeneration of the heart. In order to understand the mechanisms underlying this plasticity we performed longitudinal studies on single cardiomyocytes in culture. We find that the majority of cardiomyocytes can enter S phase, a process that occurs in response to serum-activated pathways and is dependent on the phosphorylation of the retinoblastoma protein. However, more than half of these cells stably arrest at either entry to mitosis or during cytokinesis, thus resembling the behaviour observed in mammalian cardiomyocytes. Approximately a third of the cells progress through mitosis and may enter successive cell divisions. When cardiomyocytes divided more than once, the proliferative behaviour of sister cells was significantly correlated, in terms of whether they underwent a subsequent cell cycle, and if so, the duration of that cycle. These observations suggest a mechanism whereby newt heart regeneration depends on the retention of proliferative potential in a subset of cardiomyocytes. The regulation of the remaining newt cardiomyocytes is similar to that described for their mammalian counterparts, as they arrest during mitosis or cytokinesis. Understanding the nature of this block and why it arises in some but not other newt cardiomyocytes may lead to an augmentation of the regenerative potential in the mammalian heart.


Programmable dispersion on a photonic integrated circuit for classical and quantum applications.
We demonstrate a large-scale tunable-coupling ring resonator array, suitable for high-dimensional classical and quantum transforms, in a CMOS-compatible silicon photonics platform. The device consists of a waveguide coupled to 15 ring-based dispersive elements with programmable linewidths and resonance frequencies. The ability to control both quality factor and frequency of each ring provides an unprecedented 30 degrees of freedom in dispersion control on a single spatial channel. This programmable dispersion control system has a range of applications, including mode-locked lasers, quantum key distribution, and photon-pair generation. We also propose a novel application enabled by this circuit - high-speed quantum communications using temporal-mode-based quantum data locking - and discuss the utility of the system for performing the high-dimensional unitary optical transformations necessary for a quantum data locking demonstration.


Hyperintense globus pallidus on T1-weighted MR imaging in acute kernicterus: is it common or rare?
Globus pallidus involvement is a well-known magnetic resonance (MR) imaging finding of acute kernicterus. However, it is not clear how early the involvement of globus pallidus occurs and whether or not it is seen in every case. Therefore, we aimed to investigate the globus pallidus involvement in 13 neonates with acute kernicterus by MR imaging. Thirteen neonates who were admitted with jaundice, encephalopathy and indirect hyperbilirubinemia (mean, 37.0 mg/dl) were prospectively evaluated with cranial MR imaging. Pathological signal changes were noted concerning the globus pallidus. Eight of the 13 patients demonstrated bilateral, symmetric increased signal intensity in the globus pallidus on T1-weighted MR imaging. These lesions were not apparent on T2-weighted images. Multiple parenchymal punctuate T1 hyperintense lesions were detected in one patient without globus pallidus involvement. This appearance was consistent with hemorrhage. The MR imaging findings of the other four patients showed no evidence of abnormality. The symmetric involvement of globus pallidus seen as hyperintense on T1-weighted MR imaging is a common and characteristic finding of acute kernicterus.


Correlates of age at attainment of developmental milestones in HIV-infected infants receiving early antiretroviral therapy.
Infant HIV-1 infection is associated with impaired neurologic and motor development. Antiretroviral therapy (ART) has the potential to improve developmental outcomes but the relative contributions of pre-ART disease status, growth, treatment regimen and ART response during infancy are unknown. Kenyan ART-naive infants <5-months old initiated ART and had monthly assessment of age of full neck control, unsupported walking and monosyllabic speech during 24 months of follow-up. Pre-ART and post-ART correlates of age at milestone attainment were evaluated using t tests or multivariate linear regression. Among 99 infants, pre-ART correlates of later milestone attainment included: underweight and stunted (neck control, walking and speech, all P values <0.05), missed prevention of mother-to-child transmission (P = 0.04) (neck control), previous hospitalization, World Health Organization (WHO) Stage III/IV, low CD4 count, and wasting (speech and walking, all P values <0.05), and low maternal CD4 (speech, P = 0.04). Infants initiated ART at a median of 14 days following enrollment. Infants receiving nevirapinevs lopinavir/ritonavir-based ART attained later speech (18.1 vs. 15.5 months, P = 0.003) [corrected]. Adjusting for pre-ART level, lower 6-month gain in CD4% was associated with later walking (0.18 months earlier per unit increase in CD4%; P = 0.004) and speech (0.12 months earlier per unit increase in CD4%; P = 0.05), and lower 6-month gains in weight-for-age (P = 0.009), height-for-age (P = 0.03) and weight-for-height (P = 0.02) were associated with later walking. In HIV-infected infants, compromised pre-ART immune and growth status, poor post-ART immune and growth responses, and use of nevirapine- vs. lopinavir/ritonavir-based ART were each associated with later milestone attainment [corrected]. The long-term consequences of these delays are unknown.


Visible-blind photodetector based on p-i-n junction GaN nanowire ensembles.
We report the synthesis, fabrication and extensive characterization of a visible-blind photodetector based on p-i-n junction GaN nanowire ensembles. The nanowires were grown by plasma-assisted molecular beam epitaxy on an n-doped Si(111) substrate, encapsulated into a spin-on-glass and processed using dry etching and metallization techniques. The detector presents a high peak responsivity of 0.47 A W(-1) at - 1 V. The spectral response of the detector is restricted to the UV range with a UV-to-visible rejection ratio of 2 x 10(2). The dependence on the incident power and the operation speed of the photodetector are discussed.


HMMatch: peptide identification by spectral matching of tandem mass spectra using hidden Markov models.
Peptide identification by tandem mass spectrometry is the dominant proteomics workflow for protein characterization in complex samples. The peptide fragmentation spectra generated by these workflows exhibit characteristic fragmentation patterns that can be used to identify the peptide. In other fields, where the compounds of interest do not have the convenient linear structure of peptides, fragmentation spectra are identified by comparing new spectra with libraries of identified spectra, an approach called spectral matching. In contrast to sequence-based tandem mass spectrometry search engines used for peptides, spectral matching can make use of the intensities of fragment peaks in library spectra to assess the quality of a match. We evaluate a hidden Markov model approach (HMMatch) to spectral matching, in which many examples of a peptide's fragmentation spectrum are summarized in a generative probabilistic model that captures the consensus and variation of each peak's intensity. We demonstrate that HMMatch has good specificity and superior sensitivity, compared to sequence database search engines such as X!Tandem. HMMatch achieves good results from relatively few training spectra, is fast to train, and can evaluate many spectra per second. A statistical significance model permits HMMatch scores to be compared with each other, and with other peptide identification tools, on a unified scale. HMMatch shows a similar degree of concordance with X!Tandem, Mascot, and NIST's MS Search, as they do with each other, suggesting that each tool can assign peptides to spectra that the others miss. Finally, we show that it is possible to extrapolate HMMatch models beyond a single peptide's training spectra to the spectra of related peptides, expanding the application of spectral matching techniques beyond the set of peptides previously observed.


Acute phase response during radiotherapy.
The acute phase response is characterized by changes in the plasma concentrations of a number of liver-synthesized proteins, one of which is C-reactive protein (CRP). The existence of these changes in the plasma profile underlies the change in erythrocyte sedimentation rate (ESR). Acute phase response itself is an illness and may result from immunologic reactions and inflammatory processes. This study is designed to determine whether the CRP level and ESR increase during radiotherapy and whether their rise correlates with acute and late radiation morbidity. Between April 1997 and October 1998, 51 patients with the diagnosis of endometrium and cervical cancer were treated with surgery and postoperative radiotherapy. Median age at the time of radiotherapy was 52 (range, 26-73) years. Thirty patients received pelvic radiotherapy, and 21 patients were treated by pelvic-paraaortic irradiation. A total dose of 50.4 Gy to the pelvis and 45 Gy to the paraaortic field were delivered in conventional fraction. Erythrocyte sedimentation rates and CRP levels were studied before, during, and at the end of radiotherapy. The mean ESR measurements before and after radiotherapy were 40 (8-100) and 52 (10-120), and mean CRP levels were 1.4 (0.12-9.8) and 2.7 (0.12-32.2), respectively. The statistical analysis yielded significant rise in ESR and CRP levels at the end of radiotherapy (p < 0.001). The increase was more prominent in patients who were irradiated through pelvic-paraaortic field than in patients with pelvic radiation (p = 0.005 and 0.028 respectively). Acute phase response was present during radiotherapy. Radiotherapy should be considered as a cause of increase in CRP level and ESR especially in clinical conditions where acute phase response is important.


Analytical ultracentrifugation of colloids.
In this contribution the use of Analytical Ultracentrifugation (AUC) for the modern analysis of colloids is reviewed. Since AUC is a fractionation technique, distributions of the sedimentation coefficient, particle size and shape, molar mass and density can be obtained for particle sizes spanning the entire colloidal range. The Ångström resolution and the reliable statistics with which particle size distributions can be obtained from analytical ultracentrifugation makes this a high resolution analysis technique for the characterization of nanoparticles in solution or suspension. Several examples showing successful applications of AUC to complex problems in colloid science are given to illustrate the broad range and versatility of questions that can be answered by AUC experiments.


Transitions to adulthood: examining the influence of initiation rites on the HIV risk of adolescent girls in Mangochi and Thyolo districts of Malawi.
Although some cultural practices have been identified as a determinant of HIV transmission, research investigating how specific practices affect HIV risk is lacking. In Malawi, initiation rites, in which young people attend ceremonies around the time of puberty, have received little attention. In this qualitative study, we explored whether communities in southern Malawi perceive initiation rites to be an HIV risk factor for girls. Twelve focus group discussions were held with adolescents and adults in a rural community of Thyolo district and a peri-urban community of Mangochi district. Community members observed that certain aspects of traditional initiation rites propel girls into sexual roles expected of adulthood, without facilitating their adaption to the emerging landscape of HIV, thereby increasing HIV risk. HIV prevention programming needs to address the role of initiation rites in adolescent girls' vulnerability to HIV and help young girls navigate the conflicting messages they receive from a wide range of channels about expected sexual behavior.


Alpha-helix stability and the native state of myoglobin.
Native proteins fold to form structures that contain secondary-structure regular patterns in the peptide backbone, such as alpha-helix, beta-structure, and turns with high frequency. The role of this secondary structure in stabilizing the native folded state is presently unclear. Alanine substitutions at helical sites in myoglobin show no correlation with the helical propensity of the side chains involved. In an effort to demonstrate a relationship between the effect of a side chain on stabilizing secondary structure and the native structure, we have carried out site-directed changes in the sequence of the helical protein sperm whale myoglobin. Fully buried hydrophobic side chains were exchanged for similar side chains at sites corresponding to midhelical positions in the native state. The results show a positive correlation between the alpha-helix-forming ability of the substituted side chain and the stability of the mutant proteins, when differences between the size of the side chains are taken into account. If, in addition, each type of amino acid substitution is averaged over different sites, the helix propensities of the amino acids account for much of the residual variation. This implies that the stability of the native state of a protein is coupled to that of secondary structural elements in the structure. In magnitude, the net contribution of propensity differences is smaller than hydrophobic effects, but not negligible in terms of the net free energy of unfolding.


Proinflammatory role for let-7 microRNAS in experimental asthma.
MicroRNAs (miRNAs) are short, non-coding RNAs that target and silence protein coding genes through 3'-UTR elements. Evidence increasingly assigns an immunosuppressive role for miRNAs in immunity, but relatively few miRNAs have been studied, and an overall understanding of the importance of these regulatory transcripts in complex in vivo systems is lacking. Here we have applied multiple technologies to globally analyze miRNA expression and function in allergic lung disease, an experimental model of asthma. Deep sequencing and microarray analyses of the mouse lung short RNAome revealed numerous extant and novel miRNAs and other transcript classes. Similar to mRNAs, lung miRNA expression changed dynamically during the transition from the naive to the allergic state, suggesting numerous functional relationships. A possible role for miRNA editing in altering the lung mRNA target repertoire was also identified. Multiple members of the highly conserved let-7 miRNA family were the most abundant lung miRNAs, and we confirmed in vitro that interleukin 13 (IL-13), a cytokine essential for expression for allergic lung disease, is regulated by mmu-let-7a. However, inhibition of let-7 miRNAs in vivo using a locked nucleic acid profoundly inhibited production of allergic cytokines and the disease phenotype. Our findings thus reveal unexpected complexity in the miRNAome underlying allergic lung disease and demonstrate a proinflammatory role for let-7 miRNAs.


Percutaneous extrahepatic portacaval shunt with covered prostheses: feasibility study.
To assess the anatomic feasibility of creating a percutaneous extrahepatic portosystemic shunt (PEPS) between the main portal vein (MPV) and the inferior vena cava (IVC) in patients with cirrhosis and to evaluate the feasibility of this approach in an animal model. In human studies, computed tomographic (CT) scans from 34 patients with cirrhosis were reviewed to assess the distance and anatomic structures found between the MPV and IVC. The MPV was divided into upper, middle, and lower thirds for analysis. In the experimental model, PEPS were created in 10 beagle dogs by placing between the MPV and IVC a tubular polyurethane-covered prosthesis with flared ends designed for this study. Different approaches, devices, and prostheses were assayed. In human studies, the shortest mean distance between the IVC and the MPV was found in the lower third of the MPV (1.18 cm +/- 0.6). The lower third, the nearest to the confluence of splenic and superior mesenteric veins, also presented fewer intervening structures, and the spatial relationship between the veins at this level was predictable. In the experimental model, direct portography was performed, with a small mesenteric vein catheterized through a minilaparotomy and a transjugular access to the IVC. A needle was advanced from the MPV to the IVC, and a polyurethane cone-shaped covered prosthesis was placed to bridge the path between the veins. Six of 10 animals died from bleeding that occurred either because several punctures were made during the procedure or because the prosthesis became dislodged when the mesentery was moved before suturing the minilaparotomy. The remaining four were kept alive for 1, 5, 60, and 90 days after the procedure. PEPS creation in patients with cirrhosis is anatomically possible. The lower third of the MPV should be the most suitable level at which to create the shunt. Preliminary studies carried out in beagle dogs support the feasibility of this approach. However, further work is needed to improve the efficacy of this technique.


Induced Abortion, Birth Control Methods, and Breast Cancer Risk: A Case-Control Study in China.
The association between induced abortion and birth control methods (including oral contraceptives and intrauterine devices) and breast cancer may vary among countries, due to the different usage and frequency of birth control methods and induced abortion among countries. A better understanding of this association may help in determining safer birth control methods for Chinese women. A case-control study was conducted with a total of 794 cases and 805 controls. Standardized questionnaires were used to collect information on demographic characteristics, exposure to induced abortion, birth control methods, and other risk factors for breast cancer. Multivariate logistic regression was conducted to explore the association between birth control methods and breast cancer. Multivariate logistic regression analyses showed that having a history of medical abortions, ≥3 surgical abortions, or both medical and surgical abortions was associated with an increased risk of breast cancer in post-menopausal women (odds ratio [OR] 2.48; 95% confidence interval [CI], 1.14-5.40). Pre-menopausal women who had used intra-uterine devices (IUDs) for more than 20 years tended to have a lower breast cancer risk than other age-matched pre-menopausal women (OR 0.41; 95% CI, 0.25-0.68). Both pre-menopausal and post-menopausal women who had <20 years exposure to IUDs and those who had used two or more birth control methods (with the exception of women who used IUDs for more than 20 years) tended to have much higher breast cancer risk. The relationship between induced abortion and birth control methods and breast cancer was complex, though being exposed to induced abortion and two or more birth control methods in one's lifetime appeared to be risk factors for breast cancer in Chinese women.


[Isolation and characterization of Rahnella aquatilis lipopolysaccharides].
Lipopolysaccharides (LPS) of six strains of Rahnella aquatilis isolated from freshwater reservoirs, plant rhizosphere, and from patient have been investigated. It was shown, that LPS of type strain was characterized by the presence of rhamnose and mannose as predominant monosaccharides, while LPS of the rest strains contained galactose and fucose. The glucosamine content was insignificant (0.42-1.0%) in LPS of all strains studied. It was shown by double immunodiffusion in agar, immunoelectrophoresis and rocket immunoelectrophoresis that all R. aquatilis LPS were antigens in homological systems. The results of serological cross reactions evidence for immunochemical heterogeneity of R. aquatilis species. LPS of R. aquatilis display pyrogeneity and toxicity (LD50 from 0.20 to 0.33 mg/kg of experimental animals weight).


Diagnosis of malarial infection using change in properties of optically trapped red blood cells.
In previous work studying the properties of red blood cells (RBCs) held in an optical tweezers trap, we observed an increase in the spectrum of Brownian fluctuations for RBCs from a Plasmodium falciparum culture-due to increased rigidity of the cells-compared to normal RBCs. We wanted to extend the study to patient samples, since the earlier work was done with cultures grown in the lab. Individual RBCs were held in an optical-tweezers trap. Its position fluctuations were measured and the power spectrum determined. The corner frequency (fc) of the spectrum gave a quantitative measurement of the spectrum. The value of fc was 25 Hz for normal cells, which increased to 29 Hz for infected cells-both for P. falciparum and Plasmodium vivax infections. The technique of measuring fc can be used as a screening tool for malaria in patients with fever, since RBCs not carrying the parasite will also show the change due to the bystander effect, irrespective of whether it is caused by P. falciparum or P. vivax.


Outcome of the bladder cooling test in children with nonneurogenic bladder problems.
The bladder cooling test (BCT) engages a primitive neonatal spinal reflex that becomes suppressed by descending signals in older children and may reappear with suprasacral lesions. We assessed the outcome of the BCT in a large group of children with nonneurogenic bladder problems. The BCT was evaluated in a consecutive series of 178 girls and 106 boys, 1 month to 18 years old with bladder problems without overt neurology. The test was performed at the end of routine cystometry by a rapid control infusion of body warm saline followed, after fluid evacuation, by the same volume of cold saline (3 to 10C). The test was considered positive if a detrusor contraction greater than 30 cm H2O was evoked by the cold but not the warm fluid. Most children younger than 4 years had a history of pyelonephritis (29 of 34) and/or had vesicoureteral reflux (grade IV to V in 26 of 34). For those younger than 2 years 87% of the BCTs were positive while only 21% of the tests were positive in 2 to 3-year-old children. Most children older than 4 years had idiopathic urge incontinence, and greater than 50% of the BCTs were positive in the youngest (less than 6 years) with a gradual decline to 0% at age 13 years. Conversion of positive to negative BCTs at about age 2 years presumably represents normal maturation while positive tests in older incontinent children suggest delayed maturation of the central neuronal control of the bladder.


First-principles study of silicon nanocrystals: structural and electronic properties, absorption, emission, and doping.
Total energy calculations within the Density Functional Theory have been carried out in order to investigate the structural, electronic, and optical properties of un-doped and doped silicon nanostructures of different size and different surface terminations. In particular the effects induced by the creation of an electron-hole pair on the properties of hydrogenated silicon nanoclusters as a function of dimension are discussed in detail showing the strong interplay between the structural and optical properties of the system. The distortion induced on the structure by an electronic excitation of the cluster is analyzed and considered in the evaluation of the Stokes shift between absorption and emission energies. Besides we show how many-body effects crucially modify the absorption and emission spectra of the silicon nanocrystals. Starting from the hydrogenated clusters, different Si/O bonding at the cluster surface have been considered. We found that the presence of a Si--O--Si bridge bond originates significative excitonic luminescence features in the near-visible range. Concerning the doping, we consider B and P single- and co-doped Si nanoclusters. The neutral impurities formation energies are calculated and their dependence on the impurity position within the nanocrystal is discussed. In the case of co-doping the formation energy is strongly reduced, favoring this process with respect to the single doping. Moreover the band gap and the optical threshold are clearly red-shifted with respect to that of the pure crystals showing the possibility of an impurity based engineering of the absorption and luminescence properties of Si nanocrystals.


Functional characterisation of the non-essential protein kinases and phosphatases regulating Aspergillus nidulans hydrolytic enzyme production.
Despite recent advances in the understanding of lignocellulolytic enzyme regulation, less is known about how different carbon sources are sensed and the signaling cascades that result in the adaptation of cellular metabolism and hydrolase secretion. Therefore, the role played by non-essential protein kinases (NPK) and phosphatases (NPP) in the sensing of carbon and/or energetic status was investigated in the model filamentous fungus Aspergillus nidulans. Eleven NPKs and seven NPPs were identified as being involved in cellulase, and in some cases also hemicellulase, production in A. nidulans. The regulation of CreA-mediated carbon catabolite repression (CCR) in the parental strain was determined by fluorescence microscopy, utilising a CreA::GFP fusion protein. The sensing of phosphorylated glucose, via the RAS signalling pathway induced CreA repression, while carbon starvation resulted in derepression. Growth on cellulose represented carbon starvation and derepressing conditions. The involvement of the identified NPKs in the regulation of cellulose-induced responses and CreA derepression was assessed by genome-wide transcriptomics (GEO accession 47810). CreA::GFP localisation and the restoration of endocellulase activity via the introduction of the ∆creA mutation, was assessed in the NPK-deficient backgrounds. The absence of either the schA or snfA kinase dramatically reduced cellulose-induced transcriptional responses, including the expression of hydrolytic enzymes and transporters. The mechanism by which these two NPKs controlled gene transcription was identified, as the NPK-deficient mutants were not able to unlock CreA-mediated carbon catabolite repression under derepressing conditions, such as carbon starvation or growth on cellulose. Collectively, this study identified multiple kinases and phosphatases involved in the sensing of carbon and/or energetic status, while demonstrating the overlapping, synergistic roles of schA and snfA in the regulation of CreA derepression and hydrolytic enzyme production in A. nidulans. The importance of a carbon starvation-induced signal for CreA derepression, permitting transcriptional activator binding, appeared paramount for hydrolase secretion.


Effect of high blood flow on the expression of endothelial constitutive nitric oxide synthase in rats with femoral arteriovenous shunts.
The effect of high blood flow on the expression of endothelial nitric oxide synthase has been investigated in the femoral arteriovenous shunt (AVS) rats created by inserting U-shaped polyurethane tubes in the left femoral arteries and veins. Three days after inserting the femoral AVS, the mean aortic blood flow rate in the abdominal aorta of the AVS rats was about 2.0 times higher than that in the control rats (110.0 +/- 8.4 ml/min vs 52.7 +/- 2.7 ml/min, p < 0.001). The competitive reverse transcriptase-polymerase chain reaction (RT-PCR) data revealed that the mRNA expression level of the endothelial constitutive nitric oxide synthase (ecNOS) was increased in the aortas of the femoral AVS rats compared to that in the control rats. Western blot analysis using a monoclonal antibody against ecNOS revealed that the ecNOS protein levels were markedly increased in the aortas of femoral AVS rats, but ecNOS protein levels in aortas without endothelium were not significantly increased. Inducible nitric oxide synthase (iNOS) protein was not expressed in the aortic tissues with and without endothelium in the control rats. This iNOS expression was not increased by the high blood flow in the femoral AVS rats. These findings suggest that high blood flow could up-regulate the expression levels of ecNOS mRNA and proteins in femoral arteriovenous shunt rats.


A High-Saturated-Fat, High-Sucrose Diet Aggravates Bone Loss in Ovariectomized Female Rats.
Estrogen deficiency in women and high-saturated fat, high-sucrose (HFS) diets have both been recognized as risk factors for metabolic syndrome. Studies on the combined actions of these 2 detrimental factors on the bone in females are limited. We sought to determine the interactive actions of estrogen deficiency and an HFS diet on bone properties and to investigate the underlying mechanisms. Six-month-old Sprague Dawley sham or ovariectomized (OVX) rats were pair fed the same amount of either a low-saturated-fat, low-sucrose (LFS) diet (13% fat calories; 15% sucrose calories) or an HFS diet (42% fat calories; 30% sucrose calories) for 12 wk. Blood, liver, and bone were collected for correspondent parameters measurement. Ovariectomy decreased bone mineral density in the tibia head (TH) by 62% and the femoral end (FE) by 49% (P < 0.0001). The HFS diet aggravated bone loss in OVX rats by an additional 41% in the TH and 37% in the FE (P < 0.05). Bone loss in the HFS-OVX rats was accompanied by increased urinary deoxypyridinoline concentrations by 28% (P < 0.05). The HFS diet induced cathepsin K by 145% but reduced osteoprotegerin mRNA expression at the FE of the HFS-sham rats by 71% (P < 0.05). Ovariectomy significantly increased peroxisome proliferator-activated receptor γ mRNA expression by 136% and 170% at the FE of the LFS- and HFS-OVX rats, respectively (P < 0.05). The HFS diet aggravated ovariectomy-induced lipid deposition and oxidative stress (OS) in rat livers (P < 0.05). Trabecular bone mineral density at the FE was negatively correlated with rat liver malondialdehyde concentrations (R(2) = 0.39; P < 0.01). The detrimental actions of the HFS diet and ovariectomy on bone properties in rats occurred mainly in cancellous bones and were characterized by a high degree of bone resorption and alterations in OS.


Hearing screening in children with skeletal dysplasia.
To determine the prevalence of hearing loss and abnormal tympanometry in children with skeletal dysplasia. Clinical screening program. National convention of the Little People of America. Convenience sample of volunteers aged 18 years or younger with skeletal dysplasias. Hearing screening with behavioral testing and/or otoacoustic emissions, otoscopy, and tympanometry. A failed hearing screen was defined as hearing 35 dB HL (hearing level) or greater at 1 or more tested frequencies or by a "fail" otoacoustic emissions response. Types B and C tympanograms were considered abnormal. A total of 58 children (aged ≤18 years) with skeletal dysplasia enrolled, and 56 completed hearing screening. Forty-one children had normal hearing (71%); 9 failed in 1 ear (16%); and 6 failed in both ears (10%). Forty-four children had achondroplasia, and 31 had normal hearing in both ears (71%); 8 failed hearing screening in 1 ear (18%), and 3 in both ears (7%). Tympanometry was performed in 45 children, with normal tympanograms found in 21 (47%), bilateral abnormal tympanograms in 15 (33%), and unilateral abnormal tympanograms in 9 (20%). Fourteen children with achondroplasia had normal tympanograms (42%); 11 had bilateral abnormal tympanograms (33%); and 8 had unilateral abnormal tympanograms (24%). For those children without functioning tympanostomy tubes, there was a 9.5 times greater odds of hearing loss if there was abnormal tympanometry (P = .03). Hearing loss and middle-ear disease are both highly prevalent in children with skeletal dysplasias. Abnormal tympanometry is highly associated with the presence of hearing loss, as expected in children with eustachian tube dysfunction. Hearing screening with medical intervention is recommended for these children.


[Subfrontal approach in sellar and suprasellar lesions].
A variety of mass lesions are placed in and around of the sella turcica. Although their common location these lesions have distinguishing features and different approaches can be selected. There are conventional transcranial and sophisticated skull base approaches. We report our experience with a subfrontal route to the sellar region. Between February 1997 and March 1998, 19 tumors placed around the sella have been treated surgically by this method. Eleven of them were pituitary tumors, 3 were craniopharyngeomas, 2 were meningiomas, and 1 was germinoma. Total removal was achieved in 17 cases. There was not operative mortality. Postoperative complications included twelve cases of unilateral anosmia and four cases of transitory diabetes insipidus. Progressive stroke occurred in one patient. These results stress the importance of the subfrontal approach to reach such lesions in sellar region.


Structure/function of oxygen-regulated isoforms in cytochrome c oxidase.
Eukaryotic cytochrome c oxidases are complex oligomeric membrane proteins composed of subunit polypeptides encoded by both nuclear and mitochondrial genomes. While the mitochondrially encoded subunits are encoded by unique genes, some of the nuclear-encoded subunits are encoded by multigene families. The isoforms produced by these multigene families are tissue-specific and/or developmentally regulated in mammals and environmentally regulated in lower eukaryotes. Isoforms for one of the subunits, V, in the yeast Saccharomyces cerevisiae and one of the subunits, VII, in the slime mold Dictyostelium discoideum are regulated differentially by oxygen concentration. Extensive studies with the yeast subunit V isoforms have revealed that the genes for these proteins are switched on or off at very low oxygen concentrations (0.5-1 micromol l-1 O2) and that they affect the catalytic properties of holocytochrome c oxidase differentially. By altering an internal step in electron transfer between heme a and the binuclear reaction center (composed of heme a3 and CuB), the 'hypoxic' isoform, Vb, enhances the catalytic constant three- to fourfold relative to the 'aerobic' isoform, Va. Modeling studies suggest that this occurs by an interaction between transmembrane helix VII of subunit I and the transmembrane helix in subunit V. The inverse regulation of these two isoforms allows cells to assemble different types of holoenzyme isoenzymes in response to oxygen concentration. Oxygen also regulates the level of transcription of the genes for the other nuclear-coded subunits of yeast cytochrome c oxidase and affects the level of two of the mitochondrially encoded subunits (I and II) post-transcriptionally. Thus, the level of cytochrome c oxidase activity that is produced at different oxygen tensions in yeast is determined in part by the number of holoenzyme molecules that are assembled and in part by the oxygen-regulated isoforms of subunit V. The possibility that this type of control exists in other organisms is considered.


Meat odour and flavour and indoles concentration in ruminal fluid and adipose tissue of lambs fed green herbage or concentrates with or without tannins.
A 2 × 2 factorial experiment was carried out to evaluate the effect of herbage or concentrate feeding system and tannin addition to diet on skatole and indole in ruminal fluid and adipose tissue and meat sensory properties. Twenty-eight male lambs aged 45 days were randomly assigned to one of two feeding systems (vetch green herbage or concentrates, n = 14) and within feeding system to one supplement (quebracho tannins added to the diet or none). Animals were kept in singular pens and slaughtered at the age of 105 days. Indole (P < 0.05) and skatole (P < 0.01) concentrations in ruminal fluid were higher in lambs fed herbage compared to those given concentrates. Skatole in ruminal fluid tended to be present at lower concentrations in animals that received the tannin supplementation (P = 0.07). Indole was also higher in the caudal fat of animals fed green vetch compared to those fed concentrate (P = 0.04). Skatole concentration was lower in the fat of lambs fed concentrates compared to those given herbage (P = 0.05) and was lower in the fat of animals supplemented with tannins compared to the animals not supplemented (P = 0.01). Sheep meat odour was lower in meat from animals supplemented with tannins compared to those not supplemented (P < 0.01). It is concluded that tannins are more effective in reducing skatole formation in ruminants when they are associated with concentrate diets than green herbages.


Ability of Nonstrain Diastolic Parameters to Predict Doxorubicin-Induced Cardiomyopathy: A Systematic Review With Meta-Analysis.
Doxorubicin is an important cause of chemotherapy-induced cardiomyopathy. Prior studies have found conflicting results of whether nonstrain diastolic parameters can predict doxorubicin-induced cardiotoxicity. We performed a systematic review of English written publications using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The following inclusion criteria were applied: cancer subjects, echo-derived nonstrain diastolic profile, and patients compared before and after treatment to predict systolic dysfunction. The following exclusion criteria were applied: other cardiotoxic agents, non-echo studies, or used protective medications. Meta-analysis was performed using comprehensive meta-analysis software V3 to calculate cumulative means, SD, and odds ratios (ORs). Only 4 studies were designed to predict doxorubicin-induced cardiotoxicity. Of the 7 common parameters identified among studies, only 4 were significant: mitral E [OR: 3.4; 95% confidence interval (CI): 1.5-7.8; P = 0.003]; lateral E' (OR: 3.7; 95% CI: 1.5-9.4; P < 0.005); mitral E/A (OR: 4.3; 95% CI: 2.1-8.9; P < 0.0001); and lateral S' (OR: 2.7; 95% CI: 1.2-5.8; P = 0.01). We found that conventional nonstrain diastolic parameters predicted doxorubicin-induced systolic dysfunction. Whether nonstrain diastolic parameters can be used to supplement strain imaging for predicting doxorubicin-induced systolic function warrants further investigation in larger studies.


Reduced vitamin D levels in painful diabetic peripheral neuropathy.
Recent studies have reported an association between low vitamin D levels and diabetic peripheral neuropathy. However, many of these did not differentiate between people with painful diabetic peripheral neuropathy and those with painless diabetic peripheral neuropathy, or assess major confounding factors including sunlight exposure and daily activity. Our study addressed these limitations and evaluated vitamin D levels in people with carefully phenotyped diabetic peripheral neuropathy and controls. Forty-five white Europeans with Type 2 diabetes and 14 healthy volunteers underwent clinical and neurophysiological assessments. People with Type 2 diabetes were then divided into three groups (17 with painful diabetic peripheral neuropathy, 14 with painless diabetic peripheral neuropathy and 14 with no diabetic peripheral neuropathy). All had seasonal sunlight exposure and daily activity measured, underwent a lower limb skin biopsy and had 25-hydroxyvitamin D measured during the summer months, July to September. After adjusting for age, BMI, activity score and sunlight exposure, 25-hydroxyvitamin D levels (nmol/l) (se) were significantly lower in people with painful diabetic peripheral neuropathy [painful diabetic peripheral neuropathy 34.9 (5.8), healthy volunteers 62.05 (6.7), no diabetic peripheral neuropathy 49.6 (6.1), painless diabetic peripheral neuropathy 53.1 (6.2); ANCOVAP = 0.03]. Direct logistic regression was used to assess the impact of seven independent variables on painful diabetic peripheral neuropathy. Vitamin D was the only independent variable to make a statistically significant contribution to the model with an inverted odds ratio of 1.11. Lower 25-hydroxyvitamin D levels also correlated with lower cold detection thresholds (r = 0.39, P = 0.02) and subepidermal nerve fibre densities (r = 0.42, P = 0.01). We have demonstrated a significant difference in 25-hydroxyvitamin D levels in well-characterized people with painful diabetic peripheral neuropathy, while accounting for the main confounding factors. This suggests a possible role for vitamin D in the pathogenesis of painful diabetic peripheral neuropathy. Further prospective and intervention trials are required to prove causality between low vitamin D levels and painful diabetic peripheral neuropathy.


Cutting edge: cross-presentation as a mechanism for efficient recruitment of tumor-specific CTL to the brain.
The number and localization of effector cells to the tumor site are crucial elements for immune rejection of solid tumors. However, for cerebral malignancies, antitumor responses need to be finely tuned to avoid neuropathologic consequences. In this study, we determine factors that regulate CTL localization and tumoricidal function after intracerebral implantation of tumors expressing model Ag. H-2(bxd) mice implanted with a CW3(+) murine glioma lacking H-2K(d) molecules necessary to present the CW3(170-179) epitope demonstrate cross-priming of H-2K(d)-restricted CTL, and moreover, Ag-dependent accumulation of functional H-2K(d)/CW3(170-179)-specific CTL within the tumor bed. This implicates a role for cross-presentation not only in priming, but also in retention of fully differentiated CTL in the tumor stroma at the effector stage of the response. Modulating cross-presentation of Ag may be the key in regulating specific immune responses in the brain: either by augmenting protective responses or by down-modulating destructive autoimmune reactions.


The Potential Impact of Recreational Cannabis Legalization on the Prevalence of Cannabis Use Disorder and Psychotic Disorders: A Retrospective Observational Study.
The principal objective of our study was to document the short-term impact of the legalization of recreational cannabis on active cannabis use, cannabis use disorder, and various psychotic disorders. We carried out a retrospective observational study of patients who were at least 12 years old and who had visited a psychiatrist in the emergency unit of the Centre hospitalier universitaire de Sherbrooke (CHUS). We included all the consultations of this type over a 5-month period, immediately following the legalization of recreational cannabis in Canada. We then divided our population into an adult (over 18) and teenager group (12 to 17) compared the data to the data from consultations made 2 years earlier, using a generalized linear mixed model. We examined consultations in patients over 18 years old in prelegalization (n = 1,247) and postlegalization (n = 1,368) groups. We observed a statistically significant increase in the use of cannabis (28.0% to 37.1%; odds ratio [OR] = 1.81 [1.34 to 2.44], P = 0.00011) as well as an increase in diagnoses of active cannabis use disorder (17.7% to 24.3%; OR = 1.53 [1.13 to 2.08], P = 0.0064). The increase in cannabis use disorder was more prominent among patients between 18 and 24 years old (17.3% to 25.9%; OR = 2.27 [1.17 to 4.40], P = 0.015). We observed no statistically significant difference in terms of psychotic disorder diagnoses (27.4% to 29.2%; OR = 1.17 [0.84 to 1.63], P = 0.35)]. Conversely, we identified a greater proportion of patients who had a personality disorder diagnosis in the postlegalization period (39.6% to 44.9%; OR = 1.35 [1.02 to 1.80], P = 0.038). Examination of pediatric (under 18 years old) consultations revealed no statistically significant differences. Although an affirmative conclusion is tentative, the current findings suggest a first link between the legalization of cannabis in Canada and increased diagnoses of cannabis use disorder, as well as cannabis use in general among patients in a university hospital psychiatric emergency department.