The investigation of paper mill industry wastewater treatment and activated sludge properties in a submerged membrane bioreactor.
The paper mill industry produces high amounts of wastewater and, for this reason, stringent discharge limits are applied for sustainable reclamation and reuse of paper mill industry wastewater in many countries. Submerged membrane bioreactor (sMBR) systems can create new opportunities to eliminate dissolved substances present in paper mill wastewater including. In this study, a sMBR was operated for the treatment of paper mill industry wastewater at 35 h of hydraulic retention time (HRT) and 40 d of sludge retention time (SRT). The chemical oxygen demand (COD), NH3-N and total phosphorus (TP) removal efficiencies were found to be 98%, 92.99% and 96.36%. The results demonstrated that sMBR was a suitable treatment for the removal of organic matter and nutrients for treating paper mill wastewater except for the problem of calcium accumulation. During the experimental studies, it was noted that the inorganic fraction of the sludge increased as a result of calcium accumulation in the reactor and increased membrane fouling was observed on the membrane surface due to the calcification problem encountered. The properties of the sludge, such as extracellular polymeric substances (EPS) and soluble microbial products (SMP), relative hydrophobicity, zeta potential and floc size distribution were also monitored. According to the obtained results, the total EPS was found to be 43.93 mg/gMLSS and the average total SMP rejection by the membrane was determined as 66.2%.


Polymorphisms of sepiapterin reductase gene alter promoter activity and may influence risk of bipolar disorder.
In a previous investigation, we observed altered expression of sepiapterin reductase (SPR) in cultured neural cells chronically exposed to paroxetine. SPR is an enzyme, which catalyzes the final step in the synthesis of tetrahydrobiopterin (BH4). BH4 is an essential cofactor for synthesis of many neurotransmitters including serotonin. Given the pivotal role of SPR in neurotransmitter production, we sought to test the hypothesis that SPR would influence susceptibility to mood disorders and patient response to antidepressants. We tested for association of SPR promoter polymorphisms with antidepressant response in a well-characterized triad cohort of mood disorders. We evaluated the functional effect of these variants using the Dual-Luciferase Reporter Gene Assay System in two independent cell lines. Two promoter single nucleotide polymorphisms (rs1876487 and rs2421095) in SPR were identified that occurred in three distinct haplotypes. We found a statistically significant association of haplotype pair 2,3 with bipolar I disorder [odds ratio: 5.47; 95% confidence interval: (1.68-17.88); P<0.005] and the personality measure self-transcendence (P = 0.020). Moreover, we found preliminary evidence that individuals with haplotype pair 2,3 responded better to the treatment with selective serotonin reuptake inhibitors. Reporter gene assays revealed a 1.4-fold to 1.6-fold decrease in the transcription rate of the two less common haplotypes (2 and 3) compared with haplotype 1, in the two cell lines investigated. This reduced transcription rate for SPR promoter haplotypes 2 and 3 may impact on BH4-mediated neurotransmitter production, thus suggesting a biological process through which SPR gene variants might influence antidepressant response and susceptibility to bipolar disorder.


A Phase Ib Dose-Escalation Study of Encorafenib and Cetuximab with or without Alpelisib in Metastatic BRAF-Mutant Colorectal Cancer.
Preclinical evidence suggests that concomitant BRAF and EGFR inhibition leads to sustained suppression of MAPK signaling and suppressed tumor growth in BRAFV600E colorectal cancer models. Patients with refractory BRAFV600-mutant metastatic CRC (mCRC) were treated with a selective RAF kinase inhibitor (encorafenib) plus a monoclonal antibody targeting EGFR (cetuximab), with (n = 28) or without (n = 26) a PI3Kα inhibitor (alpelisib). The primary objective was to determine the maximum tolerated dose (MTD) or a recommended phase II dose. Dose-limiting toxicities were reported in 3 patients receiving dual treatment and 2 patients receiving triple treatment. The MTD was not reached for either group and the phase II doses were selected as 200 mg encorafenib (both groups) and 300 mg alpelisib. Combinations of cetuximab and encorafenib showed promising clinical activity and tolerability in patients with BRAF-mutant mCRC; confirmed overall response rates of 19% and 18% were observed and median progression-free survival was 3.7 and 4.2 months for the dual- and triple-therapy groups, respectively.Significance: Herein, we demonstrate that dual- (encorafenib plus cetuximab) and triple- (encorafenib plus cetuximab and alpelisib) combination treatments are tolerable and provide promising clinical activity in the difficult-to-treat patient population with BRAF-mutant mCRC. Cancer Discov; 7(6); 610-9. ©2017 AACR.See related commentary by Sundar et al., p. 558This article is highlighted in the In This Issue feature, p. 539.


Stability of blood pressure in vegetarians receiving dietary protein supplements.
Vegetarians have relatively low blood pressure (BP) levels and consume less protein than do nonvegetarians , and there have been suggestions that certain proteins may raise BP. To determine whether dietary protein supplements raise the BP of vegetarians, 58 g/per day of a 60:40 mixture of soy and wheat proteins and an isocaloric low protein supplement supplying 7 g/day of rice protein were added for 6-week periods to the diet of 18 vegetarians in a 2-group crossover design. Mean daily protein intake during consumption of the low and high protein supplements was 63 and 119 g, respectively. Mean BP was 109/72 mm Hg after the high protein and 108/71 mm Hg after the low protein diet. Consumption of other major nutrients, mean body weight, and sodium and potassium excretion did not change significantly. Thus, protein supplementation of a vegetarian diet that contained a below average but nutritionally adequate amount of protein did not significantly affect BP over 6 weeks.


Expression and developmental regulation of Na+,K+ adenosine triphosphatase in the rat small intestine.
The Na+,K(+)-ATPase ion pump plays a critical role in fluid and electrolyte physiology of the small intestine. Here we show that, of the three known alpha isotypes (alpha 1, alpha 2, and alpha 3) of the sodium pump found in the rat, only alpha 1 is expressed in the small intestine. The expression of this isotype, considered at the level of mRNA, is under developmental control, with the adult intestine exhibiting approximately a threefold increase in alpha 1 message over the neonate. Cortisone treatment of the neonate results in near-adult levels of alpha 1 mRNA expression. An increase in the abundance of alpha 1 isotype parallels the changes in its mRNA expression. beta subunit mRNA is expressed coordinately with the alpha 1 subunit mRNA. A four- to five-fold rise in the Na+,K(+)-ATPase activity is also developmentally induced.


The impact of barriers to providing high-quality care on nurses' intentions to leave London hospitals.
Previous research on nurse retention has focused mainly on its relationship with employment conditions. This study aimed to include an examination of the impact of nurses' perceived barriers to delivering high-quality patient-centred care on their intentions to leave their current employers. An American employee questionnaire was adapted for use with British nurses. The questionnaire was mailed to 6160 nurses directly employed by 20 London hospitals. Up to two reminders were sent to non-responders. The questionnaire asked nurses to report on experiences in their working lives and to state their intentions to leave or stay with their current employer. Demographic and employment history information was also elicited. Responses were received from 2880 (47%). Nurses report that the care they are able to provide often falls short of recognised standards. Factor analysis combined 82 questions on nurses' experiences into four patient-centred and four nurse-centred dimensions. Nurses who report more problems in both nurse-centred and patient-centred dimensions are more likely to intend to leave their current employers. Satisfaction with pay and the cleanliness of work areas are also important factors. Standards of care are often perceived by nurses to be unacceptably poor. Furthermore, their experience of barriers to care has a demonstrable impact on their decision to leave or stay with their current employer. Nurse managers need to address the perceived barriers to providing high-quality care when considering nurse retention strategies.


Dietary magnesium deficiency impairs hippocampus-dependent memories without changes in the spine density and morphology of hippocampal neurons in mice.
Magnesium (Mg2+) is an essential mineral for maintaining biological functions. One major action of Mg2+ in the brain is modulating the voltage-dependent blockade of N-methyl-d-aspartate type glutamate receptors, thereby controlling their opening, which is crucial for synaptic plasticity. Therefore, Mg2+ has been shown to play critical roles in learning and memory, and synaptic plasticity. However, the effects of dietary Mg2+ deficiency (MgD) on learning and memory and the morphology of neurons contributing to memory performance have not been examined in depth. Here, we show that MgD impairs hippocampus-dependent memories in mice. Mice fed an MgD diet showed deficits in hippocampus-dependent contextual fear, spatial and social recognition memories, although they showed normal amygdala- and insular cortex-dependent conditioned taste aversion memory, locomotor activity, and emotional behaviors such as anxiety-related and social behaviors. However, MgD mice showed normal spine density and morphology of hippocampal neurons. These findings suggest that MgD impairs hippocampus-dependent memory without affecting the morphology of hippocampal neurons.


UNEXPECTED PROPERTIES OF BANDWIDTH CHOICE WHEN SMOOTHING DISCRETE DATA FOR CONSTRUCTING A FUNCTIONAL DATA CLASSIFIER.
The data functions that are studied in the course of functional data analysis are assembled from discrete data, and the level of smoothing that is used is generally that which is appropriate for accurate approximation of the conceptually smooth functions that were not actually observed. Existing literature shows that this approach is effective, and even optimal, when using functional data methods for prediction or hypothesis testing. However, in the present paper we show that this approach is not effective in classification problems. There a useful rule of thumb is that undersmoothing is often desirable, but there are several surprising qualifications to that approach. First, the effect of smoothing the training data can be more significant than that of smoothing the new data set to be classified; second, undersmoothing is not always the right approach, and in fact in some cases using a relatively large bandwidth can be more effective; and third, these perverse results are the consequence of very unusual properties of error rates, expressed as functions of smoothing parameters. For example, the orders of magnitude of optimal smoothing parameter choices depend on the signs and sizes of terms in an expansion of error rate, and those signs and sizes can vary dramatically from one setting to another, even for the same classifier.


Factors influencing men undertaking active surveillance for the management of low-risk prostate cancer.
To identify and describe decision-making influences on men who decide to manage their low-risk prostate cancer with active surveillance. Qualitative, semistructured interview. The Prostate Centre at Vancouver General Hospital in Canada. 25 patients diagnosed with low-risk prostate cancer and on active surveillance. An interpretative, descriptive, qualitative design. Factors that influenced men's decisions to take up active surveillance. The specialists' description of the prostate cancer was the most influential factor on men choosing active surveillance. Patients did not consider their prostate cancer to be life threatening and, in general, were relieved that no treatment was required. Avoiding treatment-related suffering and physical dysfunction and side effects such as impotence and incontinence was cited as the major reason to delay treatment. Few men actively sought treatment or health-promotion information following their treatment decision. Female partners played a supportive role in the decision. The need for active treatment if the cancer progressed was acknowledged. Patients were hopeful that new treatments would be available when and if they needed them. Being older and having comorbidities did not preclude the desire for future active treatment. Patients carried on with their lives as usual and did not report having any major distress related to being on active surveillance. The study findings indicate that men are strongly influenced by the treating specialist in taking up active surveillance and planning future active treatments. As such, most men relied on their specialists' recommendation and did not perceive the need for any adjunct therapy or support until the cancer required active treatment. Oncology nurses should work collaborative-ly with specialists to ensure that men receive the information they need to make informed treatment decisions.


A nonparametric Bayesian approach for clustering bisulfate-based DNA methylation profiles.
DNA methylation occurs in the context of a CpG dinucleotide. It is an important epigenetic modification, which can be inherited through cell division. The two major types of methylation include hypomethylation and hypermethylation. Unique methylation patterns have been shown to exist in diseases including various types of cancer. DNA methylation analysis promises to become a powerful tool in cancer diagnosis, treatment and prognostication. Large-scale methylation arrays are now available for studying methylation genome-wide. The Illumina methylation platform simultaneously measures cytosine methylation at more than 1500 CpG sites associated with over 800 cancer-related genes. Cluster analysis is often used to identify DNA methylation subgroups for prognosis and diagnosis. However, due to the unique non-Gaussian characteristics, traditional clustering methods may not be appropriate for DNA and methylation data, and the determination of optimal cluster number is still problematic. A Dirichlet process beta mixture model (DPBMM) is proposed that models the DNA methylation expressions as an infinite number of beta mixture distribution. The model allows automatic learning of the relevant parameters such as the cluster mixing proportion, the parameters of beta distribution for each cluster, and especially the number of potential clusters. Since the model is high dimensional and analytically intractable, we proposed a Gibbs sampling "no-gaps" solution for computing the posterior distributions, hence the estimates of the parameters. The proposed algorithm was tested on simulated data as well as methylation data from 55 Glioblastoma multiform (GBM) brain tissue samples. To reduce the computational burden due to the high data dimensionality, a dimension reduction method is adopted. The two GBM clusters yielded by DPBMM are based on data of different number of loci (P-value < 0.1), while hierarchical clustering cannot yield statistically significant clusters.


Synaptic transformations underlying highly selective auditory representations of learned birdsong.
Stimulus-specific neuronal responses are a striking characteristic of several sensory systems, although the synaptic mechanisms underlying their generation are not well understood. The songbird nucleus HVC (used here as a proper name) contains projection neurons (PNs) that fire temporally sparse bursts of action potentials to playback of the bird's own song (BOS) but are essentially silent when presented with other acoustical stimuli. To understand how such remarkable stimulus specificity emerges, it is necessary to compare the auditory-evoked responsiveness of the afferents of HVC with synaptic responses in identified HVC neurons. We found that inactivating the interfacial nucleus of the nidopallium (NIf) could eliminate all auditory-evoked subthreshold activity in both HVC PN types, consistent with NIf serving as the major auditory afferent of HVC. Simultaneous multiunit extracellular recordings in NIf and intracellular recordings in HVC revealed that NIf population activity and HVC subthreshold responses were similar in their selectivity for BOS and that NIf spikes preceded depolarizations in all HVC cell types. These results indicate that information about the BOS as well as other auditory stimuli is transmitted synaptically from NIf to HVC. Unlike HVC PNs, however, HVC-projecting NIf neurons fire throughout playback of BOS as well as non-BOS stimuli. Therefore, temporally sparse BOS-evoked firing and enhanced BOS selectivity, manifested as an absence of suprathreshold responsiveness to non-BOS stimuli, emerge in HVC. The transformation to a sparse auditory representation parallels differences in NIf and HVC activity patterns seen during singing, which may point to a common mechanism for encoding sensory and motor representations of song.


Preoperative vascular mapping for facial allotransplantation: four-dimensional computed tomographic angiography versus magnetic resonance angiography.
Facial allotransplantation requires a detailed arterial and venous assessment for surgical planning. Target vessels are often depleted by multiple reconstructive attempts or the severe facial injury itself. The purpose of this study was to retrospectively compare the diagnostic performance of computed tomography and magnetic resonance angiography in the preoperative assessment. Four-dimensional (three spatial planes plus time) computed tomographic and magnetic resonance images including 126 potential vessels (76 arteries and 50 veins) from five candidates were analyzed independently by two radiologists using a four-point image quality scale. Computed tomographic versus magnetic resonance image quality was compared directly, using a computed tomographic angiography consensus read as reference standard. Vessels with metal artifact on magnetic resonance imaging, computed tomography, or both underwent separate analyses to determine the impact of metal implants on image quality. Considering all 126 vessels, the mean computed tomographic image quality was superior to that of magnetic resonance angiography. When considering individual vessels, all except for major neck vessels were better visualized by computed tomography. Images of 26 vessels were degraded by metal artifact; magnetic resonance image quality was inferior for those vessels. Considering images of major vessels with no metal artifact, there was no significant mean image quality difference between computed tomography and magnetic resonance imaging. Computed tomographic angiography should be used as the first-choice modality for preoperative imaging of facial transplant patients because, when compared with magnetic resonance imaging, the visualization of small vessels is far superior and images have fewer artifacts. Diagnostic, II.


The potential role of exhaled breath analysis in the diagnostic process of pneumonia-a systematic review.
Diagnostic strategies currently used for pneumonia are time-consuming, lack accuracy and suffer from large inter-observer variability. Exhaled breath contains thousands of volatile organic compounds (VOCs), which include products of host and pathogen metabolism. In this systematic review we investigated the use of so-called 'breathomics' for diagnosing pneumonia. A Medline search yielded 18 manuscripts reporting on animal and human studies using organic and inorganic molecules in exhaled breath, that all could be used to answer whether analysis of VOC profiles could potentially improve the diagnostic process of pneumonia. Papers were categorised based on their specific aims; the exclusion of pneumonia; the detection of specific respiratory pathogens; and whether targeted or untargeted VOC analysis was used. Ten studies reported on the association between VOCs and presence of pneumonia. Eight studies demonstrated a difference in exhaled VOCs between pneumonia and controls; in the individual studies this discrimination was based on unique sets of VOCs. Eight studies reported on the accuracy of a breath test for a specific respiratory pathogen: five of these concerned pre-clinical studies in animals. All studies were valued as having a high risk of bias, except for one study that used an external validation cohort. The findings in the identified studies are promising. However, as yet no breath test has been shown to have sufficient diagnostic accuracy for pneumonia. We are in need of studies that further translate the knowledge from discovery studies to clinical practice.


Development and Implementation of a Pediatric Palliative Care Program in a Developing Country.
Palliative care is recognized as an important component of care for children with cancer and other life-limiting conditions. In resource limited settings, palliative care is a key component of care for children with cancer and other life-limiting conditions. Globally, 98% of children who need palliative care live in low- or middle-income countries, where there are very few palliative care services available. There is limited evidence describing the practical considerations for the development and implementation of sustainable and cost-effective palliative care services in developing countries. Our aim is to describe the key considerations and initiatives that were successful in planning and implementing a hospital-based pediatric palliative care service specifically designed for a resource-limited setting. Bangabandu Sheikh Mujib Medical University (BSMMU) is a tertiary referral hospital in Bangladesh. Local palliative care services are very limited and focused on adult patients. In partnership with World Child Cancer, a project establishing a pediatric palliative care service was developed for children with cancer at BSMMU. We describe four key elements which were crucial for the success of this program: (1) raising awareness and sensitizing hospital administrators and clinical staff about pediatric palliative care; (2) providing education and training on pediatric palliative care for clinical staff; (3) forming a pediatric palliative care team; and (4) collecting data to characterize the need for pediatric palliative care. This model of a hospital-based pediatric palliative care service can be replicated in other resource-limited settings and can be expanded to include children with other life-limiting conditions. The development of pilot programs can generate interest among local physicians to become trained in pediatric palliative care and can be used to advocate for the palliative care needs of children.


Neonatal encephalopathy following fetal distress. A clinical and electroencephalographic study.
Twenty-one neonates of over 36 weeks' gestation suffered perinatal asphyxia but not chronic hypoxia. Three clinical stages of postanoxic encephalopathy were distinguished. Stage 1 lasted less than 24 hours and was characterized by hyperalertness, uninhibited Moro and stretch reflexes, sympathetic effects, and a normal electroencephalogram. Stage 2 was marked by obtundation, hypotonia, strong distal flexion, and multifocal seizures. The EEG showed a periodic pattern sometimes preceded by continuous delta activity. Infants in stage 3 were stuporous, flaccid, and brain stem and autonomic functions were suppressed. The EEG was isopotential or had infrequent periodic discharges. Infants who did not enter stage 3 and who had signs of stage 2 for less than five days appeared normal in later infancy. Persistence of stage 2 for more than seven days or failure of the EEG to revert to normal was associated with later neurologic impairment or death.


Risk models and scores for type 2 diabetes: systematic review.
To evaluate current risk models and scores for type 2 diabetes and inform selection and implementation of these in practice. Systematic review using standard (quantitative) and realist (mainly qualitative) methodology. Inclusion criteria Papers in any language describing the development or external validation, or both, of models and scores to predict the risk of an adult developing type 2 diabetes. Medline, PreMedline, Embase, and Cochrane databases were searched. Included studies were citation tracked in Google Scholar to identify follow-on studies of usability or impact. Data were extracted on statistical properties of models, details of internal or external validation, and use of risk scores beyond the studies that developed them. Quantitative data were tabulated to compare model components and statistical properties. Qualitative data were analysed thematically to identify mechanisms by which use of the risk model or score might improve patient outcomes. 8864 titles were scanned, 115 full text papers considered, and 43 papers included in the final sample. These described the prospective development or validation, or both, of 145 risk prediction models and scores, 94 of which were studied in detail here. They had been tested on 6.88 million participants followed for up to 28 years. Heterogeneity of primary studies precluded meta-analysis. Some but not all risk models or scores had robust statistical properties (for example, good discrimination and calibration) and had been externally validated on a different population. Genetic markers added nothing to models over clinical and sociodemographic factors. Most authors described their score as "simple" or "easily implemented," although few were specific about the intended users and under what circumstances. Ten mechanisms were identified by which measuring diabetes risk might improve outcomes. Follow-on studies that applied a risk score as part of an intervention aimed at reducing actual risk in people were sparse. Much work has been done to develop diabetes risk models and scores, but most are rarely used because they require tests not routinely available or they were developed without a specific user or clear use in mind. Encouragingly, recent research has begun to tackle usability and the impact of diabetes risk scores. Two promising areas for further research are interventions that prompt lay people to check their own diabetes risk and use of risk scores on population datasets to identify high risk "hotspots" for targeted public health interventions.


Structure and mechanism of a molecular rheostat, an RNA thermometer that modulates immune evasion by Neisseria meningitidis.
Neisseria meningitidis causes bacterial meningitis and septicemia. It evades the host complement system by upregulating expression of immune evasion factors in response to changes in temperature. RNA thermometers within mRNAs control expression of bacterial immune evasion factors, including CssA, in the 5'-untranslated region of the operon for capsule biosynthesis. We dissect the molecular mechanisms of thermoregulation and report the structure of the CssA thermometer. We show that the RNA thermometer acts as a rheostat, whose stability is optimized to respond in a small temperature range around 37°C as occur within the upper airways during infection. Small increases in temperature gradually open up the structure to allow progressively increased access to the ribosome binding site. Even small changes in stability induced by mutations of imperfect base pairs, as in naturally occurring polymorphisms, shift the thermometer response outside of the desired temperature range, suggesting that its activity could be modulated by pharmacological intervention.


Management of Diminutive Colon Polyps Based on Endoluminal Imaging.
Diminutive colon polyps, defined as 5 mm or less, are encountered increasingly at colonoscopy. The risk of serious pathology in such polyps is low. There is a risk and cost of resecting all such polyps and sending tissue for pathologic evaluation. Enhancement of endoluminal imaging may enable discrimination of neoplastic vs non-neoplastic polyps. If this discrimination can be performed accurately with high confidence, it may be possible to either resect and discard diminutive adenomas, or inspect and do-not-resect diminutive hyperplastic polyps. In 2011, an expert group recommended thresholds of 90% negative predictive value for adenomas, and 90% accuracy in predicting appropriate surveillance intervals. Since 2011, criteria for polyp discrimination have been published and validated by experts and nonexperts. In vivo studies have been performed to compare endoscopic impression and pathologic diagnosis. An expert panel was convened in late 2014 to review the literature to determine if the proposed thresholds for discrimination can be attained and to recommend the next steps for introducing changes in clinical practice. We conclude that threshold levels can be achieved with several endoscopic image enhancements. The next steps to implementation of practice change include acquiring data on training and competence, determining best practices for auditing performance, understanding patient education needs, and the potential cost benefit of such changes.


Receptor activator of NF-kappaB and podocytes: towards a function of a novel receptor-ligand pair in the survival response of podocyte injury.
Glomerulosclerosis correlates with reduction in podocyte number that occurs through mechanisms which include apoptosis. Podocyte injury or podocyte loss in the renal glomerulus has been proposed as the crucial mechanism in the development of glomerulosclerosis. However, the mechanism by which podocytes respond to injury is poorly understood. TNF and TNF receptor superfamilies are important in the pathogenesis of podocyte injury and apoptosis. The ligand of receptor activator of NF-kappaB (RANKL) and receptor activator of NF-kappaB (RANK) are members of the TNF and receptor superfamilies. We investigated whether RANK-RANKL is a receptor-ligand complex for podocytes responding to injury. In this study, RANKL and RANK were examined in human podocyte diseases and a rat model of puromycin aminonucleoside nephrosis (PAN). Compared with controls, RANK and RANKL were increased in both human podocyte diseases and the rat PAN model; double immunofluorescence staining revealed that RANK protein expression was mainly attributed to podocytes. Immunoelectron microscopy showed that RANK was localized predominantly at the top of the foot process membrane and the cytoplasm of rat podocyte. In addition, RANK was upregulated in mouse podocytes in vitro after injury induced by puromycin aminonucleoside (PA). Knockdown of RANK expression by small interference RNA (siRNA) exacerbated podocyte apoptosis induced by PA. However, RANKL inhibited significantly the apoptosis of podocytes induced by PA. These findings suggest the increase in RANK-RANKL expression is a response to podocyte injury, and RANK-RANKL may be a novel receptor-ligand complex for the survival response during podocyte injury.


The anti-HIV pentameric pseudopeptide HB-19 binds the C-terminal end of nucleolin and prevents anchorage of virus particles in the plasma membrane of target cells.
The multivalent pseudopeptide HB-19 that binds the cell-surface-expressed nucleolin is a potent inhibitor of human immunodeficiency virus (HIV) infection by blocking virus particle attachment and thus anchorage in the plasma membrane. We show that cross-linking of surface-bound HB-19A (like HB-19 but with a modified template) results in aggregation of HB-19A with surface nucleolin. Consistent with its specific action, HB-19A binding to different types of cells reaches saturation at concentrations that have been reported to result in inhibition of HIV infection. By using Chinese hamster ovary mutant cell lines, we confirm that the binding of HB-19A to surface nucleolin is independent of heparan and chondroitin sulfate proteoglycans. In vitro generated full-length nucleolin was found to bind HB-19A, whereas the N-terminal part containing the acidic amino acid stretches of nucleolin did not. The use of various deletion constructs of the C-terminal part of nucleolin then permitted the identification of the extreme C-terminal end of nucleolin, containing repeats of the amino acid motif, RGG, as the domain that binds HB-19A. Finally, a synthetic peptide corresponding to the last C-terminal 63 amino acids was able to inhibit HIV infection at the stage of HIV attachment to cells, thus suggesting that this domain could be functional in the HIV anchorage process.


UV-Vis-NIR luminescence properties and energy transfer mechanism of LiSrPO4:Eu2+, Pr3+ suitable for solar spectral convertor.
An efficient near-infrared (NIR) phosphor LiSrPO(4):Eu(2+), Pr(3+) is synthesized by solid-state reaction and systematically investigated using x-ray diffraction, diffuse reflection spectrum, photoluminescence spectra at room temperature and 3 K, and the decay curves. The UV-Vis-NIR energy transfer mechanism is proposed based on these results. The results demonstrate Eu(2+) can be an efficient sensitizer for harvesting UV photon and greatly enhancing the NIR emission of Pr(3+) between 960 and 1060 nm through efficient energy feeding by allowed 4f-5d absorption of Eu(2+) with high oscillator strength. Eu(2+)/Pr(3+) may be an efficient donor-acceptor pair as solar spectral converter for Si solar cells.


Extrathymic origin of intestinal intraepithelial lymphocytes bearing T-cell antigen receptor gamma delta.
The kinetics of postnatal intestinal colonization by T cells carrying gamma delta and alpha beta T-cell antigen receptors were studied in nude and normal mice by flow cytometry and immunohistology. Furthermore, gamma delta and alpha beta T-cell development was analyzed in lethally irradiated mice that were reconstituted by fetal liver precursors with or without a thymus. Our results establish that a major subpopulation of gamma delta intestinal intraepithelial lymphocytes is produced from uncommitted precursors at extrathymic sites. This work further shows that a small pool of T cells carrying alpha beta T-cell receptors can also differentiate extrathymically from CD3- fetal liver precursors but with rates of production and peripheral expansion much reduced as compared with those observed in thymus-bearing animals.


QALYs, standard gambles, and the expected budget constraint.
This paper shows that when quality adjustment factors for use in constructing QALY indices are established through answers to standard-gamble questions or similar methods, the assumptions that are made by respondents about the financial consequences of changing probabilities of illness and death are critically important for the use of QALYs in cost-utility analysis (CUA). It qualifies Meltzer's [Journal of Health Economics 16 (1997) 33] result that the cost per quality-adjusted life-year (QALY) for life-saving medical interventions should include the future consumption of those who would otherwise not have survived, by showing that its validity depends on how the QALY index has been established. The paper also shows that, contrary to a widely held notion, allocation of a fixed health care budget through CUA does not generally result in a second-best efficient allocation. Another finding is that failure to specify carefully what respondents to standard-gamble questions are supposed to assume about the financial consequences of ill health may result in a bias against providing care to older individuals.


Development of Plasmodium vivax in Anopheles superpictus under experimental conditions.
The susceptibility of Anopheles superpictus for Plasmodium vivax was described quantitatively under laboratory conditions. Of the 697 laboratory females studied in 16 groups, 513 (73.5%) females took a bloodmeal, of which 88.4% developed ookinetes on day 1, 56.1% oocysts between days 3 and 11, and 52.5% sporozoites in the salivary gland on days 15 to 63 post-infection. Sporogony was completed in 10-11 days post-infection. There was no difference in the longevity of uninfected and infected females. Infected females survived an average of 30 days (maximum 63 days). Sporozoites survived up to 50 days in the salivary glands without any observable changes in structure and motility. These data indicate that An. superpictus is an efficient laboratory vector of P. vivax and should not be ignored in future entomological field studies.


Beyond information retrieval and electronic health record use: competencies in clinical informatics for medical education.
Physicians in the 21st century will increasingly interact in diverse ways with information systems, requiring competence in many aspects of clinical informatics. In recent years, many medical school curricula have added content in information retrieval (search) and basic use of the electronic health record. However, this omits the growing number of other ways that physicians are interacting with information that includes activities such as clinical decision support, quality measurement and improvement, personal health records, telemedicine, and personalized medicine. We describe a process whereby six faculty members representing different perspectives came together to define competencies in clinical informatics for a curriculum transformation process occurring at Oregon Health & Science University. From the broad competencies, we also developed specific learning objectives and milestones, an implementation schedule, and mapping to general competency domains. We present our work to encourage debate and refinement as well as facilitate evaluation in this area.


HIV-Associated Cryptococcal Immune Reconstitution Inflammatory Syndrome Is Associated with Aberrant T Cell Function and Increased Cytokine Responses.
Cryptococcal meningitis remains a significant opportunistic infection among HIV-infected patients, contributing 15-20% of HIV-related mortality. A complication of initiating antiretroviral therapy (ART) following opportunistic infection is immune reconstitution inflammatory syndrome (IRIS). IRIS afflicts 10-30% of HIV-infected patients with cryptococcal meningitis (CM), but its immunopathogenesis is poorly understood. We compared circulating T cell memory subsets and cytokine responses among 17 HIV-infected Ugandans with CM: 11 with and 6 without CM-IRIS. At meningitis diagnosis, stimulation with cryptococcal capsule component, glucuronoxylomannan (GXM) elicited consistently lower frequencies of CD4+ and CD8+ T cell memory subsets expressing intracellular cytokines (IL-2, IFN-γ, and IL-17) among subjects who subsequently developed CM-IRIS. After ART initiation, T cells evolved to show a decreased CD8+ central memory phenotype. At the onset of CM-IRIS, stimulation more frequently generated polyfunctional IL-2+/IL-17+ CD4+ T cells in patients with CM-IRIS. Moreover, CD8+ central and effector memory T cells from CM-IRIS subjects also demonstrated more robust IL-2 responses to antigenic stimulation vs. controls. Thus, ART during CM elicits distinct differences in T cell cytokine production in response to cryptococcal antigens both prior to and during the development of IRIS, suggesting an immunologic foundation for the development of this morbid complication of CM infection.


International collaborative study of cardiovascular disease in Asia: design, rationale, and preliminary results.
The overall objective of the International Collaborative Study of Cardiovascular Disease in Asia (InterASIA) was to estimate the prevalence and distribution of cardiovascular disease risk factors, including hypertension, hypercholesterolemia, diabetes, obesity, cigarette smoking, and physical inactivity, in the general population of both China and Thailand. A multistage cluster sampling method was used to select a nationally representative sample of 15,838 adults, aged 35-74 years, in China, and 5,350 similarly aged adults in Thailand. Data on medical history, cigarette smoking, alcohol consumption, diet, physical activity, and awareness and control of risk factors for cardiovascular disease, were collected. Blood pressure, body weight and height, and hip and waist circumferences, were measured using standard methods. Fasting blood specimens were collected to measure levels of total cholesterol, high-density lipoprotein cholesterol, triglycerides, glucose, and creatinine. All data were carefully collected by specially trained, experienced observers using standardized methods and a stringent level of quality control. The prevalence of self-reported cardiovascular disease in Chinese adults aged 35-74 years was 3.3% in men and 3.6% in women (representing 8,147,000 male and 8,270,000 female cases nationally). The prevalence of self-reported cardiovascular disease in Thai adults was 1.5% in men and 1.7% in women (representing 184,000 male and 226,000 female cases). The InterASIA study provides important information on the current prevalence and control of both cardiovascular disease and its risk factors in the region. These findings will be useful for developing national strategies to reduce the large, and increasing, burden of cardiovascular disease in China and Thailand.


Low Genetic Diversity in Diplomystes camposensis, an Endemic and Endangered Catfish from South Chile.
Carlos P. Muñoz-Ramírez, Evelyn Habit, Peter J. Unmack, Jerald B. Johnson, and Pedro F. Victoriano (2016) Despite the fundamental importance of the family Diplomystidae for understanding catfish evolution, its species are poorly known and most of them endangered. Diplomystes camposensis, restricted to a single river basin in southern Chile, is perhaps the most vulnerable species due to its small geographic range and imminent habitat alterations by dam constructions. Using mitochondrial DNA sequences, we describe the genetic diversity across its entire distribution in the Valdivia basin and test hypotheses related to the impact of glacial cycles on the genetic diversity and structure. We found that Diplomystes camposensis has low genetic diversity and structure across the entire Valdivia basin along with a pattern of decreasing nucleotide and haplotype diversity from West to East. Demographic analyses showed evidence of population expansion in agreement with the glaciated history of the basin. Analyses of population structure showed no evidence of population subdivision. However, coalescent analyses indicated that very recent subdivision (in the last 50 years) cannot be ruled out. Low genetic diversity and genetic structure across the entire basin suggest that the species might be highly vulnerable to habitat fragmentation. Thus, the imminent construction of hydropower dams represents a serious threat to its conservation. Our results suggest that the low genetic diversity can be the product of the glaciated history of the basin, although the influence of species-specific biological traits may also add to this condition. Despite the overall low genetic diversity, higher diversity was found in the central portion of the basin suggesting high priority of conservation for this area as it might be used as a source population in case translocations are required among potential management plans.


Dietary fish oil supplementation affects serum fatty acid concentrations in horses.
Thirteen horses of Thoroughbred or Standardbred breeding were used to study the effect of dietary fish oil supplementation on blood lipid characteristics. Horses were assigned to either fish oil (n = 7) or corn oil (n = 6) treatment groups for 63 d. The fish oil contained 10.8% eicosapentaenoic acid (EPA) and 8% docosahexaenoic acid (DHA). Each horse received timothy hay and a mixed-grain concentrate at rates necessary to maintain BW. Oil (corn or fish) was top-dressed on the concentrate daily at a rate of 324 mg/ kg of BW. The n-6:n-3 ratio was approximately 3.6:1 for horses receiving the corn oil diet and 1.4:1 for horses receiving the fish oil diet. Horses were exercised 5 d/wk during the study. Before supplementation, there was no difference in the concentrations of any serum fatty acids between the 2 treatment groups. The mean basal concentrations of EPA and DHA on d 0 were 0.04 and 0.01 mg/mL, respectively. After 63 d, horses receiving the fish oil treatment, but not those receiving the corn oil treatment, had increased concentrations of EPA and DHA (P <0.05). Fish oil supplementation for 63 d also increased the concentrations of C22:0, C22:1, and C22:5 fatty acids (P <0.05). Overall, horses receiving fish oil had a decreased concentration of n-6 fatty acids (P <0.05) and a greater concentration of n-3 fatty acids (P <0.01), resulting in a lower n-6:n-3 fatty acid ratio after 63 d (P <0.05). Serum cholesterol concentrations increased (P <0.05) during the supplementation period in horses receiving the corn oil but not in horses receiving the fish oil. Compared with horses receiving corn oil, horses receiving fish oil had lower serum triglycerides at d 63 (P <0.05). These results demonstrate that 63 d of fish oil supplementation at 324 mg/kg of BW was sufficient to alter the fatty acid profile and blood lipid properties of horses receiving regular exercise.


Thermal stability of dialkylimidazolium tetrafluoroborate and hexafluorophosphate ionic liquids: ex situ bulk heating to complement in situ mass spectrometry.
Thermal decomposition (TD) products of the ionic liquids (ILs) [CnC1Im][BF4] and [CnC1Im][PF6] ([CnC1Im]+ = 1-alkyl-3-methylimidazolium, [BF4]- = tetrafluoroborate, and [PF6]- = hexafluorophosphate) were prepared, ex situ, by bulk heating experiments in a bespoke setup. The respective products, CnC1(C3N2H2)BF3 and CnC1(C3N2H2)PF5 (1-alkyl-3-methylimidazolium-2-trifluoroborate and 1-alkyl-3-methylimidazolium-2-pentafluorophosphate), were then vaporized and analyzed by direct insertion mass spectrometry (DIMS) in order to identify their characteristic MS signals. During IL DIMS experiments we were subsequently able, in situ, to identify and monitor signals due to both IL vaporization and IL thermal decomposition. These decomposition products have not been observed in situ during previous analytical vaporization studies of similar ILs. The ex situ preparation of TD products is therefore perfectly complimentary to in situ thermal stability measurements. Experimental parameters such as sample surface area to volume ratios are consequently very important for ILs that show competitive vaporization and thermal decomposition. We have explained these experimental factors in terms of Langmuir evaporation and Knudsen effusion-like conditions, allowing us to draw together observations from previous studies to make sense of the literature on IL thermal stability. Hence, the design of experimental setups are crucial and previously overlooked experimental factors.


Predictive Value of Upper Limb Muscles and Grasp Patterns on Functional Outcome in Cervical Spinal Cord Injury.
To determine which single or combined upper limb muscles as defined by the International Standards for the Neurological Classification of Spinal Cord Injury (ISNCSCI); upper extremity motor score (UEMS) and the Graded Redefined Assessment of Strength, Sensibility, and Prehension (GRASSP), best predict upper limb function and independence in activities of daily living (ADLs) and to assess the predictive value of qualitative grasp movements (QlG) on upper limb function in individuals with acute tetraplegia. As part of a Europe-wide, prospective, longitudinal, multicenter study ISNCSCI, GRASSP, and Spinal Cord Independence Measure (SCIM III) scores were recorded at 1 and 6 months after SCI. For prediction of upper limb function and ADLs, a logistic regression model and unbiased recursive partitioning conditional inference tree (URP-CTREE) were used. Results: Logistic regression and URP-CTREE revealed that a combination of ISNCSCI and GRASSP muscles (to a maximum of 4) demonstrated the best prediction (specificity and sensitivity ranged from 81.8% to 96.0%) of upper limb function and identified homogenous outcome cohorts at 6 months. The URP-CTREE model with the QlG predictors for upper limb function showed similar results. Prediction of upper limb function can be achieved through a combination of defined, specific upper limb muscles assessed in the ISNCSCI and GRASSP. A combination of a limited number of proximal and distal muscles along with an assessment of grasping movements can be applied for clinical decision making for rehabilitation interventions and clinical trials.


Using optical coherence tomography to improve diagnostic and therapeutic bronchoscopy.
Flexible bronchoscopy is a common procedure that is used in both diagnostic and therapeutic settings but does not readily permit measurement of central airway dimensions. Anatomic optical coherence tomography (a OCT), a modification of conventional optical coherence tomography (OCT), is a novel light-based imaging tool with the capacity to measure the diameter and lumen area of the central airways accurately during bronchoscopy. This study describes the first clinical use of aOCT imaging in the lower airways in three individuals with common endobronchial pathologies. During bronchoscopy, a specialized fiberoptic probe was passed through the biopsy channel of a standard flexible bronchoscope to the site of airway pathology. Airway dimensions were measured from the generated cross-sectional images in three subjects, one with subglottic tracheal stenosis (subject 1), one with malignant left main bronchus (LMB) obstruction (subject 2), and another with severe tracheomalacia (subject 3). Measured dimensions included internal airway diameter, cross-sectional area, and, in subject 1, stenosis length. Tracheal stenosis dimensions, measured using aOCT imaging, correlated with chest CT scan findings and guided the choice of airway stent (subject 1). The airway beyond a malignant obstruction of the LMB, and beyond bronchoscopic view, could be imaged using aOCT, and the distal extent of obstructing tumor identified (subject 2). The severity of newly diagnosed tracheomalacia was able to be quantified using aOCT imaging (subject 3). aOCT imaging during bronchoscopy allows accurate real-time airway measurements and may assist bronchoscopic assessment.


Unique demands of the femoral anatomy and pathology and the need for unique interventions.
With the aging of the population the incidence of peripheral artery disease (PAD) is increasing, which is histologically characterized by fibrocalcific intimal plaques as well as underlying Mönckeberg's medial calcinosis as compared to coronary and carotid artery disease. Superficial femoral artery (SFA) is one of the longest and most dynamically active vessels in the body undergoing torsion, compression, flexion, and extension from leg motion, and is known to be more susceptible to atherosclerosis because of low shear stress or spiral flow, best appreciated in the long segment in its lesser curvature. Endovascular interventions are now considered the first-line strategy for the treatment of PAD patients presenting with claudication or critical limb ischemia, where physiologic stresses on the arterial wall, anatomic considerations, and lesion characteristics impact on their success. Stent fracture and malapposition, are a common phenomenon in PAD which are attributed to severe calcification and fibrosis along with greater motion of the lower extremity, that result in the dampening of the efficacy of stenting and balloon angioplasty. Better designs of self-expanding stents have resulted in either reduction in stent fracture rates or its elimination at least in the short-term follow-up studies, to date. Although drug-eluting stents (DES) have reduced restenosis rates in the coronary circulation, this benefit has not been consistently observed in PAD. However, recent clinical studies utilizing novel Zilver-PTX self-expanding stent (DES) have demonstrated favorable patency rate. Also, in patients with critical limb ischemia, better outcomes have been reported for below-the-knee utilization of DES. Nevertheless, drawbacks of stent technology remain and interests in the greater use of drug-coated balloons (DCB) for PAD have emerged. Randomized controlled trials have consistently shown superiority of DCB over uncoated balloons in reducing neointimal formation in patients with SFA disease. Moreover, there is a growing interest in atherectomy as an alternative treatment strategy for PAD, thus decreasing plaque burden with possibly avoidance of barotrauma. The results from registries support the effectiveness of the atherectomy devices; however, prospective randomized controlled trials are needed to confirm their benefit.


Recipes for the linear analysis of EEG.
In this paper, we describe a simple set of "recipes" for the analysis of high spatial density EEG. We focus on a linear integration of multiple channels for extracting individual components without making any spatial or anatomical modeling assumptions, instead requiring particular statistical properties such as maximum difference, maximum power, or statistical independence. We demonstrate how corresponding algorithms, for example, linear discriminant analysis, principal component analysis and independent component analysis, can be used to remove eye-motion artifacts, extract strong evoked responses, and decompose temporally overlapping components. The general approach is shown to be consistent with the underlying physics of EEG, which specifies a linear mixing model of the underlying neural and non-neural current sources.


GC-rich sequences in the 5-lipoxygenase gene promoter are required for expression in Mono Mac 6 cells, characterization of a novel Sp1 binding site.
5-lipoxygenase (5LO) catalyzes formation of leukotrienes, mediators with roles in several inflammatory disorders, including atherosclerosis. The human 5LO gene promoter contain multiple GC-boxes. The relevance of these for expression of 5LO in the human monocytic cell line Mono Mac 6 (MM6) was studied. A downregulating effect of the GC-box binding compound mithramycin indicated that GC-rich sequences in the 5LO gene promoter are important for expression of native 5LO. In DNase I footprinting, mithramycin and Sp1 protected known GC-boxes, but also a novel Sp1 binding site was found, comprising 20 bp upstream of the major transcription initiation site, beside an Initiator-like sequence. Mutation of this site reduced Sp1 binding and expression of reporter genes in MM6 cells, compatible with a function as basal promoter element for the TATA-less 5LO gene. When differentiation was induced by TGFbeta and vitamin D(3), 5LO expression became prominent, but expression levels of Sp1/3 and Egr-1 were the same as for control cells. Also, 5LO reporter gene activity in transiently transfected MM6 cells was insensitive to differentiation. Thus, the GC-rich part of the 5LO gene promoter, including a novel Sp1 site, appear important for basal (rather than upregulated) transcription of 5LO in MM6 cells.


Imaging chemical exchange saturation transfer (CEST) effects following tumor-selective acidification using lonidamine.
Increased lactate production through glycolysis in aerobic conditions is a hallmark of cancer. Some anticancer drugs have been designed to exploit elevated glycolysis in cancer cells. For example, lonidamine (LND) inhibits lactate transport, leading to intracellular acidification in cancer cells. Chemical exchange saturation transfer (CEST) is a novel MRI contrast mechanism that is dependent on intracellular pH. Amine and amide concentration-independent detection (AACID) and apparent amide proton transfer (APT*) represent two recently developed CEST contrast parameters that are sensitive to pH. The goal of this study was to compare the sensitivity of AACID and APT* for the detection of tumor-selective acidification after LND injection. Using a 9.4-T MRI scanner, CEST data were acquired in mice approximately 14 days after the implantation of 10(5) U87 human glioblastoma multiforme (GBM) cells in the brain, before and after the administration of LND (dose, 50 or 100 mg/kg). Significant dose-dependent LND-induced changes in the measured CEST parameters were detected in brain regions spatially correlated with implanted tumors. Importantly, no changes were observed in T1- and T2-weighted images acquired before and after LND treatment. The AACID and APT* contrast measured before and after LND injection exhibited similar pH sensitivity. Interestingly, LND-induced contrast maps showed increased heterogeneity compared with pre-injection CEST maps. These results demonstrate that CEST contrast changes after the administration of LND could help to localize brain cancer and monitor tumor response to chemotherapy within 1 h of treatment. The LND CEST experiment uses an anticancer drug to induce a metabolic change detectable by endogenous MRI contrast, and therefore represents a unique cancer detection paradigm which differs from other current molecular imaging techniques that require the injection of an imaging contrast agent or tracer.


Axis I and axis II disorders as predictors of prospective suicide attempts: findings from the collaborative longitudinal personality disorders study.
This study examined diagnostic predictors of prospectively observed suicide attempts in a personality disorder (PD) sample. During 2 years of follow-up, 58 participants (9%) reported at least 1 definitive suicide attempt. Predictors that were examined include 4 PD diagnoses and selected Axis I diagnoses (baseline and course). Multivariate logistic regression analyses indicated that baseline borderline personality disorder (BPD) and drug use disorders significantly predicted prospective suicide attempts. Controlling for baseline BPD diagnosis, proportional hazards analyses showed that worsening in the course of major depressive disorder (MDD) and of substance use disorders in the month preceding the attempt were also significant predictors. Therefore, among individuals diagnosed with PDs. exacerbation of Axis I conditions, particularly MDD and substance use, heightens risk for a suicide attempt.


Unsupervised GRN Ensemble.
Inferring gene regulatory networks from expression data is a very challenging problem that has raised the interest of the scientific community. Different algorithms have been proposed to try to solve this issue, but it has been shown that different methods have some particular biases and strengths, and none of them is the best across all types of data and datasets. As a result, the idea of aggregating various network inferences through a consensus mechanism naturally arises. In this chapter, a common framework to standardize already proposed consensus methods is presented, and based on this framework different proposals are introduced and analyzed in two different scenarios: Homogeneous and Heterogeneous. The first scenario reflects situations where the networks to be aggregated are rather similar because they are obtained with inference algorithms working on the same data, whereas the second scenario deals with very diverse networks because various sources of data are used to generate the individual networks. A procedure for combining multiple network inference algorithms is analyzed in a systematic way. The results show that there is a very significant difference between these two scenarios, and that the best way to combine networks in the Heterogeneous scenario is not the most commonly used. We show in particular that aggregation in the Heterogeneous scenario can be very beneficial if the individual networks are combined with our new proposed method ScaleLSum.


Hepatitis C. Recent advances in understanding and management.
Chronic hepatitis C is a major health issue, affecting up to 1.4% of the US population. A high proportion of hepatitis C virus (HCV) infections are chronic. Significant liver disease (chronic hepatitis that is moderate to severe, fibrosis, or cirrhosis) develops in up to 50% of patients chronically infected with HCV. Progression of the disease is unpredictable but is typically slow and evolves over decades. Viral genotype, level of viremia, severity of liver disease, and hepatic iron content influence the response of chronic hepatitis C to therapy. Standard therapy is with interferon alfa-2b (Intron A), 3 million U given subcutaneously three times a week for 6 months. Forty percent of patients have an initial response to interferon therapy, but only half (or fewer) of these patients maintain a long-term sustained response. New treatment strategies are currently being evaluated; however, none, as yet, has emerged as a significant improvement over standard interferon therapy.


Sexual function in women with Cushing's Syndrome: A controlled study.
The aim of this study is to determine the severity of female sexual dysfunction (FSD), quality of life, and depression status in female patients with Cushing's syndrome (CS). This study included 29 sexually active women with CS and 30 healthy age and body mass index matched women. The Female Sexual Function Index (FSFI) questionnaire, Beck Depression Inventory (BDI) and Short Form Health Survey (SF-36) were filled by each participant. Plasma levels of FSH, LH, PRL, cortisol, DHEA-S, 17-hydroxyprogesterone, androstenedione, free testosterone, total testosterone and estradiol were measured. Female sexual dysfunction was present in 88.9% of the women with CS and 24.1% of the control group. The CS group showed a lower total FSFI score [16.6 (IQR: 5-23)] compared to the healthy women [26.8 (IQR: 25.5-30.4) (p<0.001)]. The FSFI scores in the arousal, lubrication, orgasm, pain and satisfaction domains were all lower in the women with CS (p<0.001). Both summary scores of the SF-36 were reduced in women with Cushing's syndrome compared to the control group (p=0.001). The BDI scores of patients were significantly higher than those of the control subjects (p=0.007). In patients with CS, levels of LH, estradiol, and DHEA-S04 were significantly lower while cortisol (p<0.05), and 17 hydroxyprogestrone levels were higher than control subjects (p<0.05). This study showed that majority of the women with CS had FSD. This may be related to the inhibitory effect of cortisol on sex hormones.


Statistical models for the control phase of clinical monitoring.
The rise in the prevalence of chronic conditions means that these are now the leading causes of death and disability worldwide, accounting for almost 60% of all deaths and 43% of the global burden of disease. Management of chronic conditions requires both effective treatment and ongoing monitoring. Although costs related to monitoring are substantial, there is relatively little evidence on its effectiveness. Monitoring is inherently different to diagnosis in its use of regularly repeated tests, and increasing frequency can result in poorer rather than better statistical properties because of multiple testing in the presence of high variability. We present here a general framework for modelling the control phase of a monitoring programme, and for the estimation of quantities of potential clinical interest such as the ratio of false to true positive tests. We show how four recent clinical studies of monitoring cardiovascular disease, hypertension, diabetes and HIV infection can be thought as special cases of this framework; as well as using this framework to clarify the choice of estimation and calculation methods available. Noticeably, in each of the presented examples over-frequent monitoring appears to be a greater problem than under-frequent monitoring. We also present recalculations of results under alternative conditions, illustrating conceptual decisions about modelling the true or observed value of a clinical measure.


Emotional reactivity to a single inhalation of 35% carbon dioxide and its association with later symptoms of posttraumatic stress disorder and anxiety in soldiers deployed to Iraq.
The identification of modifiable predeployment vulnerability factors that increase the risk of combat stress reactions among soldiers once deployed to a war zone offers significant potential for the prevention of posttraumatic stress disorder (PTSD) and other combat-related stress disorders. Adults with anxiety disorders display heightened emotional reactivity to a single inhalation of 35% carbon dioxide (CO(2)); however, data investigating prospective linkages between emotional reactivity to CO(2) and susceptibility to war-zone stress reactions are lacking. To investigate the association of soldiers' predeployment emotional reactivity to 35% CO(2) challenge with several indices of subsequent war-zone stress symptoms assessed monthly while deployed in Iraq. Prospective cohort study of 158 soldiers with no history of deployment to a war zone were recruited from the Texas Combat Stress Risk Study between April 2, 2007, and August 28, 2009. Multilevel regression models were used to investigate the association between emotional reactivity to 35% CO(2) challenge (assessed before deployment) and soldiers' reported symptoms of general anxiety/stress, PTSD, and depression while deployed to Iraq. Growth curves of PTSD, depression, and general anxiety/stress symptoms showed a significant curvilinear relationship during the 16-month deployment period. War-zone stressors reported in theater were associated with symptoms of general anxiety/stress, PTSD, and depression. Consistent with the prediction, soldiers' emotional reactivity to a single inhalation of 35% CO(2)-enriched air before deployment significantly potentiated the effects of war-zone stressors on the subsequent development of PTSD symptoms and general anxiety/stress symptoms but not on the development of depression, even after accounting for the effects of trait anxiety and the presence of past or current Axis I mental disorders. Soldiers' emotional reactivity to a 35% CO(2) challenge may serve as a vulnerability factor for increasing soldiers' risk for PTSD and general anxiety/stress symptoms in response to war-zone stressors.


Changes in thyroid status during perinatal development of MCT8-deficient male mice.
Patients with the monocarboxylate transporter 8 (MCT8) deficiency syndrome present with a severe psychomotor retardation and abnormal serum thyroid hormone (TH) levels, consisting of high T(3) and low T(4) and rT(3). Mice deficient in Mct8 replicate the thyroid phenotype of patients with the MCT8 gene mutations. We analyzed the serum TH levels and action in the cerebral cortex and in the liver during the perinatal period of mice deficient in Mct8 to assess how the thyroid abnormalities of Mct8 deficiency develop and to study the thyroidal status of specific tissues. During perinatal life, the thyroid phenotype of Mct8-deficient mice is different from that of adult mice. They manifest hyperthyroxinemia at embryonic day 18 and postnatal day 0. This perinatal hyperthyroxinemia is accompanied by manifestations of TH excess as evidenced by a relative increase in the expression of genes positively regulated by T3 in both the cerebral cortex and liver. An increased tissue accumulation of T(4) and T(3) and the expression of TH alternative transporters, including Lat1, Lat2, Oatp1c1, and Oatp3a1 in the cortex and Lat2 and Oatp1b2 in the liver, suggested that Mct8 deficiency either directly interferes with tissue efflux of TH or indirectly activates other transporters to increase TH uptake. This report is the first to identify that the ontogenesis of TH abnormalities in Mct8-deficient mice manifests with TH excess in the perinatal period.


SAPHO Syndrome Diagnosis and Treatment: Report of Five Cases and Review of the Literature.
The term "SAPHO (Synovitis, Acne, Pustulosis, Hyperostosis and Osteitis) syndrome" includes a variety of musculoskeletal disorders associated with skin conditions; Osteitis is the most prominent skeletal lesion, whereas palmoplantar pustulosis and acne are the main skin lesions. Diagnosing SAPHO syndrome is difficult, because this syndrome is often confused with suppurative osteomyelitis, which has similar clinical and pathologic findings. SAPHO diagnosis is even more difficult when atypical sites are involved and there are no skin lesions. This case series presents five patients (3 women, 2 men), ages 27 to 44 years, who came to the Orthopaedic Department outpatient clinic for evaluation of pain in the humerus, clavicle, sacroiliac joints, and/or distal radius, and were diagnosed with SAPHO syndrome. Clinical and radiologic findings, treatment and outcome data, with up to 4 years of follow-up are presented. An extensive discussion of the clinical presentation, published literature, treatment options and outcome of SAPHO syndrome is also included. Once the diagnosis of SAPHO syndrome was established, treatment with antibiotics (clindamycin) and non steroid anti-inflammatory drugs (lornoxicam) was remarkably effective. All patients did well and remained symptom free for up to four years, after a 3-8 month course of treatment. SAPHO syndrome should be included in the differential diagnosis when evaluating patients with lytic, sclerotic, or hyperostotic bone lesions and pain. Prompt SAPHO syndrome recognition, followed by appropriate therapy with antibiotics and NSAIDs can produce rapid symptom resolution, while avoiding unnecessary procedures and longterm antibiotic therapy.


Compositions and structures of niobium oxide cluster ions, NbmOn±, (m = 2-12), revealed by ion mobility mass spectrometry.
Herein, the compositions and geometrical structures of niobium oxide cluster ions were studied and compared with those of the lighter Group 5 counterpart vanadium oxide cluster ions by ion-mobility mass spectrometry (IM-MS). As a result of collision-induced dissociation in IM-MS, the compositions were found to be dependent on an odd and even number of niobium atoms, whereby the ions with (NbO2)(Nb2O5)(m-1)/2+ and (NbO3)(Nb2O5)(m-1)/2- were identified as stable compositions for an odd number of Nb atoms, whereas (Nb2O5)m/2± and (Nb2O6)(Nb2O5)(m-2)/2- were identified as stable compositions for an even number of Nb atom clusters. Furthermore, structural transitions were observed between m = 8 and 9 for cluster cations and m = 7 and 8 for cluster anions for experimental collision cross-sections (CCSs), which were determined from the arrival times in the ion-mobility measurements. Quantum chemical calculations were conducted on several structural candidates of these compositions for m = 2-12. For cluster cations with the sizes between m = 2 and 8 and cluster anions with m = 2-7, the structures were found to be similar to those of vanadium oxide cluster ions upon comparing the experimental CCSs with the theoretical CCSs of optimized structures. As compared to the vanadium oxide cluster ions, niobium oxide cluster cations with m ≥ 9 and anions with m ≥ 8 consisted of structures where some niobium atoms had more than five oxygen-atom coordination; thus, compact structures could be achieved in the case of niobium oxide cluster ions.


Examining the Use of a Visual Analytics System for Sensemaking Tasks: Case Studies with Domain Experts.
While the formal evaluation of systems in visual analytics is still relatively uncommon, particularly rare are case studies of prolonged system use by domain analysts working with their own data. Conducting case studies can be challenging, but it can be a particularly effective way to examine whether visual analytics systems are truly helping expert users to accomplish their goals. We studied the use of a visual analytics system for sensemaking tasks on documents by six analysts from a variety of domains. We describe their application of the system along with the benefits, issues, and problems that we uncovered. Findings from the studies identify features that visual analytics systems should emphasize as well as missing capabilities that should be addressed. These findings inform design implications for future systems.


Parental body mass index and its association with body composition, physical fitness and lifestyle factors in their 4-year-old children: results from the MINISTOP trial.
To examine the association between parental body mass index (BMI) and their offspring's body composition, physical fitness and lifestyle factors (that is, sedentary time, physical activity and diet). A total of 307 preschoolers (4.5±0.1 years) and their parents (fathers: 38.1±5.1 years and mothers: 35.6±4.2 years) participated in this study. Parental BMI was calculated using self-reported weight and height. Preschoolers body composition was assessed using: BMI, fat mass percentage, fat mass index, fat-free mass index (measured via air-displacement plethysmography) and waist circumference. Physical fitness was assessed by the PREFIT fitness battery. Lifestyle factors were assessed using the ActiGraph wGT3x-BT (sedentary time and physical activity), and the mobile-phone based tool for energy balance in children (diet). Parental BMI were positively associated with their offspring's BMI (paternal BMI: standardised beta, β=0.233, P<0.001; maternal BMI: β=0.186, P=0.001), fat mass index (paternal BMI: β=0.130, P=0.026; maternal BMI: β=0.163, P=0.005), fat-free mass index (paternal BMI: β=0.214, P<0.001; maternal BMI: β=0.119, P=0.036) and waist circumference (paternal BMI: β=0.178, P=0.001; maternal BMI: β=0.179, P=0.001). A negative association was found between maternal BMI and their offspring's standing long jump test (β=-0.132, P=0.022). Paternal BMI was associated with their offspring's sedentary time (β=0.100, P=0.026), whereas parental BMI was not associated with neither physical activity nor diet (all P⩾0.104). Parental BMI was positively associated with their offspring's BMI, fat as well as fat-free mass index and waist circumference. Moreover, a higher paternal and maternal BMI were related to higher levels of sedentary time and a lower performance in the standing long jump test of their offspring, respectively.


EAN/ERS/ESO/ESRS statement on the impact of sleep disorders on risk and outcome of stroke.
Sleep disorders are highly prevalent in the general population and may be linked in a bidirectional fashion to stroke, which is one of the leading causes of morbidity and mortality.Four major scientific societies established a task force of experts in neurology, stroke, respiratory medicine, sleep medicine and methodology, to critically evaluate the evidence regarding potential links and the impact of therapy. 13 research questions were evaluated in a systematic literature search using a stepwise hierarchical approach: first, systematic reviews and meta-analyses; second, primary studies post-dating the systematic reviews/meta-analyses. A total of 445 studies were evaluated and 88 included. Statements were generated regarding current evidence and clinical practice.Severe obstructive sleep apnoea (OSA) doubles the risk for incident stroke, especially in young to middle-aged patients. Continuous positive airway pressure (CPAP) may reduce stroke risk, especially in treatment-compliant patients. The prevalence of OSA is high in stroke patients and can be assessed by polygraphy. Severe OSA is a risk factor for recurrence of stroke and may be associated with stroke mortality, while CPAP may improve stroke outcome. It is not clear if insomnia increases stroke risk, while pharmacotherapy of insomnia may increase it. Periodic limb movements in sleep (PLMS), but not restless limb syndrome (RLS), may be associated with an increased risk of stroke. Preliminary data suggest a high frequency of post-stroke insomnia and RLS and their association with a less favourable stroke outcome, while treatment data are scarce.Overall, the evidence base is best for OSA relationship with stroke and supports active diagnosis and therapy. Research gaps remain especially regarding insomnia and RLS/PLMS relationships with stroke.


Phenome-wide association study (PheWAS) of colorectal cancer risk SNP effects on health outcomes in UK Biobank.
Associations between colorectal cancer (CRC) and other health outcomes have been reported, but these may be subject to biases, or due to limitations of observational studies. We set out to determine whether genetic predisposition to CRC is also associated with the risk of other phenotypes. Under the phenome-wide association study (PheWAS) and tree-structured phenotypic model (TreeWAS), we studied 334,385 unrelated White British individuals (excluding CRC patients) from the UK Biobank cohort. We generated a polygenic risk score (PRS) from CRC genome-wide association studies as a measure of CRC risk. We performed sensitivity analyses to test the robustness of the results and searched the Danish Disease Trajectory Browser (DTB) to replicate the observed associations. Eight PheWAS phenotypes and 21 TreeWAS nodes were associated with CRC genetic predisposition by PheWAS and TreeWAS, respectively. The PheWAS detected associations were from neoplasms and digestive system disease group (e.g. benign neoplasm of colon, anal and rectal polyp and diverticular disease). The results from the TreeWAS corroborated the results from the PheWAS. These results were replicated in the observational data within the DTB. We show that benign colorectal neoplasms share genetic aetiology with CRC using PheWAS and TreeWAS methods. Additionally, CRC genetic predisposition is associated with diverticular disease.


Prevalence and incidence of postnatal depression: what can systematic reviews tell us?
Postnatal depression (PND) has a significant impact on maternal mental health. Systematic reviews provide a useful tool to summarise research, however little is known about the quantity and quality of existing systematic reviews of prevalence and incidence of PND. The objective of this paper is to provide a systematic overview of existing systematic reviews of prevalence and incidence of PND in the first 12 postnatal months. Medline, Embase, Cinahl, PsychInfo and the Cochrane Library were searched for systematic reviews of prevalence and incidence of PND which met the Database of Abstracts of Reviews of Effects (DARE) criteria. Characteristics of selected reviews, completeness of reporting results and methodological quality were evaluated. Five reviews were selected for appraisal. Only one systematic review was identified; four reviews were non-systematic. Only two reviews provided a quantitative summary estimate of prevalence of PND. Completeness of reporting results using published guidelines was not undertaken by any review. The methodological quality of four reviews revealed limitations. Limited generalisable evidence exists in the form of high-quality systematic reviews to inform current knowledge of the prevalence and incidence of PND. The implication of this represents an important limitation for health services planning and service delivery.


Effect of human papillomavirus 16/18 L1 viruslike particle vaccine among young women with preexisting infection: a randomized trial.
Viruslike particle human papillomavirus (HPV) vaccines were designed to prevent HPV infection and development of cervical precancers and cancer. Women with oncogenic HPV infections might consider vaccination as therapy. To determine whether vaccination against HPV types 16 and 18 increases the rate of viral clearance in women already infected with HPV. Phase 3, masked, community-based randomized trial conducted in 2 provinces of Costa Rica. A total of 2189 women aged 18 to 25 years who were recruited between June 2004 and December 2005. Participants were positive for HPV DNA at enrollment, had at least 6 months of follow-up, and had follow-up HPV DNA results. Participants were randomly assigned to receive 3 doses of a bivalent HPV-16/18 L1 protein viruslike particle AS04 candidate vaccine (n = 1088) or a control hepatitis A vaccine (n = 1101) over 6 months. Presence of HPV DNA was determined in cervical specimins by a molecular hybridization assay using chemiluminescence with HPV RNA probes and by polymerase chain reaction using SPF10 primers and a line probe assay detection system before vaccination and by polymerase chain reaction after vaccination. We compared rates of type-specific viral clearance using generalized estimating equations methods at the 6-month visit (after 2 doses) and 12-month visit (after 3 doses) in the 2 study groups. There was no evidence of increased viral clearance at 6 or 12 months in the group who received HPV vaccine compared with the control group. Clearance rates for HPV-16/18 infections at 6 months were 33.4% (82/248) in the HPV vaccine group and 31.6% (95/298) in the control group (vaccine efficacy for viral clearance, 2.5%; 95% confidence interval, -9.8% to 13.5%). Human papillomavirus 16/18 clearance rates at 12 months were 48.8% (86/177) in the HPV vaccine group and 49.8% (110/220) in the control group (vaccine efficacy for viral clearance, -2.0%; 95% confidence interval, -24.3% to 16.3%). There was no evidence of a therapeutic effect for other oncogenic or nononcogenic HPV categories, among women receiving all vaccine doses, among women with single infections, or among women stratified by the following entry variables: HPV-16/18 serology, cytologic results, HPV DNA viral load, time since sexual debut, Chlamydia trachomatis or Neisseria gonorrhoeae infection, hormonal contraceptive use, or smoking. In women positive for HPV DNA, HPV-16/18 vaccination does not accelerate clearance of the virus and should not be used to treat prevalent infections. clinicaltrials.gov Identifier: NCT00128661.


Synonymous Virus Genome Recoding as a Tool to Impact Viral Fitness.
Synthetic genome recoding is a novel method of generating viruses with altered phenotypes, whereby many synonymous mutations are introduced into the protein coding region of the virus genome without altering the encoded proteins. Virus genome recoding with large numbers of slightly deleterious mutations has produced attenuated forms of several RNA viruses. Virus genome recoding can also aid in investigating virus interactions with innate immune responses, identifying functional virus genome structures, strategically ameliorating cis-inhibitory signaling sequences related to complex viral functions, to unravel the relevance of codon usage for the temporal regulation of viral gene expression and improving our knowledge of virus mutational robustness and adaptability. The present review discusses the impacts of synonymous genome recoding with regard to expanding our comprehension of virus biology, and the development of new and better therapeutic strategies.


Assessing personal financial management in patients with bipolar disorder and its relation to impulsivity and response inhibition.
Impulsivity and risk-taking behaviours are reported in bipolar disorder (BD). We examined whether financial management skills are related to impulsivity in patients with BD. We assessed financial management skills using the Executive Personal Finance Scale (EPFS), impulsivity using the Barratt Impulsiveness Scale (BIS) and response inhibition using an emotional go/no-go task in bipolar individuals (N = 21) and healthy controls (HC; N = 23). Patients had fewer financial management skills and higher levels of impulsivity than HC. In patients and controls, increased impulsivity was associated with poorer personal financial management. Patients and HC performed equally on the emotional go/no-go task. Higher BIS scores were associated with faster reaction times in HC. In patients, however, higher BIS scores were associated with slower reaction times, possibly indicating compensatory cognitive strategies to counter increased impulsivity. Patients with BD may have reduced abilities to manage personal finances, when compared against healthy participants. Difficulty with personal finance management may arise in part as a result of increased levels of impulsivity. Patients may learn to compensate for increased impulsivity by modulating response times in our experimental situations although whether such compensatory strategies generalize to real-world situations is unknown.


Distinct roles of long/short fimbriae and gingipains in homotypic biofilm development by Porphyromonas gingivalis.
Porphyromonas gingivalis, a periodontal pathogen, expresses a number of virulence factors, including long (FimA) and short (Mfa) fimbriae as well as gingipains comprised of arginine-specific (Rgp) and lysine-specific (Kgp) cysteine proteinases. The aim of this study was to examine the roles of these components in homotypic biofilm development by P. gingivalis, as well as in accumulation of exopolysaccharide in biofilms. Biofilms were formed on saliva-coated glass surfaces in PBS or diluted trypticase soy broth (dTSB). Microscopic observation showed that the wild type strain formed biofilms with a dense basal monolayer and dispersed microcolonies in both PBS and dTSB. A FimA deficient mutant formed patchy and small microcolonies in PBS, but the organisms proliferated and formed a cohesive biofilm with dense exopolysaccharides in dTSB. A Mfa mutant developed tall and large microcolonies in PBS as well as dTSB. A Kgp mutant formed markedly thick biofilms filled with large clumped colonies under both conditions. A RgpA/B double mutant developed channel-like biofilms with fibrillar and tall microcolonies in PBS. When this mutant was studied in dTSB, there was an increase in the number of peaks and the morphology changed to taller and loosely packed biofilms. In addition, deletion of FimA reduced the autoaggregation efficiency, whereas autoaggregation was significantly increased in the Kgp and Mfa mutants, with a clear association with alteration of biofilm structures under the non-proliferation condition. In contrast, this association was not observed in the Rgp-null mutants. These results suggested that the FimA fimbriae promote initial biofilm formation but exert a restraining regulation on biofilm maturation, whereas Mfa and Kgp have suppressive and regulatory roles during biofilm development. Rgp controlled microcolony morphology and biovolume. Collectively, these molecules seem to act coordinately to regulate the development of mature P. gingivalis biofilms.


Human umbilical cord blood hematopoietic progenitor cells: are they the same as their adult bone marrow counterparts?
In an attempt to expand the hematopoietic progenitor cell (HPC) content of a single collection of umbilical cord blood (CB), we investigated the ex vivo proliferative potential of CB CD34+ cells and the rate of exit of these cells from G0/G1 phases of cell cycle in response to different cytokine combinations. Initial experiments in which phenotypically defined populations of CB and adult bone marrow (BM) CD34+ cells were examined for their HPC content revealed that, contrary to BM, CB CD34+ human leukocyte A (HLA)-DR+ cells appeared to contain the majority of primitive HPC. In cultures of BM CD34+ HLA-DR+ cells incubated with stem cell factor (SCF)+interleukin-3 (IL-3), CD34+ cells increased five-fold over 5 days, while CD34+ cells from CB CD34+ HLA-DR+ cultures increased 11-fold under these same conditions, illustrating an enhanced proliferative potential of CB CD34+ HLA-DR+ cells vs. similar cells from adult BM. Furthermore, a 6.2-fold increase in the number of CB CD34+ still residing in G0/G1 was observed on day 5 in cultures supplemented with SCF and IL-3, suggesting the generation of large numbers of primitive HPC in vitro. The effect of SCF on the exit of CB and BM CD34+ HLA-DR+ cells from G0/G1 was then examined. Following 36- to 48-hour exposure to SCF, 45% of quiescent CB cells exited G0/G1 in contrast to only 13% of quiescent BM cells. In serum-free media supplemented with either SCF or IL-3 alone, CB CD34+ HLA-DR+ cells did not exit G0/G1 phases of cell cycle as rapidly as when CB plasma was present, unless SCF and IL-3 were added simultaneously. Collectively, these results suggest that CB CD34+ cells are more responsive to cytokine stimulation, especially SCF, and may represent more suitable candidates for ex vivo expansion of HPC than BM cells. Furthermore, these data illustrate potentially important biologic differences between the HPC content of subpopulations of BM and CB cells, and the response of these subpopulations to cytokine stimulation.


Enumeration of T cells specific for RD1-encoded antigens suggests a high prevalence of latent Mycobacterium tuberculosis infection in healthy urban Indians.
Knowledge of the prevalence of latent Mycobacterium tuberculosis infection is crucial for effective tuberculosis control, but tuberculin skin test surveys have major limitations, including poor specificity because of the broad antigenic cross-reactivity of tuberculin. The M. tuberculosis RD1 genomic segment encodes proteins, such as early secretory antigenic target (ESAT)-6, that are absent from M. bovis bacille Calmette-Guérin (BCG) and most environmental mycobacteria. We recently identified circulating ESAT-6-specific T cells as an accurate marker of M. tuberculosis infection. Here, interferon-gamma-secreting T cells specific for peptides derived from ESAT-6 and a second RD1 gene product, CFP10, were enumerated in 100 prospectively recruited healthy adults in Bombay (Mumbai), India. Eighty percent responded to >/=1 antigen, and many donors had high frequencies of T cells that were specific for certain immunodominant peptides. In contrast, of 40 mostly BCG-vaccinated, United Kingdom-resident healthy adults, none responded to either antigen. This study suggests an 80% prevalence of latent M. tuberculosis infection in urban India.


Index for measuring child feeding practices.
The present investigation was undertaken with the objective of creating an Infant and Child Feeding Index (ICFI) from a set of complementary feeding (CF) practices and to determine its association with growth of infants and young children (6-23 months). A semi-structured interview schedule was used to collect information for 204 children from one large slum (n=104) and two private pediatric clinics (n=100) of urban Vadodara. Results revealed that about half (50.5%) of the children were stunted Ht for Age Z score (HAZ<-2SD), nearly one-fourth (25.5%) were underweight Wt for Age Z score (WAZ<-2SD), but wasting (WHZ Wt for Ht Z score<-2SD) was low (3%). Significant associations were revealed between almost all positive CF practices and nutritional status of the children as measured by HAZ and WAZ (p<0.01), but not with WHZ. Good associations were revealed between ICFI and HAZ and WAZ, but not with WHZ. On multivariate analysis of factors affecting the HAZ, WAZ and WHZ scores, ICFI was not found to be significant whereas maternal education was the most significant factor, which was also found to be associated significantly with ICFI. It is concluded that the composite index in its present form can reflect the CF practices more holistically than just one or few behaviors studied separately. More research is needed in the direction of constituting a composite index which can then be used for research, monitoring, evaluation and much needed advocacy for complementary feeding.


The roles of the red clover necrotic mosaic virus capsid and cell-to-cell movement proteins in systemic infection.
The red clover necrotic mosaic dianthovirus (RCNMV) genome is split between two single-stranded RNA species termed RNA-1 and RNA-2. RNA-2 is required for infection of whole plants but is dispensable for infection and virion formation in protoplasts. We have used full-length cDNA clones of RNA-1 and -2 from which infectious in vitro transcripts can be derived to construct a number of mutations in the RNA-1 encoded capsid protein and the RNA-2 encoded cell-to-cell movement protein genes. The capsid protein and the RNA sequence encoding the capsid protein were dispensable for infection of the inoculated leaves of Nicotiana benthamiana and N. clevelandii at both 15 and 25 degrees. In addition, capsid protein was not necessary for systemic infection of N. benthamiana at 15 degrees. As many as 39 amino acid residues could be deleted from the carboxyl-terminus of the RNA-2 encoded 35-kDa cell-to-cell movement protein without loss of or reduction in the rate of cell-to-cell movement or systemic infection. However, larger deletions within the cell-to-cell movement protein gene prevented cell-to-cell movement and systemic infection of N. benthamiana. These data suggest that the spread of RCNMV in a systemic host is a combination of two distinct events: cell-to-cell movement and long distance transport. We conclude that the RCNMV 35-kDa movement protein is required for cell-to-cell movement, whereas the capsid protein is not necessary for cell-to-cell movement and, depending on host genotype and environmental factors, may or may not be required for long distance transport.


Effects of furosemide on the racing times of Thoroughbreds.
The effects of furosemide on the racing times of 79 horses without exercise-induced pulmonary hemorrhage (EIPH) and 52 horses with EIPH were investigated. Racing times were adjusted to 1-mile equivalent racing times by 2 speed handicapping methods, and analysis of covariance was used to adjust actual racing times by winning time and distance for each race. All 3 methods of determining racing time indicated that geldings without EIPH had significantly faster racing times (P less than 0.05) when given furosemide before racing than when furosemide was not given before racing. Females and colts without EIPH were determined to have faster racing times when furosemide was given before racing, but the difference was not significant. Geldings with EIPH had significantly faster racing times (P = 0.0231) when given furosemide before racing, as determined by one of the speed handicapping methods. There was a strong correlation (range 0.9314 to 0.9751) between the 1-mile equivalent racing times, as determined by the 2 speed handicapping methods for horses with and without EIPH. Furosemide failed to prevent the development of EIPH in many horses that were previously considered to be EIPH-negative. When given furosemide, 62 (25.3%) of 235 EIPH-negative horses were EIPH-positive after racing. Furosemide had questionable efficacy for prevention of EIPH in known EIPH-positive horses. Thirty-two (61.5%) of 52 EIPH-positive horses given furosemide before a race remained EIPH-positive after that race.


Early weaning results in less active behaviour, accompanied by lower 5-HT1A and higher 5-HT2A receptor mRNA expression in specific brain regions of female pigs.
In rodents and humans stressful events in early life e.g. maternal deprivation, can increase sensitivity to stress in later life. Humans may become more susceptible to mood disorders, e.g. depression. In livestock species, such as pigs, early weaning is a form of maternal deprivation. We investigated behavioural consequences in 99 female pigs weaned at three different ages (12, 21 and 42 days; d12, d21, d42). Pigs were habituated to an open field arena over 6 days before being given 5-min open-field tests over three subsequent days (days 77-79). Early-weaned pigs (d12) showed behavioural inhibition (reduced vocalisations and lower activity) compared with later-weaned pigs, although in all groups these measures declined over the three tests, so this treatment difference might reflect more rapid habituation to the test in d12 pigs. Long-term effects on mood-related 5-HT receptor subtypes were measured in the brain at 90 days in a random sample of the d12 (n=8) and d42 pigs (n=8), using (3)H-ligand-binding and autoradiography and in situ hybridisation histochemistry. There were no differences between weaning ages in binding of (3)H-8-OH-DPAT (5-HT(1A) receptor agonist) or of (3)H-ketanserin (5-HT(2A) receptor antagonist) to any brain region studied. In d12 pigs, 5-HT(1A) receptor mRNA expression per unit area was 29%, 63%, 52% and 64% lower than in d42 pigs in the parvocellular PVN, amygdala and hippocampal dentate gyrus and pyramidal cell layer, respectively. The ratio of expression per cell to expressing cells per unit area was also lower, by 31%, in the pars horizontalis of the PVN in d12 pigs. Conversely, 5-HT(2A) receptor mRNA was expressed at a 25% and 28% higher density per unit area in the amygdala and pyramidal cell layer of the hippocampus, respectively, in these d12 pigs. In individual pigs, across brain regions, 5-HT(1A) receptor mRNA data were 70-79% correlated with binding data but no correlation was found for 5-HT(2A) data, suggesting different regulatory mechanisms. The behavioural and neurobiological responses to early weaning might represent either dysfunction or adaptation. Further investigation is required.


Virulence of Mexican isolates of entomopathogenic fungi (Hypocreales: Clavicipitaceae) upon Rhipicephalus=Boophilus microplus (Acari: Ixodidae) larvae and the efficacy of conidia formulations to reduce larval tick density under field conditions.
The first objective was laboratory evaluation of the virulence of 53 Mexican isolates of fungi against larvae of Rhipicephalus (Boophilus) microplus. Thirty-three isolates of Metarhizium anisopliae var. anisopliae (Metschnickoff) Sorokin (Hypocreales: Clavicipitaceae) and 20 isolates of Isaria (Paecilomyces) fumosorosea (fumosoroseus) (Wize) (Eurotiales: Trichomaceae) were tested on 7-day-old larvae under laboratory conditions. Larvae were immersed in a suspension containing 10(8)conidia/mL and the CL(50) values were estimated. Then, field tests were conducted to determine the efficacy of formulations of the isolate with the highest virulence. M. anisopliae (Ma 14 isolate) was formulated with four carriers: Tween, Celite, wheat bran, and Citroline (mineral oil) and applied on pasture beds of Cynodon plectostachyus (L.), at a dose of 2 x 10(9)CFU/m(2). In the first trial, M. anisopliae was applied on plots naturally infested with larvae; in the second trial, tick populations in the experimental plots were eliminated and then re-infested with 20,000 7-day-old larvae. In the laboratory, all M. anisopliae isolates infected larvae with a mortality range between 2 and 100%; also, 13 of 20 I. fumosorosea isolates caused mortality rates between 7 and 94%. In the first field trial, 14 days post-application, conidial formulations in Celite and wheat bran caused 67.8 and 94.2% population reduction, respectively. In the second trial, the Tween formulation caused the highest larval reduction, reaching up to 61% (28 days post-application). Wheat bran formulation caused 58.3% larval reduction (21 days post-application) and was one of the most effective. The carriers and emulsifiers have a large impact on the effectiveness of conidial formulations.