The prevalence of thyrotoxicosis-related seizures.
Central nervous system dysfunction, such as hyperexcitation, irritability, and disturbance of consciousness, may occur in patients with thyrotoxicosis. There are also a few case reports of seizures attributed to thyrotoxicosis. The objective of the present study was to determine the prevalence of seizures that appeared to be related to the thyrotoxic state in patients with thyrotoxicosis. We retrospectively determined the prevalence and clinical features of seizures in 3382 patients with hyperthyroidism. Among patients with seizures, we excluded those with other causes of seizures or a history of epilepsy. We did not exclude two patients in whom later work-up showed an abnormal magnetic resonance imaging, as their seizures resolved after they became euthyroid. Among the 3382 patients with hyperthyroidism, there were seven patients (0.2%) with seizures who met our criteria. Primary generalized tonic-clonic seizures occurred in four patients (57%), complex partial seizures with secondary generalized tonic-clonic seizures occurred in two patients (29%), and one patient had a focal seizure (14%). The initial electroencephalography (EEG) was normal in two patients (29%), had generalized slow activity in four patients (57%), and had diffuse generalized beta activity in one patient (14%). On magnetic resonance imaging, one patient had diffuse brain atrophy, and one had an old basal ganglia infarct. After the patients became euthyroid, the EEG was repeated and was normal in all patients. During follow-up periods ranging from 18 to 24 months, none of the patients had seizures. Hyperthyroidism is the precipitating cause of seizures in a small percentage of these patients. In these patients, the prognosis is good if they become euthyroid. The prevalence of thyrotoxicosis-related seizures reported here can be used in conjunction with the prevalence of thyrotoxicosis in the population to estimate the prevalence of thyrotoxicosis-related seizures in populations.


Complex molecular epidemiology of methicillin-resistant staphylococcus aureus isolates from children with cystic fibrosis in the era of epidemic community-associated methicillin-resistant S aureus.
Limited data exist about the molecular types of methicillin-resistant Staphylococcus aureus (MRSA) strains found in children with cystic fibrosis (CF). We sought to characterize MRSA strains from these patients and compare them with MRSA strains from non-CF pediatric patients. All MRSA isolates were collected prospectively at Children's Medical Center in Dallas, TX, and the University of Chicago Comer Children's Hospital in 2004 to 2005. All CF MRSA isolates underwent susceptibility testing, multilocus sequence typing, Panton-Valentine leukocidin gene detection (pvl+), and staphylococcal chromosome cassette mec (SCCmec) typing. A total of 22 of 34 MRSA isolates (64.7%) from patients with CF belonged to clonal complex (CC) 5 and contained SCCmec II, so-called health-care associated MRSA (HA-MRSA) strains. Nine of 34 MRSA strains (26.5%) were CC 8, and contained SCCmec IV, so-called community-associated MRSA (CA-MRSA) strains. The CA-MRSA strains tended to be isolated from newly colonized CF patients. In contrast, CC8 isolates predominated among the non-CF patients (294 of 331 patients; 88.8%). MRSA isolates from children with CF were more likely to be resistant to clindamycin (65% vs 19%, respectively) and ciprofloxacin (62% vs 17%, respectively) compared with strains from non-CF patients (p < 0.001). There was no difference in the rate of pvl+ isolate recovery from children with CF undergoing a surveillance culture (7 of 23 children) compared with those with pulmonary exacerbation (3 of 11 children; p = 1.0). Both CA-MRSA (CC8) isolates and HA-MRSA (CC5) isolates populate the respiratory tracts of children with CF. HA-MRSA isolates predominated, but CA-MRSA strains predominated among CF patients with newly acquired MRSA strains and among the non-CF patients. The presence of CA-MRSA strains in children with CF was not associated with exacerbation or necrotizing pneumonia.


Cytomegalovirus-Productive Infection Is Associated With Acute Coronary Syndrome.
Although an association between human herpesvirus (HHV) infection and atherosclerosis has been suggested, the data supporting such an association are controversial and, in most cases, are based on serological evidence or on the presence of cell-associated HHV DNA, which do not report about actual viral replication. We quantified the DNA of all 8 types of HHVs in plasma, in which their presence is evidence of viral replication. Using quantitative real-time polymerase chain reaction, we evaluated the presence of HHV DNA in blood samples obtained at the time of hospitalization from 71 patients with acute coronary syndrome, 26 patients with stable coronary artery disease, and 53 healthy volunteers and in atherosclerotic plaques of 22 patients with peripheral artery disease who underwent endarterectomy. HHV-5 (cytomegalovirus [CMV]) was the only HHV with a level that was higher in acute coronary syndrome patients than in the control group and that correlated with the level of high-sensitivity C-reactive protein. The numbers of effector memory T cells positively correlated with the numbers of CMV genome copies in carotid arteries plaques, whereas the numbers of central memory T cells negatively correlated with CMV copy numbers. Of all HHV levels, only CMV was higher in patients with stable coronary artery disease and acute coronary syndrome than in the healthy group, and its load correlated with the level of high-sensitivity C-reactive protein. The level of CMV in atherosclerotic plaques correlated with the state of immunoactivation of lymphocytes in plaques, suggesting that the reactivation of CMV may contribute to the immune activation associated with the progression of atherosclerosis.


Sequential Allylic Alcohol Formation by a Multifunctional Cytochrome P450 Monooxygenase with Rare Redox Partners.
Caryoynencin is a toxic and antifungal fatty acid derivative produced by a number of plant-pathogenic and insect-protective bacteria (Trinickia caryophylli and Burkholderia spp.). In addition to the reactive tetrayne unit, the presence of an allylic alcohol moiety is critical for antimicrobial activities. By a combination of mutational analyses, heterologous expression and in vitro reconstitution experiments we show that the cytochrome P450 monooxygenase CayG catalyzes the complex transformation of a saturated carbon backbone into an allylic alcohol. Unexpectedly, CayG employs a ferritin-like protein (CayK) or a rubredoxin (CayL) component for electron transport. A desaturation-hydroxylation sequence was deduced from a time-course study and in vitro biotransformations with pathway intermediates, substrate analogues, protegencin congeners from Pseudomonas protegens Pf-5, and synthetic derivatives. This unusual multifunctional oxygenase may inspire future biocatalytic applications.


A network analysis of depressive symptoms and metabolomics.
Depression is associated with metabolic alterations including lipid dysregulation, whereby associations may vary across individual symptoms. Evaluating these associations using a network perspective yields a more complete insight than single outcome-single predictor models. We used data from the Netherlands Study of Depression and Anxiety (N = 2498) and leveraged networks capturing associations between 30 depressive symptoms (Inventory of Depressive Symptomatology) and 46 metabolites. Analyses involved 4 steps: creating a network with Mixed Graphical Models; calculating centrality measures; bootstrapping for stability testing; validating central, stable associations by extra covariate-adjustment; and validation using another data wave collected 6 years later. The network yielded 28 symptom-metabolite associations. There were 15 highly-central variables (8 symptoms, 7 metabolites), and 3 stable links involving the symptoms Low energy (fatigue), and Hypersomnia. Specifically, fatigue showed consistent associations with higher mean diameter for VLDL particles and lower estimated degree of (fatty acid) unsaturation. These remained present after adjustment for lifestyle and health-related factors and using another data wave. The somatic symptoms Fatigue and Hypersomnia and cholesterol and fatty acid measures showed central, stable, and consistent relationships in our network. The present analyses showed how metabolic alterations are more consistently linked to specific symptom profiles.


Peripheral blood metabolome predicts mood change-related activity in mouse model of bipolar disorder.
Bipolar disorder is a major mental illness characterized by severe swings in mood and activity levels which occur with variable amplitude and frequency. Attempts have been made to identify mood states and biological features associated with mood changes to compensate for current clinical diagnosis, which is mainly based on patients' subjective reports. Here, we used infradian (a cycle > 24 h) cyclic locomotor activity in a mouse model useful for the study of bipolar disorder as a proxy for mood changes. We show that metabolome patterns in peripheral blood could retrospectively predict the locomotor activity levels. We longitudinally monitored locomotor activity in the home cage, and subsequently collected peripheral blood and performed metabolomic analyses. We then constructed cross-validated linear regression models based on blood metabolome patterns to predict locomotor activity levels of individual mice. Our analysis revealed a significant correlation between actual and predicted activity levels, indicative of successful predictions. Pathway analysis of metabolites used for successful predictions showed enrichment in mitochondria metabolism-related terms, such as "Warburg effect" and "citric acid cycle." In addition, we found that peripheral blood metabolome patterns predicted expression levels of genes implicated in bipolar disorder in the hippocampus, a brain region responsible for mood regulation, suggesting that the brain-periphery axis is related to mood-change-associated behaviors. Our results may serve as a basis for predicting individual mood states through blood metabolomics in bipolar disorder and other mood disorders and may provide potential insight into systemic metabolic activity in relation to mood changes.


The Molecular Biology of Phosphodiesterase 4 Enzymes as Pharmacological Targets: An Interplay of Isoforms, Conformational States, and Inhibitors.
The phosphodiesterase 4 (PDE4) enzyme family plays a pivotal role in regulating levels of the second messenger cAMP. Consequently, PDE4 inhibitors have been investigated as a therapeutic strategy to enhance cAMP signaling in a broad range of diseases, including several types of cancers, as well as in various neurologic, dermatological, and inflammatory diseases. Despite their widespread therapeutic potential, the progression of PDE4 inhibitors into the clinic has been hampered because of their related relatively small therapeutic window, which increases the chance of producing adverse side effects. Interestingly, the PDE4 enzyme family consists of several subtypes and isoforms that can be modified post-translationally or can engage in specific protein-protein interactions to yield a variety of conformational states. Inhibition of specific PDE4 subtypes, isoforms, or conformational states may lead to more precise effects and hence improve the safety profile of PDE4 inhibition. In this review, we provide an overview of the variety of PDE4 isoforms and how their activity and inhibition is influenced by post-translational modifications and interactions with partner proteins. Furthermore, we describe the importance of screening potential PDE4 inhibitors in view of different PDE4 subtypes, isoforms, and conformational states rather than testing compounds directed toward a specific PDE4 catalytic domain. Lastly, potential mechanisms underlying PDE4-mediated adverse effects are outlined. In this review, we illustrate that PDE4 inhibitors retain their therapeutic potential in myriad diseases, but target identification should be more precise to establish selective inhibition of disease-affected PDE4 isoforms while avoiding isoforms involved in adverse effects. SIGNIFICANCE STATEMENT: Although the PDE4 enzyme family is a therapeutic target in an extensive range of disorders, clinical use of PDE4 inhibitors has been hindered because of the adverse side effects. This review elaborately shows that safer and more effective PDE4 targeting is possible by characterizing 1) which PDE4 subtypes and isoforms exist, 2) how PDE4 isoforms can adopt specific conformations upon post-translational modifications and protein-protein interactions, and 3) which PDE4 inhibitors can selectively bind specific PDE4 subtypes, isoforms, and/or conformations.


Has Uganda experienced any stalled fertility transitions? Reflecting on the last four decades (1973-2011).
Persistent high fertility is associated with mother and child mortality. While most regions in the world have experienced declines in fertility rates, there are conflicting views as to whether Uganda has entered a period of fertility transition. There are limited data available that explicitly detail the fertility trends and patterns in Uganda over the last four decades, from 1973 to 2011. Total fertility rate (TFR) is number of live births that a woman would have throughout her reproductive years if she were subject to the prevailing age specific fertility patterns. The current TFR for Uganda stands at 6.2 children born per woman, which is one of the highest in the region. This study therefore sought to examine whether there has been a fertility stall in Uganda using all existing Demographic Health Survey data, to provide estimates for the current fertility levels and trends in Uganda, and finally to examine the demographic and socioeconomic factors responsible for fertility levels in Uganda. This is a secondary analysis of data from five consecutive Ugandan Demographic Health Surveys (UDHS); 1988/1989, 1995, 2000/2001, 2006 and 2011. Using pooled data to estimate for fertility levels, patterns and trends, we applied a recently developed fertility estimation approach. A Poisson regression model was also used to analyze fertility differentials over the study period. Over the studied period, fertility trends and levels fluctuated from highs of 8.8 to lows of 5.7, with no specific lag over the study period. These findings suggest Uganda is at the pre-transitional stage, with indications of imminent fertility rate reductions in forthcoming years. Marital status remained a strong predictor for number of children born, even after controlling for other variables. This study suggests there is no evidence of a fertility stall in Uganda, but demonstrates an onset of fertility transition in the country. If this trend continues, Uganda will experience a low fertility rate in the future-a finding pertinent for policy makers, especially as the continent and the country focus on harnessing the demographic dividend.


Sexual selection on plumage and behavior in an avian hybrid zone: experimental tests of male-male interactions.
In western Panama, an unusual hybrid zone exists between white-collared manakins, Manacus candei, and golden-collared manakins, M. vitellinus. Unidirectional introgression of plumage traits from vitellinus into candei has created a region in which all definitively plumaged males have a collar that is lemon-colored. These males are nearly indistinguishable from white-collared candei genetically and morphometrically, but strongly resemble golden-collared vitellinus due to the introgression of secondary sexual plumage traits, particularly the lemon-colored collar. The introgression could be explained by sexual selection for golden-collared traits or by a series of mechanisms that do not invoke sexual selection (e.g., neutral diffusion, dominant allele). Sexual selection on male-male interactions implies behavioral differences among the plumage forms--specifically that golden- and lemon-collared males should be more aggressive than white-collared males. In contrast, the nonsexual hypotheses predict behavioral similarity between lemon- and white-collared males, based on their nearly identical genetics. We tested the sexual selection hypothesis experimentally, by presenting males with taxidermic mounts of the three forms. As response variables, we monitored vocalizations and attacks on the mounts by replicate subject males. Both golden-collared and lemon-collared males were more likely to attack than were white-collared males, as predicted under sexual selection but not by the nonsexual hypotheses. Lemon-collared males were more vocally reactive than either parental form, contrary to the prediction of the nonsexual hypotheses. Our study demonstrates that sexual selection on male-male interactions may play an important role in the dynamics of character evolution and hybrid zones.


CD4 confers susceptibility to human immunodeficiency virus type 1 infection in a rat fibroblast cell line.
A new model system is delineated that will enable study of CD4 cofactors and gp120 binding proteins other than CD4. We have previously described a nontransformed rat fibroblast cell line that can efficiently produce HIV-1 upon transfection with an HIV-1 infectious clone, in contrast to other nonhuman mammalian cell lines tested. In the present study we analyzed the susceptibility to HIV-1 infection of Rat2 cells expressing the human CD4 protein. We have used the mammalian expression vector pKS286, in which HIV-1 LTR drives the expression of the CD4 gene. We show that the Rat2 cell line, expressing the human CD4 (Rat2/CD4), is susceptible to fusion with and infection by HIV-1. The virus produced by the Rat2/CD4 cells was infectious. CD4 expression in the Rat2/CD4 was down-regulated over time, similarly to HIV-1 expression in HIV-1-transfected Rat2 cells. Transfection of the Rat2/CD4 cells with a tat expression vector reestablished the CD4 expression on the surface of those cells, as expected. We conclude that the expression of a gp120 binding protein on the Rat2 cells' surface suffices to render the Rat2 cells susceptible to HIV-1 infection.


Diagnosis and management of pseudohypoparathyroidism and related disorders: first international Consensus Statement.
This Consensus Statement covers recommendations for the diagnosis and management of patients with pseudohypoparathyroidism (PHP) and related disorders, which comprise metabolic disorders characterized by physical findings that variably include short bones, short stature, a stocky build, early-onset obesity and ectopic ossifications, as well as endocrine defects that often include resistance to parathyroid hormone (PTH) and TSH. The presentation and severity of PHP and its related disorders vary between affected individuals with considerable clinical and molecular overlap between the different types. A specific diagnosis is often delayed owing to lack of recognition of the syndrome and associated features. The participants in this Consensus Statement agreed that the diagnosis of PHP should be based on major criteria, including resistance to PTH, ectopic ossifications, brachydactyly and early-onset obesity. The clinical and laboratory diagnosis should be confirmed by a molecular genetic analysis. Patients should be screened at diagnosis and during follow-up for specific features, such as PTH resistance, TSH resistance, growth hormone deficiency, hypogonadism, skeletal deformities, oral health, weight gain, glucose intolerance or type 2 diabetes mellitus, and hypertension, as well as subcutaneous and/or deeper ectopic ossifications and neurocognitive impairment. Overall, a coordinated and multidisciplinary approach from infancy through adulthood, including a transition programme, should help us to improve the care of patients affected by these disorders.


Microbial production of isotopically light iron(II) in a modern chemically precipitated sediment and implications for isotopic variations in ancient rocks.
The inventories and Fe isotope composition of aqueous Fe(II) and solid-phase Fe compounds were quantified in neutral-pH, chemically precipitated sediments downstream of the Iron Mountain acid mine drainage site in northern California, USA. The sediments contain high concentrations of amorphous Fe(III) oxyhydroxides [Fe(III)(am)] that allow dissimilatory iron reduction (DIR) to predominate over Fe-S interactions in Fe redox transformation, as indicated by the very low abundance of Cr(II)-extractable reduced inorganic sulfur compared with dilute HCl-extractable Fe. delta(56)Fe values for bulk HCl- and HF-extractable Fe were approximately 0. These near-zero bulk delta(56)Fe values, together with the very low abundance of dissolved Fe in the overlying water column, suggest that the pyrite Fe source had near-zero delta(56)Fe values, and that complete oxidation of Fe(II) took place prior to deposition of the Fe(III) oxide-rich sediment. Sediment core analyses and incubation experiments demonstrated the production of millimolar quantities of isotopically light (delta(56)Fe approximately -1.5 to -0.5 per thousand) aqueous Fe(II) coupled to partial reduction of Fe(III)(am) by DIR. Trends in the Fe isotope composition of solid-associated Fe(II) and residual Fe(III)(am) are consistent with experiments with synthetic Fe(III) oxides, and collectively suggest an equilibrium Fe isotope fractionation between aqueous Fe(II) and Fe(III)(am) of approximately -2 per thousand. These Fe(III) oxide-rich sediments provide a model for early diagenetic processes that are likely to have taken place in Archean and Paleoproterozoic marine sediments that served as precursors for banded iron formations. Our results suggest pathways whereby DIR could have led to the formation of large quantities of low-delta(56)Fe minerals during BIF genesis.


Attachment and emotion in school-aged children.
One of the primary functions of the attachment behavioral system is to regulate emotional experience under conditions of threat. Although research supports this association among infants and adults, few studies examine the relation between emotion and attachment in middle childhood. This study examined the concurrent associations among children's attachment organization and three indices of emotion reactivity/regulation: self- and parent-assessments of emotion, neuroendocrine reactivity, and fear-potentiated startle response. Ninety-seven 8- to 12-year-old children completed the Child Attachment Interview (CAI) and a fear-potentiated startle paradigm on separate occasions, with salivary cortisol assessed before and after each assessment. Greater attachment security was related to greater child-reported positive trait- and state-level emotion, lower pre-CAI cortisol levels, higher initial startle magnitude during threat, and a faster decrease in startle magnitude during threat. The findings provide initial support that attachment security is related to select measures of emotion, though different methods of assessment yielded discrepant findings. The findings are discussed in terms of their contribution to theory and research examining attachment and emotion.


Cognitive testing of the STAR-Q: insights in activity and sedentary time reporting.
The qualitative attributes and quantitative measurement properties of physical activity questionnaires are equally important considerations in questionnaire appraisal, yet fundamental aspects such as question comprehension are not often described in the literature. Here we describe the use of cognitive interviewing to evaluate the Sedentary Time and Activity Reporting Questionnaire (STAR-Q), a self-administered questionnaire designed to assess overall activity energy expenditure and sedentary behavior. Several rounds of one-on-one interviews were conducted by an interviewer trained in qualitative research methods. Interviewees included a convenience sample of volunteers and participants in the Tomorrow Project, a large cohort study in Alberta, Canada. Following each round of interviews the STAR-Q was revised and cognitively tested until saturation was achieved. Six rounds of cognitive interviewing in 22 adults (5 males, 17 females) age 23-74 years, led to revisions involving 1) use of recall aids; 2) ambiguous terms; and 3) specific tasks, such as averaging across multiple routines, reporting time asleep and self-care, and reporting by activity domain. Cognitive interviewing is a critical step in questionnaire development. Knowledge gained in this study led to revisions that improved respondent acceptability and comprehension of the STAR-Q and will complement ongoing validity testing.


Long noncoding RNA DSCAM-AS1 is associated with poor clinical prognosis and contributes to melanoma development by sponging miR-136.
Accumulating evidence suggests that long non-coding RNAs (lncRNAs) are playing critical roles in tumorigenesis. The present study aimed to investigate the expression pattern and effects of lncRNA DSCAM-AS1 (DSCAM-AS1) that was a newly discovered lncRNA in melanoma. Real-time quantitative PCR (polymerase chain reaction) was performed to determine the expression of DSCAM-AS1 in melanoma tissues and cell lines. Kaplan-Meier and Cox regression analyses were utilized to assess the association between the DSCAM-AS1 and overall survival of patients in melanoma patients. The CCK-8 assay, colony formation assay, flow cytometry assays, transwell and wound scratch assays were performed to determine the biological function of DSCAM-AS1 in tumor cells behaviors. Then, DSCAM-AS1-specific miRNA was further confirmed using the dual-luciferase reporter assay and Western blotting. In this research, we showed that the expression of DSCAM-AS1 was significantly upregulated in melanoma samples and cell lines. Clinical investigation indicated that higher expression of DSCAM-AS1 was associated with ulceration and advanced stage and led to significantly poorer survival time. High DSCAM-AS1 expression in melanoma was confirmed to be an independent predictor of poor survival of patients using univariate and multivariate analysis. Functional investigations revealed that knockdown of DSCAM-AS1 inhibited the ability of cell proliferation, colony formation, migration, invasion, whereas promoted cell apoptosis. Furthermore, mechanistic investigations indicated that DSCAM-AS1 could interact with miR-136 and negatively influence the expression of miR-136. Our findings showed that DSCAM-AS1 is a novel tumor-related molecule involved in melanoma progression as well as a potential prognostic biomarker and therapeutic target.


A prospective study of the risk of congenital defects associated with maternal obesity and diabetes mellitus.
This study was designed to evaluate the effects of maternal obesity and diabetes mellitus on the risk of nonchromosomal congenital defects. We used data from 22,951 pregnant women enrolled in a prospective cohort study of early prenatal exposures and pregnancy outcome. The relative risks [prevalence ratios (PRs)] of major nonchromosomal congenital defects associated with obesity and diabetes, alone or in combination, were calculated using multiple logistic regression analysis. In this study, in the absence of diabetes, obese women (body mass index > or =28) had no higher risk, overall, of having an offspring with a major defect [PR = 0.95; 95% confidence interval (CI) = 0.62-1.5]. Their offspring, however, did have a higher prevalence of certain types of defects, including orofacial clefts; club foot; cardiac septal defects; and, to a lesser extent, hydrocephaly and abdominal wall defects. Women with pre-existing or gestational diabetes who were not obese also had no excess risk overall of having offspring affected by a major defect (PR = 0.98; 95% CI = 0.43-2.2), although they did have a higher prevalence of musculoskeletal defects. The pregnancies of women who were both obese and diabetic were 3.1 times as likely (95% CI = 1.2-7.6) to result in an offspring with a defect than were those of nonobese, nondiabetic women, which suggests that obesity and diabetes mellitus may act synergistically in the pathogenesis of congenital anomalies. The defects were largely craniofacial or musculoskeletal.


Probing gene expression in live cells, one protein molecule at a time.
We directly observed real-time production of single protein molecules in individual Escherichia coli cells. A fusion protein of a fast-maturing yellow fluorescent protein (YFP) and a membrane-targeting peptide was expressed under a repressed condition. The membrane-localized YFP can be detected with single-molecule sensitivity. We found that the protein molecules are produced in bursts, with each burst originating from a stochastically transcribed single messenger RNA molecule, and that protein copy numbers in the bursts follow a geometric distribution. The quantitative study of low-level gene expression demonstrates the potential of single-molecule experiments in elucidating the workings of fundamental biological processes in living cells.


Survival of glioma and colorectal cancer patients using tricyclic antidepressants post-diagnosis.
Tricyclic antidepressants have been demonstrated in the laboratory to have anticancer properties. A recent study by our group also suggested a protective effect against development of colorectal cancer and glioma. This study aims to determine whether the anticancer action of tricyclics translates to improved survival in these cancers post-diagnosis. A study using the General Practice Research Database examined whether tricyclic antidepressant exposure in the months following diagnosis of glioma or colorectal cancer would affect longer term all-cause mortality. Cox proportional hazards modelling adjusted for age, gender, smoking, body mass index, comorbidity, and diagnosed depression. A cohort of 1,364 glioma and 16,519 colorectal cancer patients were identified. There was a non-significant reduction in the hazard for glioma patients treated with tricyclics (HR = 0.83, CI = 0.53-1.30). This was mainly found in patients who were not previously exposed to tricyclics (HR = 0.56, CI = 0.26-1.18). In contrast, a significant increase in hazard was found for colorectal cancer (HR = 1.37, CI = 1.21-1.54). This was mostly in patients prescribed low-dose tricyclics (HR = 1.57, CI = 1.33-1.86). We have shown no significant mortality reduction in colorectal cancer or glioma patients treated with tricyclics. An apparent detrimental effect observed in colorectal cancer may be related to prescription of low-dose tricyclics in the management of pain related to disseminated cancer. We cannot rule out small effects or an effect that occurs exclusively at higher doses. Blinded clinical studies may therefore be the only method of determining efficacy in glioma patients.


Resilience through the lens of interactionism: a systematic review.
This systematic review presents findings from a conceptual and methodological review of resilience measures using an interactionist theoretical framework. The review is also intended to update findings from previous systematic reviews. Two databases (EBSCOHost and Scopus) were searched to retrieve empirical studies published up until 2013, with no lower time limit. All articles had to meet specific inclusion criteria, which resulted in 17 resilience measures selected for full review. Measures were conceptually evaluated against an interactionist framework and methodologically reviewed using Skinner's (1981) validity evidence framework. We conclude that inconsistencies associated with the definition and operationalization of resilience warrant further conceptual development to explain resilience as a dynamic and interactive phenomenon. In particular, measures of resilience may benefit from a greater focus on within-person variance typically associated with behavioral consistency across situations. The use of alternative measurement modalities to self-report scales, such as situational judgment tests, is proposed as a way of advancing knowledge in this area.


Skin blood flow differentially affects near-infrared spectroscopy-derived measures of muscle oxygen saturation and blood volume at rest and during dynamic leg exercise.
The impact of skin blood flow changes on near-infrared spectroscopy (NIRS)-derived measures of muscle oxygen saturation (SmO(2)) and blood volume has not been fully established. We measured SmO(2) and total hemoglobin concentration ([tHb]) responses of the right vastus lateralis during rest and dynamic knee extension exercise in ten young, healthy males. The protocol was repeated four times: twice without thigh heating for reliability, and twice with different grades of thigh heating for assessing the impact of cutaneous vasodilation on SmO(2) and Δ[tHb]. The reliability of our SmO(2) and [tHb] measurements was good. Thigh heating at 37 and 42°C caused marked increases in cutaneous vascular conductance (CVC) during rest and exercise (P < 0.001 between each condition), and small increases in SmO(2) during rest (from 69 ± 8% to 71 ± 7% and 73 ± 6%, respectively; P < 0.05 between each condition), but not during exercise (e.g. 1 min exercise: 51 ± 11% vs. 51 ± 11% and 52 ± 11%, respectively; P > 0.05 at all time points). In contrast, heating-induced increases in %CVC(peak) were accompanied by increases in [tHb] at rest and during exercise and a decrease in Δ[tHb] during exercise (all P < 0.05). Our findings suggest that NIRS-derived measures of SmO(2) and blood volume are differentially affected by skin blood flow at rest and during exercise. The findings from this study should be considered in NIRS experiments where skin blood flow can change markedly (e.g. high-intensity and/or prolonged exercise).


An evaluation of new and established methods to determine T-DNA copy number and homozygosity in transgenic plants.
Stable transformation of plants is a powerful tool for hypothesis testing. A rapid and reliable evaluation method of the transgenic allele for copy number and homozygosity is vital in analysing these transformations. Here the suitability of Southern blot analysis, thermal asymmetric interlaced (TAIL-)PCR, quantitative (q)PCR and digital droplet (dd)PCR to estimate T-DNA copy number, locus complexity and homozygosity were compared in transgenic tobacco. Southern blot analysis and ddPCR on three generations of transgenic offspring with contrasting zygosity and copy number were entirely consistent, whereas TAIL-PCR often underestimated copy number. qPCR deviated considerably from the Southern blot results and had lower precision and higher variability than ddPCR. Comparison of segregation analyses and ddPCR of T1 progeny from 26 T0 plants showed that at least 19% of the lines carried multiple T-DNA insertions per locus, which can lead to unstable transgene expression. Segregation analyses failed to detect these multiple copies, presumably because of their close linkage. This shows the importance of routine T-DNA copy number estimation. Based on our results, ddPCR is the most suitable method, because it is as reliable as Southern blot analysis yet much faster. A protocol for this application of ddPCR to large plant genomes is provided.


Comprehensive analysis of cancer-associated somatic mutations in class I HLA genes.
Detection of somatic mutations in human leukocyte antigen (HLA) genes using whole-exome sequencing (WES) is hampered by the high polymorphism of the HLA loci, which prevents alignment of sequencing reads to the human reference genome. We describe a computational pipeline that enables accurate inference of germline alleles of class I HLA-A, B and C genes and subsequent detection of mutations in these genes using the inferred alleles as a reference. Analysis of WES data from 7,930 pairs of tumor and healthy tissue from the same patient revealed 298 nonsilent HLA mutations in tumors from 266 patients. These 298 mutations are enriched for likely functional mutations, including putative loss-of-function events. Recurrence of mutations suggested that these 'hotspot' sites were positively selected. Cancers with recurrent somatic HLA mutations were associated with upregulation of signatures of cytolytic activity characteristic of tumor infiltration by effector lymphocytes, supporting immune evasion by altered HLA function as a contributory mechanism in cancer.


Smartphone-Based Meditation for Myeloproliferative Neoplasm Patients: Feasibility Study to Inform Future Trials.
Myeloproliferative neoplasm (MPN) patients often report high symptom burden that persists despite the best available pharmacologic therapy. Meditation has gained popularity in recent decades as a way to manage cancer patient symptoms. The aim of this study was to examine the feasibility of 2 different consumer-based meditation smartphone apps in MPN patients and to examine the limited efficacy of smartphone-based meditation on symptoms compared with an educational control group. Patients (n=128) were recruited nationally through organizational partners and social media. Eligible and consented patients were enrolled into 1 of 4 groups, 2 of which received varying orders of 2 consumer-based apps (10% Happier and Calm) and 2 that received one of the apps alone for the second 4 weeks of the 8-week intervention after an educational control condition. Participants were asked to perform 10 min of meditation per day irrespective of the app and the order in which they received the apps. Feasibility outcomes were measured at weeks 5 and 9 with a Web-based survey. Feasibility outcomes were acceptability, demand, and limited efficacy for depression, anxiety, pain intensity, sleep disturbance, sexual function, quality of life, global health, and total symptom burden. A total of 128 patients were enrolled across all 4 groups, with 73.4% (94/128) patients completing the intervention. Of the participants who completed the 10% Happier app, 61% (46/76) enjoyed it, 66% (50/76) were satisfied with the content, and 77% (59/76) would recommend to others. Of those who completed the Calm app, 83% (56/68) enjoyed it, 84% (57/68) were satisfied with the content, and 97% (66/68) would recommend to others. Of those who completed the educational control, 91% (56/61) read it, 87% (53/61) enjoyed it, and 71% (43/61) learned something. Participants who completed the 10% Happier app averaged 31 (SD 33) min/week; patients completing the Calm app averaged 71 (SD 74) min/week. 10% Happier app participants saw small effects on anxiety (P<.001 d=-0.43), depression (P=.02; d=-0.38), sleep disturbance (P=.01; d=-0.40), total symptom burden (P=.13; d=-0.27), and fatigue (P=.06; d=-0.30), and moderate effects on physical health (P<.001; d=0.52). Calm app participants saw small effects on anxiety (P=.29; d=-0.22), depression (P=.09; d=-0.29), sleep disturbance (P=.002; d=-0.47), physical health (P=.005; d=0.44), total symptom burden (P=.13; d=-0.27), and fatigue (P=.13; d=-0.27). Educational control participants (n=61) did not have effects on any patient-reported outcome except for a moderate effect on physical health (P<.001; d=0.77). Delivering meditation via the Calm app is feasible and scored higher in terms of feasibility when compared with the 10% Happier app. The Calm app will be used to implement a randomized controlled trial, testing the effects of meditation on symptom burden in MPNs. ClinicalTrials.gov NCT03726944; https://clinicaltrials.gov/ct2/show/NCT03726944 (Archived by WebCite at http://www.webcitation.org/77MVdFJwM).


Women's menarche stories from a multicultural sample.
This paper reports on the findings of a focus group study that examines how women have experienced menarche at the personal level and in relation to the larger cultural, religious, and societal environment. Fifty-three women from 34 different countries were recruited in 13 focus groups. On the one hand, at the personal level, menarche stories shared in this study revealed salient themes concerning feelings experienced at the time of menarche, the importance of mother's reactions to their daughter's first menstruation, difficulties around understanding the meanings attached to menarche by others, managing menstrual products, as well as making sense of formal education related to menstruation, and the age of menarche. On the other hand, the discussions concerning how women experienced menarche in relation to the larger cultural, religious, and societal environment revealed secrecy to be a defining feature of many stories. Cultural expectations of learning, and following the rules and regulations surrounding menstruation led to different reactions in women at the time of their menarche. Very few women mentioned a ritual or celebration at the time of their menarche. Findings are discussed in terms of similarities and differences in menarche stories of women from different cultural backgrounds. Limitations of the study are mentioned and suggestions for future research are provided.


Maternal growth hormone treatment from day 35 to 80 of gestation alters nutrient partitioning in favor of uteroplacental growth in the overnourished adolescent sheep.
Overnourishing the pregnant adolescent ewe promotes maternal tissue synthesis at the expense of placental growth and leads to a major reduction in lamb birth weight at term. Growth hormone (GH) secretion is attenuated in these overnourished dams and the maternal somatotrophic axis may play a key role in coordinating nutrient usage in the pregnant adolescent. Thus we investigated whether increasing maternal GH during the period of rapid placental proliferation alters nutrient partitioning between the maternal, placental, and fetal tissues as assessed at Day 81 of gestation. Adolescent recipient ewes were implanted with singleton embryos, derived from superovulated dams and a single sire on Day 4 postestrus. Thereafter, the ewes were offered either a high (H) or moderate intake (M) of the same complete diet. From Day 35 to 80 of gestation, ewes were either injected twice daily (s.c. at 0800 and 1800 h) with recombinant bovine GH (bGH, 0.14 mg/kg live weight/day) or remained untreated (n = 8 ewes per group). Maternal concentrations of GH, insulin, insulin-like growth factor (IGF-1), glucose, and non-esterified fatty acids (NEFAs) were higher, and leptin secretion lower, in bGH-treated dams from both nutritional groups. Maternal body weight gain was higher in H versus M groups and was independent of bGH treatment. Treatment with bGH reduced relative perirenal and carcass fat deposition and increased carcass protein content in both H and M dams. Uteroplacental mass (uterus + placentomes + fetal membranes) averaged 1099, 1069, 1112, and 1754 g in M, H, M+GH, and H+GH groups. This significant increase in uteroplacental development in the H+GH group was associated with higher fetal kidney and liver weights and elevated fetal insulin, glucose, and lactate concentrations. Treatment with bGH also induced polyhydramnios in the H group. The transplacental glucose gradient was increased twofold in the H+GH group but placental GLUT- 1 and GLUT-3 expression was unaffected. In conclusion, administration of GH during the period of rapid placental proliferation alters endocrine status and thus nutrient partitioning in the overnourished adolescent dam in favor of uteroplacental and fetal growth. It remains to be established whether these effects are due wholly to alterations in maternal metabolism or if they also reflect an effect of bGH and/or the IGF system at the level of the uteroplacenta.


Limitations of methods for measuring out-of-pocket and catastrophic private health expenditures.
To investigate the effect of survey design, specifically the number of items and recall period, on estimates of household out-of-pocket and catastrophic expenditure on health. We used results from two surveys--the World Health Survey and the Living Standards Measurement Study--that asked the same respondents about health expenditures in different ways. Data from the World Health Survey were used to compare estimates of average annual out-of-pocket spending on health care derived from a single-item and from an eight-item measure. This was done by calculating the ratio of the average obtained with the single-item measure to that obtained with the eight-item measure. Estimates of catastrophic spending from the two measures were also compared. Data from the Living Standards Measurement Study from three countries (Bulgaria, Jamaica and Nepal) with different recall periods and varying numbers of items in different modules were used to compare estimates of average annual out-of-pocket spending derived using various methods. In most countries, a lower level of disaggregation (i.e. fewer items) gave a lower estimate for average health spending, and a shorter recall period yielded a larger estimate. However, when the effects of aggregation and recall period are combined, it is difficult to predict which of the two has the greater influence. The magnitude of both out-of-pocket and catastrophic spending on health is affected by the choice of recall period and the number of items. Thus, it is crucial to establish a method to generate valid, reliable and comparable information on private health spending.


The great escape - AIDS viruses and immune control.
Many studies have been designed to address the role of CTL immune escape in HIV-1 infection, but have not given conclusive answers. Now, an elegant longitudinal analysis clearly demonstrates that progression to disease in SIV-infected macaques is associated with evasion of the CTL response (pages 1270-1276).


A critical comparison of coarse-grained structure-based approaches and atomic models of protein folding.
Structure-based coarse-grained Gō-like models have been used extensively in deciphering protein folding mechanisms because of their simplicity and tractability. Meanwhile, explicit-solvent molecular dynamics (MD) simulations with physics-based all-atom force fields have been applied successfully to simulate folding/unfolding transitions for several small, fast-folding proteins. To explore the degree to which coarse-grained Gō-like models and their extensions to incorporate nonnative interactions are capable of producing folding processes similar to those in all-atom MD simulations, here we systematically compare the computed unfolded states, transition states, and transition paths obtained using coarse-grained models and all-atom explicit-solvent MD simulations. The conformations in the unfolded state in common Gō models are more extended, and are thus more in line with experiment, than those from all-atom MD simulations. Nevertheless, the structural features of transition states obtained by the two types of models are largely similar. In contrast, the folding transition paths are significantly more sensitive to modeling details. In particular, when common Gō-like models are augmented with nonnative interactions, the predicted dimensions of the unfolded conformations become similar to those computed using all-atom MD. With this connection, the large deviations of all-atom MD from simple diffusion theory are likely caused in part by the presence of significant nonnative effects in folding processes modelled by current atomic force fields. The ramifications of our findings to the application of coarse-grained modeling to more complex biomolecular systems are discussed.


Deep supercooling, vitrification and limited survival to -100{degrees}C in the Alaskan beetle Cucujus clavipes puniceus (Coleoptera: Cucujidae) larvae.
Larvae of the freeze-avoiding beetle Cucujus clavipes puniceus (Coleoptera: Cucujidae) in Alaska have mean supercooling points in winter of -35 to -42 degrees C, with the lowest supercooling point recorded for an individual of -58 degrees C. We previously noted that some larvae did not freeze when cooled to -80 degrees C, and we speculated that these larvae vitrified. Here we present evidence through differential scanning calorimetry that C. c. puniceus larvae transition into a glass-like state at temperatures<-58 degrees C and can avoid freezing to at least -150 degrees C. This novel finding adds vitrification to the list of insect overwintering strategies. While overwintering beneath the bark of fallen trees, C. c. puniceus larvae may experience low ambient temperatures of around -40 degrees C (and lower) when microhabitat is un-insulated because of low snow cover. Decreasing temperatures in winter are correlated with loss of body water from summer high levels near 2.0 to winter lows near 0.4 mg mg(-1) dry mass and concomitant increases in glycerol concentrations (4-6 mol l(-1)) and thermal hysteresis. Finally, we provide direct evidence that Cucujus from Wiseman, Alaska, survive temperatures to -100 degrees C.


Studying atomic structures by aberration-corrected transmission electron microscopy.
Seventy-five years after its invention, transmission electron microscopy has taken a great step forward with the introduction of aberration-corrected electron optics. An entirely new generation of instruments enables studies in condensed-matter physics and materials science to be performed at atomic-scale resolution. These new possibilities are meeting the growing demand of nanosciences and nanotechnology for the atomic-scale characterization of materials, nanosynthesized products and devices, and the validation of expected functions. Equipped with electron-energy filters and electron-energy-loss spectrometers, the new instruments allow studies not only of structure but also of elemental composition and chemical bonding. The energy resolution is about 100 milli-electron volts, and the accuracy of spatial measurements has reached a few picometers. However, understanding the results is generally not straightforward and only possible with extensive quantum-mechanical computer calculations.


MEDICI: Mining Essentiality Data to Identify Critical Interactions for Cancer Drug Target Discovery and Development.
Protein-protein interactions (PPIs) mediate the transmission and regulation of oncogenic signals that are essential to cellular proliferation and survival, and thus represent potential targets for anti-cancer therapeutic discovery. Despite their significance, there is no method to experimentally disrupt and interrogate the essentiality of individual endogenous PPIs. The ability to computationally predict or infer PPI essentiality would help prioritize PPIs for drug discovery and help advance understanding of cancer biology. Here we introduce a computational method (MEDICI) to predict PPI essentiality by combining gene knockdown studies with network models of protein interaction pathways in an analytic framework. Our method uses network topology to model how gene silencing can disrupt PPIs, relating the unknown essentialities of individual PPIs to experimentally observed protein essentialities. This model is then deconvolved to recover the unknown essentialities of individual PPIs. We demonstrate the validity of our approach via prediction of sensitivities to compounds based on PPI essentiality and differences in essentiality based on genetic mutations. We further show that lung cancer patients have improved overall survival when specific PPIs are no longer present, suggesting that these PPIs may be potentially new targets for therapeutic development. Software is freely available at https://github.com/cooperlab/MEDICI. Datasets are available at https://ctd2.nci.nih.gov/dataPortal.


Antimicrobial susceptibility of Streptococcus pneumoniae in Latin America: results from five years of the SENTRY Antimicrobial Surveillance Program.
A total of 1561 pneumococcal isolates were collected in 1997-2001, mainly from patients with community-acquired respiratory tract infections, and susceptibilities were tested by reference broth microdilution against 29 antimicrobial agents. In general, 69.3% of strains were considered susceptible (MIC < or = 0.06 mg/L) to penicillin. Resistance to penicillin (MIC > or = 2 mg/L) and cefotaxime (MIC > or = 4 mg/L) was found in 11.9% and 0.4% of isolates, respectively. The fluoroquinolones gatifloxacin (MIC90, 0.5 mg/L) and levofloxacin (MIC90, 1 mg/L) were active against > 99% of the isolates tested. Among the other non-beta-lactam drugs tested, the rank order of susceptibility was chloramphenicol (95.6%) > clindamycin (94.5%) > azithromycin (88.5%) > clarithromycin (87.5%) >tetracycline (79.5%) > trimethoprim + sulphamethoxazole (60.5%). The penicillin-non-susceptible isolates presented higher rates of resistance to other antimicrobial agents. The rank order of penicillin resistance rates among the seven participating countries was Mexico (25.0%) > Uruguay (19.2%) > Chile (18.3%) > Colombia = Argentina (9.9%) > Brazil (3.9%) > Venezuela (2.8%). The regional rate of penicillin resistance did not vary significantly over the years studied (p 0.339). Screening for the ermB and mefA genes by multiplex rapid cycle PCR on 23 erythromycin-resistant isolates collected during the year 2001 showed that 43.5% and 56.5%, respectively, were positive for ermB and mefA. Overall, the results indicated that antimicrobial susceptibilities of Streptococcus pneumoniae vary significantly among Latin American countries. Regional and local surveillance programmes are necessary to guide empirical therapy of pneumococcal infection in Latin American countries.


Is cooking at home associated with better diet quality or weight-loss intention?
To examine national patterns in cooking frequency and diet quality among adults in the USA, overall and by weight-loss intention. Analysis of cross-sectional 24 h dietary recall and interview data. Diet quality measures included total kilojoules per day, grams of fat, sugar and carbohydrates per day, fast-food meals per week, and frozen/pizza and ready-to-eat meals consumed in the past 30 d. Multivariable regression analysis was used to test associations between frequency of cooking dinner per week (low (0-1), medium (2-5) and high (6-7)), dietary outcomes and weight-loss intention. The 2007-2010 National Health and Nutrition Examination Survey. Adults aged 20 years and over (n 9569). In 2007-2010, 8 % of adults lived in households in which someone cooked dinner 0-1 times/week and consumed, on an average day, 9627 total kilojoules, 86 g fat and 135 g sugar. Overall, compared with low cookers (0-1 times/week), a high frequency of cooking dinner (6-7 times/week) was associated with lower consumption of daily kilojoules (9054 v. 9627 kJ, P=0·002), fat (81 v. 86 g, P=0·016) and sugar (119 v. 135 g, P<0·001). Individuals trying to lose weight consumed fewer kilojoules than those not trying to lose weight, regardless of household cooking frequency (2111 v. 2281 kJ/d, P<0·006). Cooking dinner frequently at home is associated with consumption of a healthier diet whether or not one is trying to lose weight. Strategies are needed to encourage more cooking among the general population and help infrequent cookers better navigate the food environment outside the home.


Listeria monocytogenes possesses adhesins for fibronectin.
Listeria monocytogenes is a gram-positive, nonsporulating, food-borne pathogen of humans and animals that is able to invade many eukaryotic cells. Several listerial surface components have been reported to interact with eukaryotic cell receptors, but the complete mechanism by which the bacteria interact with all of these cell types remains largely unknown. In this work, we found that L. monocytogenes binds to human fibronectin, a 450,000-Da dimeric glycoprotein found in body fluids, on the surface of cells and in an insoluble component of the extracellular matrix. The binding of fibronectin to L. monocytogenes was found to be saturable and dependent on proteinaceous receptors. Five fibronectin-binding proteins of 55.3, 48.6, 46.7, 42.4, and 26.8 kDa were identified. The 55.3-kDa protein was proved to be present at the bacterial cell surface. The binding of L. monocytogenes to fibronectin adds to the number of molecules to which the bacterium is able to adhere and emphasizes the complexity of host-pathogen interactions.


Antimicrobial susceptibility of Acinetobacter species.
The in vitro activities of 16 antimicrobial agents against 180 Acinetobacter strains isolated from blood cultures (n = 162), central venous catheters (n = 11), and cerebrospinal fluids (n = 7) were studied. MICs were determined by a microtiter broth dilution method. Considerable differences in antimicrobial drug susceptibility against strains belonging to different species could be demonstrated. Acinetobacter baumannii isolates (n = 108) were generally more resistant than isolates identified as species other than A. baumannii. Multidrug resistance was common among A. baumannii isolates. Of the antimicrobial agents tested, imipenem was highly active against all A. baumannii isolates, and the other agents tested were only moderately active or inactive. Good activity against Acinetobacter species strain 3 was demonstrated for imipenem, amikacin, and ciprofloxacin. Most of the strains belonging to other species were susceptible to imipenem, ciprofloxacin, expanded-spectrum cephalosporins, amoxicillin-clavulanate, and the aminoglycosides but were resistant to ampicillin and older cephalosporins.


The APOB insertion/deletion polymorphism (rs17240441) influences postprandial lipaemia in healthy adults.
Apolipoprotein (apo)B is the structural apoprotein of intestinally- and liver- derived lipoproteins and plays an important role in the transport of triacylglycerol (TAG) and cholesterol. Previous studies have examined the association between the APOB insertion/deletion (ins/del) polymorphism (rs17240441) and postprandial lipaemia in response to a single meal; however the findings have been inconsistent with studies often underpowered to detect genotype-lipaemia associations, focused mainly on men, or with limited postprandial characterisation of participants. In the present study, using a novel sequential test meal protocol which more closely mimics habitual eating patterns, we investigated the impact of APOB ins/del polymorphism on postprandial TAG, non-esterified fatty acids, glucose and insulin levels in healthy adults. Healthy participants (n = 147) consumed a standard test breakfast (0 min; 49 g fat) and lunch (330 min; 29 g fat), with blood samples collected before (fasting) and on 11 subsequent occasions until 480 min after the test breakfast. The ins/ins homozygotes had higher fasting total cholesterol, LDL-cholesterol, TAG, insulin and HOMA-IR and lower HDL-cholesterol than del/del homozygotes (P < 0.017). A higher area under the time response curve (AUC) was evident for the postprandial TAG (P < 0.001) and insulin (P = 0.032) responses in the ins/ins homozygotes relative to the del/del homozygotes, where the genotype explained 35% and 7% of the variation in the TAG and insulin AUCs, respectively. In summary, our findings indicate that the APOB ins/del polymorphism is likely to be an important genetic determinant of the large inter-individual variability in the postprandial TAG and insulin responses to dietary fat intake.


Pathology of renal transplantation.
Renal transplantation is the most appropriate form of treatment for end-stage renal disease in all age groups. We present the experience of two hospitals in the pathology of kidney allograft. Renal biopsy is the most adequate method for the follow-up of these patients, because it permits the differential diagnosis of acute and chronic rejection, transplant glomerulopathy, recurrent and "de novo" glomerulonephritis and immunosuppression nephrotoxicity, mainly by cyclosporine A. We present the pathology features of all these entities, and study the representativity of the biopsy for diagnosis of rejection. The actuarial survival of the graft is 82% and 71% at 1 and 5 years, respectively.


Tuning the deposition parameters for optimizing the faradaic and non-faradaic electrochemical performance of nanowire array-shaped ITO electrodes prepared by electron beam evaporation.
Nanostructured indium tin oxide (ITO) surfaces present an interesting yet unusual combination of properties (high electrical conductivity and optical transparency) at a high surface-to-volume ratio. Thus, previous studies presented nanostructured ITO electrodes as potentially suitable platforms for electrochemical biosensors, but still there is a lack of research on the optimization of preparation methods for such electrodes. We present a systematic study on the properties of nanostructured ITO electrodes prepared by physical deposition, where the substrate temperature was tuned for achieving the best combination of structural properties (namely electrical conductivity and optical transparency) and electrochemical performance. Analysis of faradaic cyclic voltammetry (CV) was performed to determine the electroactive surface area of the samples, and these results were benchmarked against those obtained by non-faradaic CV and Mott-Schottky (MS) analysis. The latter was useful to determine the dependence of some intrinsic features of the semiconductor on the substrate temperature during deposition. The results show that, out of a wide temperature range covering from 200 °C to 500 °C, there is a two-phase temperature-dependent growth, explained by the Stranski-Krastanov and self-catalytic vapor-liquid-solid (VLS) methods, and, on the other hand, that there is an optimal growth temperature at 300 °C that maximizes the electroactive surface area and sensitivity. This means that cost-effective electrodes can be prepared at low temperatures outperforming in terms of electroactive surface area, surface capacitance and sensitivity. As a proof-of-concept, nanostructured ITO electrodes were electrochemically derivatized with aryl diazonium salts (as a first step towards biochemical functionalization), and the performance of the optimized electrodes was tested in a real scenario.


Determination of the biometric characteristics of palatine rugae patterns in Uttar Pradesh population: a cross-sectional study.
Identification is the establishment of identity of an individual. The basis of dental identification is based on the observation that no two individuals can have same dentition. Palatal rugae are irregular, asymmetric ridges of the mucous membrane extending laterally from the incisive papilla and the anterior part of the palatal raphe. The location of palatal rugae inside the oral cavity confers them with stability even when exposed to high temperatures or trauma. Their resistance to trauma and their apparent unique appearance has suggested their use as a tool for forensic identification. To record the biometric characteristics of shape, size, direction, number and position of palatal rugae and analyze whether palatal rugoscopy can be used as a tool for personal identification and for sex determination. A cross-sectional study. The sample consisted of 100 subjects (50 males, 50 females) between 18 and 25 years. Maxillary impressions were made with elastomeric impression material and dental stone was used to make models. The palatal rugae patterns were traced and analyzed with a magnifying hand lens. The biometric characteristics of number, size, shape, and direction were analyzed using Thomaz and Kotz classification (1983). The casts were coded to blind the examiners about the identity of the subjects. Unpaired t-test and one-way ANOVA using SPSS 19.0 statistical program for Windows. The average number of rugae was slightly more in females. Wavy (44.9%) and curved (41.8%) shapes were more prevalent. Maximum number of rugae was found in E quadrant (40.73%). The average size was 9.221 mm. Most rugae were forwardly directed in both groups. This study concluded that rugae pattern are highly individualistic and can be used as a supplementary method for personal identification and sex determination. Further inter-observer and intra-observer variability were not found to be significant, which further validates the use of rugoscopy as a forensic tool.


Cardiorespiratory fitness and risk of prostate cancer: findings from the Aerobics Center Longitudinal Study.
To examine the association between cardiorespiratory fitness (CRF) and risk of incident prostate cancer (PrCA). Participants were 19,042 male subjects in the Aerobics Center Longitudinal Study (ACLS), ages 20-82years, who received a baseline medical examination including a maximal treadmill exercise test between 1976 and 2003. CRF levels were defined as low (lowest 20%), moderate (middle 40%), and high (upper 40%) according to age-specific distribution of treadmill duration from the overall ACLS population. PrCA was assessed from responses to mail-back health surveys during 1982-2004. Cox proportional hazards regression models, adjusted for potential confounders, were used to compute hazard ratios (HRs), 95% confidence intervals (95% CIs), and incidence rates (per 10,000 person-years of follow-up). A total of 634 men reported a diagnosis of incident PrCA during an average of 9.3 ± 7.1 years of follow-up. Adjusted HRs (95% CIs) in men with moderate and high CRF relative to low CRF were, 1.68 (1.13-2.48) and 1.74 (1.15-2.62), respectively. The positive association between CRF and PrCA was observed only in the strata of men who were not obese, had ≥ 1 follow-up examination, or who were diagnosed ≤ 1995. Rather than revealing a causal relationship, the unexpected positive association observed between CRF and incident PrCA is most likely due to a screening/detection bias in more fit men who also are more health-conscious. Results have important implications for understanding the health-related factors that predispose men to receive PrCA screening that may lead to over-detection of indolent disease.


Integrin-linked kinase--essential roles in physiology and cancer biology.
Integrin-linked kinase (ILK) is a multifunctional intracellular effector of cell-matrix interactions and regulates many cellular processes, including growth, proliferation, survival, differentiation, migration, invasion and angiogenesis. The use of recently developed Cre-lox-driven recombination and RNA-interference technologies has enabled the evaluation of the physiological roles of ILK in several major organ systems. Significant developmental and tissue-homeostasis defects occur when the gene that encodes ILK is deleted, whereas the expression of ILK is often elevated in human malignancies. Although the cause(s) of ILK overexpression remain to be fully elucidated, accumulating evidence suggests that its oncogenic capacity derives from its regulation of several downstream targets that provide cells with signals that promote proliferation, survival and migration, supporting the concept that ILK is a relevant therapeutic target in human cancer. Furthermore, a global analysis of the ILK 'interactome' has yielded several novel interactions, and has revealed exciting and unexpected cellular functions of ILK that might have important implications for the development of effective therapeutic agents.


Diet and asthma: nutrition implications from prevention to treatment.
Asthma is characterized by lung airway inflammation initiated and perpetuated by an inappropriate immune response, increased airway responsiveness, and variable airflow obstruction. In Western countries there has been a marked increase in asthma prevalence such that it has become a public health concern. It has been hypothesized that the increase may be due to changing antioxidant intake, increasing dietary ratio of n-6:n-3 polyunsaturated fatty acids (PUFA), and vitamin D deficiency (and supplementation). Observational studies have reported associations between asthma and dietary antioxidants (vitamin E, vitamin C, carotenoids, selenium, polyphenols, and fruit), PUFA, and vitamin D. However, supplementing the diets of adults with asthma with antioxidants and n-3 PUFA has minimal, if any, clinical benefit. Currently there is insufficient evidence to support the use of nutrient supplements to complement conventional treatment; however, results of ongoing studies are awaited, and additional research is required, particularly in children. Interest in the potential of dietary intervention during pregnancy to reduce the likelihood of childhood asthma has increased. A small number of cohort studies have highlighted associations between childhood asthma and reduced maternal intake of some nutrients (vitamin E, vitamin D, selenium, zinc, and PUFA) during pregnancy. Although vitamin D intervention studies during pregnancy are ongoing and two intervention studies suggest that dietary PUFA manipulation during pregnancy may be advantageous, further trials are needed to establish if modification of maternal nutrient intake during pregnancy can be used as a healthy, low cost, public health measure to reduce the prevalence of childhood asthma.


Ventral axial organs regulate expression of myotomal Fgf-8 that influences rib development.
Fgf-8 encodes a secreted signaling molecule mediating key roles in embryonic patterning. This study analyzes the expression pattern, regulation, and function of this growth factor in the paraxial mesoderm of the avian embryo. In the mature somite, expression of Fgf-8 is restricted to a subpopulation of myotome cells, comprising most, but not all, epaxial and hypaxial muscle precursors. Following ablation of the notochord and floor plate, Fgf-8 expression is not activated in the somites, in either the epaxial or the hypaxial domain, while ablation of the dorsal neural tube does not affect Fgf-8 expression in paraxial mesoderm. Contrary to the view that hypaxial muscle precursors are independent of regulatory influences from axial structures, these findings provide the first evidence for a regulatory influence of ventral, but not dorsal axial structures on the hypaxial muscle domain. Sonic hedgehog can substitute for the ventral neural tube and notochord in the initiation of Fgf-8 expression in the myotome. It is also shown that Fgf-8 protein leads to an increase in sclerotomal cell proliferation and enhances rib cartilage development in mature somites, whereas inhibition of Fgf signaling by SU 5402 causes deletions in developing ribs. These observations demonstrate: (1) a regulatory influence of the ventral axial organs on the hypaxial muscle compartment; (2) regulation of epaxial and hypaxial expression of Fgf-8 by Sonic hedgehog; and (3) independent regulation of Fgf-8 and MyoD in the hypaxial myotome by ventral axial organs. It is postulated that the notochord and ventral neural tube influence hypaxial expression of Fgf-8 in the myotome and that, in turn, Fgf-8 has a functional role in rib formation.


An empirical study of the 'underscreened' in organised cervical screening: experts focus on increasing opportunity as a way of reducing differences in screening rates.
Cervical cancer disproportionately burdens disadvantaged women. Organised cervical screening aims to make cancer prevention available to all women in a population, yet screening uptake and cancer incidence and mortality are strongly correlated with socioeconomic status (SES). Reaching underscreened populations is a stated priority in many screening programs, usually with an emphasis on something like 'equity'. Equity is a poorly defined and understood concept. We aimed to explain experts' perspectives on how cervical screening programs might justifiably respond to 'the underscreened'. This paper reports on a grounded theory study of cervical screening experts involved in program organisation. Participants were 23 experts from several countries and a range of backgrounds: gynecology; epidemiology; public health; pathology; general practice; policy making. Data were gathered via semi-structured interview and concepts developed through transcript coding and memo writing. Most experts expressed an intuitive commitment to reducing systematic differences in screening participation or cancer outcomes. They took three different implicit positions, however, on what made organised programs justifiable with respect to underscreened populations. These were: 1) accepting that population screening is likely to miss certain disenfranchised groups for practical and cultural reasons, and focusing on maximising mainstream reach; 2) identifying and removing barriers to screening; and 3) providing parallel tailored screening services that attended to different cultural needs. Positions tended to fall along country of practice lines. Experts emphasised the provision of opportunity for underscreened populations to take up screening. A focus on opportunity appeared to rely on tacit premises not supported by evidence: that provision of meaningful opportunity leads to increased uptake, and that increased uptake of an initial screening test by disadvantaged populations would decrease cervical cancer incidence and mortality. There was little attention to anything other than the point of testing, or the difficulties disadvantaged women can have in accessing follow up care. The different approaches to 'improving equity' taken by participants are differently justified, and differently justifiable, but none attend directly to the broader conditions of disadvantage.


Empowering primary care workers to improve health services: results from Mozambique's leadership and management development program.
This article is the third article in the Human Resources for Health journal's feature on the theme of leadership and management in public health. The series of six articles has been contributed by Management Sciences for Health (MSH) and will be published article-by-article over the next few weeks. The third article presents a successful application in Mozambique of a leadership development program created by Management Sciences for Health (MSH). Through this program, managers from 40 countries have learned to work in teams to identify their priority challenges and act to implement effective responses. From 2003 to 2004, 11 health units in Nampula Province, participated in a leadership and management development program called the Challenges Program. This was following an assessment which found that the quality of health services was poor, and senior officials determined that the underlying cause was the lack of human resource capacity in leadership and management in a rapidly decentralizing health care system. The program was funded by the US Agency for International Development (USAID) and implemented in partnership between the Mozambican Ministry of Health (MOH) Provincial Directorate in Nampula and Management Sciences for Health (MSH). The Challenges Program used simple management and leadership tools to assist the health units and their communities to address health service challenges. An evaluation of the program in 2005 showed that 10 of 11 health centers improved health services over the year of the program. The Challenges Program used several strategies that contributed to successful outcomes. It integrated leadership strengthening into the day-to-day challenges that staff were facing in the health units. The second success factor in the Challenges Program was the creation of participatory teams. After the program, people no longer waited passively to be trained but instead proactively requested training in needed areas. MOH workers in Nampula reported that the program's approach to improving management and leadership capacity at all levels promoted the efficient use of resources and empowered staff to make a difference.


Recent technique developments and applications of solid state NMR in characterising inorganic materials.
A broad overview is given of some key recent developments in solid state NMR techniques that have driven enhanced applications to inorganic materials science. Reference is made to advances in hardware, pulse sequences and associated computational methods (e.g. first principles calculations, spectral simulation), along with their combination to provide more information about solid phases. The resulting methodology has allowed more nuclei to be observed and more structural information to be extracted. Cross referencing between experimental parameters and their calculation from the structure has given an added dimension to NMR as a characterisation probe of materials. Emphasis is placed on the progress made in the last decade especially from those nuclei that were little studied previously. The general points about technique development and the increased range of nuclei observed are illustrated through some specific exemplars from inorganic materials science.


Antioxidant system efficiently protects goldfish gills from Ni(2+)-induced oxidative stress.
Fish gills are target organs for waterborne metal ions and this work aimed to investigate the effects of waterborne Ni(2+) (10, 25 and 50 mg L(-1)) on goldfish gills. A special focus was on the relationship between Ni uptake and the homeostasis of reactive oxygen species (ROS) in the gills, the tissue, in direct contact with the metal pollutant. Ni-accumulation in the gills occurred as a function of exposure concentration (R(2)=0.98). The main indices of oxidative stress, namely carbonyl proteins (CP) and lipid peroxides (LOOH), decreased by 21-33% and 21-24%, as well as the activities of principal antioxidant enzymes superoxide dismutase and glutathione-dependent peroxidase, by 29-47% and 41-46%, respectively, in gills of Ni-exposed fish. One of the main players in the antioxidant defense of gills seems to be catalase, which increased by 23-53% in Ni-treated fish, and low molecular mass thiol-containing compounds (L-SH), exceeding untreated controls by 73-105% after fish exposure to 10-50 mg L(-1) of Ni(2+). The increased level of L-SH, mainly represented by reduced glutathione, was supported by enhanced activities of glutathione reductase (by 27-38%), glutathione-S-transferase (56-141%) and glucose-6-phosphate dehydrogenase (by 96-117%) and demonstrates the ability of the antioxidant system of gills to resist Ni-induced oxidative stress.


Unification of the globally distributed spindle-shaped viruses of the Archaea.
Viruses with spindle-shaped virions are abundant in diverse environments. Over the years, such viruses have been isolated from a wide range of archaeal hosts. Evolutionary relationships between them remained enigmatic, however. Here, using structural proteins as markers, we define familial ties among these "dark horses" of the virosphere and segregate all spindle-shaped viruses into two distinct evolutionary lineages, corresponding to Bicaudaviridae and Fuselloviridae. Our results illuminate the utility of structure-based virus classification and bring additional order to the virosphere.


Achromatic nulling interferometer based on a geometric spin-redirection phase.
Nulling interferometry aims to perform destructive interference achromatically. It is used to detect a faint source near a bright one and to provide dark field, an annular pupil, and rotational shear. A nulling out-of-plane interferometer that utilizes the geometric phase of spin redirection is proposed. The degree of nulling is determined by beam collimation and angular orientation of mirrors. Simulations and experiments are in reasonable agreement.


Facets of Male Violence Against Women With Substance Abuse Problems: Women With a Residence and Homeless Women.
The aims of this study were to investigate the type and extent to which women with substance abuse problems have been exposed to male violence during their lifetime, and to examine possible differences between women with a residence (WR) and homeless women (HW). The total sample included 79 women (WR, n = 35; HW, n = 44; M age = 47.8 years). Of the total sample, 72 women (91%) had experienced different kinds of male violence, 88% from former partners, and 26% from male friends or acquaintances. Of the 72 women, 71% further reported "Countless occasions of violent events," and 36% had been forced to commit criminal acts. Abused women who had been forced to commit criminal acts were significantly more frequently found to be homeless, have reported parental alcohol and/or drug problems, have witnessed domestic violence in childhood, have been victims of sexual violence, have used illicit drugs as a dominant preparation, and have injected illicit drugs. Almost half of the abused women (46%) met criteria for posttraumatic stress disorder (PTSD), where HW showed an almost 4-time higher risk (RR 3.78) than WR. In conclusion there is a particular vulnerability in women with substance abuse to male violence, which has an important impact on their health status. Thus, from a public health perspective, it is suggested that for those women who have experienced male violence, treatment protocols need to include both assessing and addressing the impact of such experience in relation to substance abuse as well as concomitant health concerns.


Onyalai in pregnancy--effects on the mother and the newborn.
Eight pregnant Kavango women with documented active onyalai during pregnancy or a history of previous attacks of onyalai gave birth to 8 healthy infants who had no clinical signs of a tendency to haemorrhage and had normal platelet counts. Postpartum haemorrhage occurred in 2 patients. A splenectomy was successfully performed on the 7th day after delivery in 1 patient to control postpartum haemorrhage, and 3 months after confinement in another patient to control haemorrhage from another clinical attack of onyalai. Corticosteroids are not indicated in the management of onyalai. Infants of mothers with onyalai, unlike infants of mothers with idiopathic thrombocytopenic purpura, do not appear to be at risk of thrombocytopenia and haemorrhage.


Physical Principles in the Self-Assembly of a Simple Spherical Virus.
Viruses are unique among living organisms insofar as they can be reconstituted "from scratch", that is, synthesized from purified components. In the simplest cases, their "parts list" numbers only two: a single molecule of nucleic acid and many (but a very special number, i.e., multiples of 60) copies of a single protein. Indeed, the smallest viral genomes include essentially only two genes, on the order of a thousand times fewer than the next-simplest organisms like bacteria and yeast. For these reasons, it is possible and even fruitful to take a reductionist approach to viruses and to understand how they work in terms of fundamental physical principles. In this Account, we discuss our recent physical chemistry approach to studying the self-assembly of a particular spherical virus (cowpea chlorotic mottle virus) whose reconstitution from RNA and capsid protein has long served as a model for virus assembly. While previous studies have clarified the roles of certain physical (electrostatic, hydrophobic, steric) interactions in the stability and structure of the final virus, it has been difficult to probe these interactions during assembly because of the inherently short lifetimes of the intermediate states. We feature the role of pH in tuning the magnitude of the interactions among capsid proteins during assembly: in particular, by making the interactions between proteins sufficiently weak, we are able to stall the assembly process and interrogate the structure and composition of particular on-pathway intermediates. Further, we find that the strength of the lateral attractions between RNA-bound proteins plays a key role in addressing several outstanding questions about assembly: What determines the pathway or pathways of assembly? What is the importance of kinetic traps and hysteresis? How do viruses copackage multiple short (compared with wild-type) RNAs or single long RNAs? What determines the relative packaging efficiencies of different RNAs when they are forced to compete for an insufficient supply of protein? And what is the limit on the length of RNA that can be packaged by CCMV capsid protein?


Combined Curcumin and Luteolin Synergistically Inhibit Colon Cancer Associated with Notch1 and TGF-β Signaling Pathways in Cultured Cells and Xenograft Mice.
This study aimed to select a combination of curcumin and luteolin, two phytochemicals from food, at lower concentrations with a higher inhibitory effect on colon cancer growth and investigate possible molecular mechanisms of this anti-colon cancer effect. By pairwise combination screening, we identified that the combination of curcumin (CUR) at 15 μM and luteolin (LUT) at 30 μM (C15L30) synergistically suppressed the proliferation of human colon cancer CL-188 cells, but the individual chemicals had a little inhibitory effect at the selected concentrations. This result was also confirmed in other colon cancer DLD-1cells, suggesting that this synergistic inhibitory effect of C15L30 applies to different colon cancer cells. The combination C15L30 synergistically suppressed the wound closure (wound healing assay) in CL-188 cells. We also found that the combination of CUR and LUT (at 20 mg/kg/day and 10 mg/kg/day, respectively, IP injection, 5 days for 2 weeks) synergistically suppressed tumor growth in CL-188 cell-derived xenograft mice. Western blot results showed that protein levels of Notch1 and TGF-β were synergistically reduced by the combination, both in CL-188 cells and xenograft tumors. Tumor pathological analysis revealed that combined CUR and LUT synergistically increased necrosis, but the individual treatment with CUR and LUT had no significant effect on tumor necrosis. Therefore, combined curcumin and luteolin synergically inhibit colon cancer development by suppressing cell proliferation, necrosis, and migration associated with Notch1 and TGF-β pathways. This study provides evidence that colon cancer may be prevented/treated by consuming foods having high levels of luteolin and curcumin in humans.


Analysis of a rotary task following total knee arthroplasty: Stair descent with a cross-over turn.
Leg loading and knee angle differences have been reported in total knee replacement individuals during straight gait; however, little is known about the impact on the knee during turning. Rotary motions may be difficult following total knee replacement surgery; therefore, some individuals may develop strategies or utilize pre-surgical strategies in order to maintain function. The primary aim of this study was to identify differences in individuals with a total knee replacement as compared to their healthy counterparts during stair descent followed by a cross-over turn. Ground reaction force, knee angle and moments were recorded on 10 total knee replacement and 12 healthy individuals during stair descent followed by a turn and compared to walking straight. Variables were analyzed for the affected, unaffected and healthy knees during the gait cycle. On initial contact, the total knee replacement group had less ground reaction force on the affected leg compared to the unaffected leg (p = 0.021) and had delayed contact (p = 0.044) and a slower loading rate (p = 0.020) compared to healthy group. During mid-stance, the affected leg had less ground reaction force compared to the healthy leg (p = 0.049). The affected stance leg had less knee flexion during mid-stance in both the straight trial (p = 0.002) and turn (p = 0.010). Moment differed between straight and turn trials but not between groups. Stair descent with or without a turn was approached in a precautionary manner by individuals with a total knee replacement. Slow approach, reduced impact and weight-bearing with a more extended knee on the affected leg may suggest a protective strategy to avoid risk of fall.


Epidemiology of malaria in a village in the Rufiji River Delta, Tanzania: declining transmission over 25 years revealed by different parasitological metrics.
Assessments of the epidemiology of malaria over time are needed to understand changes in transmission and guide control and elimination strategies. A longitudinal population study was established in 1985 in Nyamisati village in the Rufiji River Delta, Tanzania. A physician and research team lived in the village 1984-2000. Parasite prevalence by microscopy and two PCR methods, spleen rates and haemoglobin levels were measured in repeated cross-sectional surveys between 1985 and 2010. Passive surveillance of malaria cases was maintained until end 1999. Bed nets were distributed after the surveys 1993, 1999 and 2010. In 1985, overall parasite prevalence by microscopy was 70% (90% in children ages two to nine years). The prevalence decreased gradually by microscopy (38.9% 1994, 26.7% 1999) and msp2-PCR (58.7% 1994, 44.8% 1999), whereas real-time PCR prevalence remained higher throughout the 1990s (69.4% 1994, 64.8% 1999). In 2010, parasite prevalence was 17.8% by real-time PCR and 16.3% by msp2-PCR, and estimated to 4.8% by microscopy. Spleen rates in children ages two to nine years decreased earlier than parasite prevalence, from >75 to 42% in the 1980s, to nil during the 1990s. The prevalence of severe and moderate anaemia decreased from 41.1 to 13.1%. No deaths at the time of acute malaria were recorded when the research team lived in the village. A marked decline in malaria transmission was observed over 25 years. The decrease was detected after the arrival of the research team and continued gradually both before and after distribution of bed nets. Spleen rates and microscopy identified early changes when transmission was still intense, whereas real-time PCR was a more sensitive metric when transmission was reduced. The study provides historical data on malaria within a closely monitored rural village and contributes to the understanding of changing epidemiology in sub-Saharan Africa.


A review of virtual reality simulators for neuroendoscopy.
Neurosurgery is a challenging surgical specialty that demands many technical and cognitive skills. The traditional surgical training approach of having a trainee coached in the operating room by the faculty is time-consuming, costly, and involves patient risk factors. Simulation-based training methods are suitable to impart the surgical skills outside the operating room. Virtual simulators allow high-fidelity repeatable environment for surgical training. Neuroendoscopy, a minimally invasive neurosurgical technique, demands additional skills for limited maneuverability and eye-hand coordination. This study provides a review of the existing virtual reality simulators for training neuroendoscopic skills. Based on the screening, the virtual training methods developed for neuroendoscopy surgical skills were classified into endoscopic third ventriculostomy and endonasal transsphenoidal surgery trainers. The study revealed that a variety of virtual reality simulators have been developed by various institutions. Although virtual reality simulators are effective for procedure-based skills training, the simulators need to include anatomical variations and variety of cases for improved fidelity. The review reveals that there should be multi-centric prospective and retrospective cohort studies to establish concurrent and predictive validation for their incorporation in the surgical educational curriculum.


Hemiarthroplasty vs primary total hip arthroplasty for displaced fractures of the femoral neck in the elderly: a meta-analysis.
Current updated meta-analysis was designed to compare clinical effects of hemiarthroplasty (HA) vs primary total hip arthroplasty (THA) for displaced femoral neck fractures in elderly patients. Five randomized and 4 quasi-randomized controlled trials with a total 1208 patients were included for final analysis. It showed that mortality and postoperative infection between HA and THA had no statistical differences, that long-term reoperation rate of HA was higher than that of THA, that medium-term dislocation rate of HA was lower than that of THA, and that pain rates of HA in short-term and long-term were both higher than THA. Summarily, treatment of THA for elderly displaced femoral neck fracture could provide better results of reduced reoperation rate and pain relief; however, HA yielded a lower incidence of postoperative dislocation.


Resting State fMRI in Mice Reveals Anesthesia Specific Signatures of Brain Functional Networks and Their Interactions.
fMRI studies in mice typically require the use of anesthetics. Yet, it is known that anesthesia alters responses to stimuli or functional networks at rest. In this work, we have used Dual Regression analysis Network Modeling to investigate the effects of two commonly used anesthetics, isoflurane and medetomidine, on rs-fMRI derived functional networks, and in particular to what extent anesthesia affected the interaction within and between these networks. Experimental data have been used from a previous study (Grandjean et al., 2014). We applied multivariate ICA analysis and Dual Regression to infer the differences in functional connectivity between isoflurane- and medetomidine-anesthetized mice. Further network analysis was performed to investigate within- and between-network connectivity differences between these anesthetic regimens. The results revealed five major networks in the mouse brain: lateral cortical, associative cortical, default mode, subcortical, and thalamic network. The anesthesia regime had a profound effect both on within- and between-network interactions. Under isoflurane anesthesia predominantly intra- and inter-cortical interactions have been observed, with only minor interactions involving subcortical structures and in particular attenuated cortico-thalamic connectivity. In contrast, medetomidine-anesthetized mice displayed subcortical functional connectivity including interactions between cortical and thalamic ICA components. Combining the two anesthetics at low dose resulted in network interaction that constituted the superposition of the interaction observed for each anesthetic alone. The study demonstrated that network modeling is a promising tool for analyzing the brain functional architecture in mice and comparing alterations therein caused by different physiological or pathological states. Understanding the differential effects of anesthetics on brain networks and their interaction is essential when interpreting fMRI data recorded under specific physiological and pathological conditions.


Atomic-layer-deposition oxide nanoglue for sodium ion batteries.
Atomic-layer-deposition (ALD) coatings have been increasingly used to improve battery performance. However, the electrochemical and mechanistic roles remain largely unclear, especially for ALD coatings on electrodes that undergo significant volume changes (up to 100%) during charging/discharging. Here we investigate an anode consisting of tin nanoparticles (SnNPs) with an ALD-Al2O3 coating. For the first time, in situ transmission electron microscopy unveiled the dynamic mechanical protection of the ALD-Al2O3 coating by coherently deforming with the SnNPs under the huge volume changes during charging/discharging. Battery tests in coin-cells further showed the ALD-Al2O3 coating remarkably boosts the cycling performance of the Sn anodes, comparing with those made of bare SnNPs. Chemomechanical simulations clearly revealed that a bare SnNP debonds and falls off the underlying substrate upon charging, and by contrast the ALD-Al2O3 coating, like ion-conductive nanoglue, robustly anchors the SnNP anode to the substrate during charging/discharging, a key to improving battery cycle performance.


Responses to simulated herbivory and water stress in two tropical C4 grasses.
The African grass Hyparrhenia rufa has established itself successfully in South American savannas (Llanos) and displaced dominant native grasses such as Trachypogon plumosus from the wetter and more fertile habitats. Several ecophysiological traits have been related to the higher competitive capacity of H. rufa. To further analyze the behavior of both species, their growth, biomass allocation, physiological and architectural responses to defoliation and water stress were compared under controlled conditions. Although total, aerial and underground biomass decreased under defoliation in both grasses, increases in clipped-leaf biomass and area compensated for defoliation in H. rufa but not in T. plumosus. This difference was due mainly to a higher proportion of assimilates being directed to leaf and tiller production and a higher leaf growth rate in the African grass as compared to T. plumosus, which showed incrased senescence under frequent defoliation. In both species, water stress ameliorated the effects of defoliation. The ability to compensate for defoliated biomass in H. rufa is possibly related to its long coevolution with large herbivores in its original African habitat and is apparently one of the causes of its success in Neotropical savannas.


Diagnostic odyssey of patients with mitochondrial disease: Results of a survey.
To document the complex "diagnostic odyssey" of patients with mitochondrial disease. We analyzed data from 210 Rare Diseases Clinical Research Network Contact Registry participants who were patients with a biochemical deficiency or self-reported diagnosis of mitochondrial disease, or their caregivers. Participants saw an average of 8.19 clinicians (SD 8.0, median 5). The first clinician consulted about symptoms was typically a primary care physician (56.7%), although 35.2% of participants initially sought a specialist. Of note, 55.2% of participants received their diagnosis from a neurologist, 18.2% from a clinical geneticist, and 11.8% from a metabolic disease specialist. A majority of the participants (54.6%) received 1 or more nonmitochondrial diagnoses before their final mitochondrial diagnosis. In their pursuit of a diagnosis, 84.8% of participants received blood tests, 71% a muscle biopsy, 60.5% MRI, and 38.6% urine organic acids. In addition, 39.5% of the participants underwent mitochondrial DNA sequencing, 19% sequencing of nuclear gene(s), and 11.4% whole-exome sequencing. The diagnostic odyssey of patients with mitochondrial disease is complex and burdensome. It features multiple consultations and tests, and, often, conflicting diagnoses. These reflect disease variety, diagnostic uncertainty, and clinician unfamiliarity. The current survey provides an important benchmark. Its replication at appropriate intervals will assist in tracking changes that may accompany increased popularity of exome testing, more rigorous diagnostic criteria, increased patient reported outcome activity, and trials for promising therapies.