Modifying peripheral IV catheters with side holes and side slits results in favorable changes in fluid dynamic properties during the injection of iodinated contrast material.
The purpose of this study was to compare a standard peripheral end-hole angiocatheter with those modified with side holes or side slits using experimental optical techniques to qualitatively compare the contrast material exit jets and using numeric techniques to provide flow visualization and quantitative comparisons. A Schlieren imaging system was used to visualize the angiocatheter exit jet fluid dynamics at two different flow rates. Catheters were modified by drilling through-and-through side holes or by cutting slits into the catheters. A commercial computational fluid dynamics package was used to calculate numeric results for various vessel diameters and catheter orientations. Experimental images showed that modifying standard peripheral IV angiocatheters with side holes or side slits qualitatively changed the overall flow field and caused the exiting jet to become less well defined. Numeric calculations showed that the addition of side holes or slits resulted in a 9-30% reduction of the velocity of contrast material exiting the end hole of the angiocatheter. With the catheter tip directed obliquely to the wall, the maximum wall shear stress was always highest for the unmodified catheter and was always lowest for the four-side-slit catheter. Modified angiocatheters may have the potential to reduce extravasation events in patients by reducing vessel wall shear stress.


Multiple, temporal-specific roles for HNF6 in pancreatic endocrine and ductal differentiation.
Within the developing pancreas Hepatic Nuclear Factor 6 (HNF6) directly activates the pro-endocrine transcription factor, Ngn3. HNF6 and Ngn3 are each essential for endocrine differentiation and HNF6 is also required for embryonic duct development. Most HNF6(-/-) animals die as neonates, making it difficult to study later aspects of HNF6 function. Here, we describe, using conditional gene inactivation, that HNF6 has specific functions at different developmental stages in different pancreatic lineages. Loss of HNF6 from Ngn3-expressing cells (HNF6(Delta endo)) resulted in fewer multipotent progenitor cells entering the endocrine lineage, but had no effect on beta cell terminal differentiation. Early, pancreas-wide HNF6 inactivation (HNF6(Delta panc)) resulted in endocrine and ductal defects similar to those described for HNF6 global inactivation. However, all HNF6(Delta panc) animals survived to adulthood. HNF6(Delta panc) pancreata displayed increased ductal cell proliferation and metaplasia, as well as characteristics of pancreatitis, including up-regulation of CTGF, MMP7, and p8/Nupr1. Pancreatitis was most likely caused by defects in ductal primary cilia. In addition, expression of Prox1, a known regulator of pancreas development, was decreased in HNF6(Delta panc) pancreata. These data confirm that HNF6 has both early and late functions in the developing pancreas and is essential for maintenance of Ngn3 expression and proper pancreatic duct morphology.


High-rate nanofluidic energy absorption in porous zeolitic frameworks.
Optimal mechanical impact absorbers are reusable and exhibit high specific energy absorption. The forced intrusion of liquid water in hydrophobic nanoporous materials, such as zeolitic imidazolate frameworks (ZIFs), presents an attractive pathway to engineer such systems. However, to harness their full potential, it is crucial to understand the underlying water intrusion and extrusion mechanisms under realistic, high-rate deformation conditions. Here, we report a critical increase of the energy absorption capacity of confined water-ZIF systems at elevated strain rates. Starting from ZIF-8 as proof-of-concept, we demonstrate that this attractive rate dependence is generally applicable to cage-type ZIFs but disappears for channel-containing zeolites. Molecular simulations reveal that this phenomenon originates from the intrinsic nanosecond timescale needed for critical-sized water clusters to nucleate inside the nanocages, expediting water transport through the framework. Harnessing this fundamental understanding, design rules are formulated to construct effective, tailorable and reusable impact energy absorbers for challenging new applications.


Odor-context effects in free recall after a short retention interval: a new methodology for controlling adaptation.
The present study investigated context effects of incidental odors in free recall after a short retention interval (5 min). With a short retention interval, the results are not confounded by extraneous odors or encounters with the experimental odor and possible rehearsal during a long retention interval. A short study time condition (4 s per item), predicted not to be affected by adaptation to the odor, and a long study time condition (8 s per item) were used. Additionally, we introduced a new method for recovery from adaptation, where a dissimilar odor was briefly presented at the beginning of the retention interval, and we demonstrated the effectiveness of this technique. An incidental learning paradigm was used to prevent overshadowing from confounding the results. In three experiments, undergraduates (N = 200) incidentally studied words presented one-by-one and received a free recall test. Two pairs of odors and a third odor having different semantic-differential characteristics were selected from 14 familiar odors. One of the odors was presented during encoding, and during the test, the same odor (same-context condition) or the other odor within the pair (different-context condition) was presented. Without using a recovery-from-adaptation method, a significant odor-context effect appeared in the 4-s/item condition, but not in the 8-s/item condition. Using the recovery-from-adaptation method, context effects were found for both the 8- and the 4-s/item conditions. The size of the recovered odor-context effect did not change with study time. There were no serial position effects. Implications of the present findings are discussed.


KDBI: Kinetic Data of Bio-molecular Interactions database.
Understanding of cellular processes and underlying molecular events requires knowledge about different aspects of molecular interactions, networks of molecules and pathways in addition to the sequence, structure and function of individual molecules involved. Databases of interacting molecules, pathways and related chemical reaction equations have been developed. The kinetic data for these interactions, which is important for mechanistic investigation, quantitative study and simulation of cellular processes and events, is not provided in the existing databases. We introduce a new database of Kinetic Data of Bio-molecular Interactions (KDBI) aimed at providing experimentally determined kinetic data of protein-protein, protein-RNA, protein-DNA, protein-ligand, RNA-ligand, DNA-ligand binding or reaction events described in the literature. KDBI contains information about binding or reaction event, participating molecules (name, synonyms, molecular formula, classification, SWISS-PROT AC or CAS number), binding or reaction equation, kinetic data and related references. The kinetic data is in terms of one or a combination of the following quantities as given in the literature of a particular event: association/dissociation or on/off rate constant, first/second/third/. order rate constant, equilibrium rate constant, catalytic rate constant, equilibrium association/dissociation constant, inhibition constant and binding affinity constant. Each entry can be retrieved through protein or nucleic acid or ligand name, SWISS-PROT AC number, ligand CAS number and full-text search of a binding or reaction event. KDBI currently contains 8273 entries of biomolecular binding or reaction events involving 1380 proteins, 143 nucleic acids and 1395 small molecules. Hyperlinks are provided for accessing references in Medline and available 3D structures in PDB and NDB. This database can be accessed at http://xin.cz3.nus.edu.sg/group/kdbi/kdbi.asp.


Xist RNA exhibits a banded localization on the inactive X chromosome and is excluded from autosomal material in cis.
The propagation of X chromosome inactivation is thought to be mediated by the cis- limited spreading of the non-protein coding Xist transcript. In this report we have investigated the localization of Xist RNA on rodent metaphase chromosomes. We show that Xist RNA exhibits a banded pattern on the inactive X and is excluded from regions of constitutive heterochromatin. The banding pattern suggests a preferential association with gene-rich, G-light regions. Analysis of X:autosome rearrangements revealed that restricted propagation of X inactivation into cis -linked autosomal material is reflected by a corresponding limited spread of Xist RNA. We discuss these results in the context of models for the function of Xist RNA in the propagation of X inactivation.


Renal cell carcinoma: focus on safety and efficacy of temsirolimus.
Metastatic renal cell carcinoma has harboured a poor prognosis for decades with immunotherapy being the only available therapy with high toxicity and modest effect. Dependance of renal cell carcinoma oncogenesis on the mTOR pathway has led to clinical development of temsirolimus in this setting. This sirolimus derivative has shown clinical efficacy in monotherapy for poor-risk renal cell carcinoma leading to an overall survival of 10.8 months in the pivotal phase III trial of this agent. Its specific adverse events consist of metabolic dysregulation (hyperlipemia, hyperglycemia), mucositis, rash and pneumonitis which can be severe and need careful monitoring and management. In this review, we will discuss of the clinical development of this molecule, its efficacy, its safety profile and future perspectives.


Pulmonary blood flow regulation in an aquatic snake.
Regulation of pulmonary blood flow was studied during voluntary diving in the aquatic file snake, Acrochordus granulatus. Measurements of pressure and blood flow in pulmonary and systemic vessels indicate that blood flow completely bypasses the lung for significant periods during prolonged and quiescent submergence (greater than 30 minutes). When the lung is ventilated, pulmonary blood flow increases to 36 milliliters per minute per kilogram of body mass (measured in the anterior pulmonary artery), and the cardiac output largely bypasses the systemic circulation. These reciprocating patterns of preferential blood flow reflect inverse relations between flow and vascular resistance, with the result that systemic and pulmonary arterial pressures remain virtually constant throughout repetitive dive cycles. Neuropharmacological studies of freely diving snakes and isolated, perfused lung preparations show that pulmonary blood flow is regulated by an interplay of adrenergic vasodilatation and cholinergic vasoconstriction within the densely innervated lung vasculature. The patterns of blood circulation shown by diving Acrochordus reflect an unusual lability of intracardiac shunts.


Identification and characterisation of a Maf1/Macoco protein complex that interacts with GABAA receptors in neurons.
The majority of fast inhibitory synaptic transmission in the mammalian nervous system is mediated by GABA(A) receptors (GABA(A)Rs). Here we report a novel interaction between the protein Maf1 and GABA(A)R beta-subunit intracellular domains. We find Maf1 to be highly expressed in brain and enriched in the hippocampus and cortex. In heterologous cells and neurons we show Maf1 co-localises with GABA(A)Rs in intracellular compartments and at the cell surface. In neurons, Maf1 is found localised in the cytoplasm in dendrites, partially overlapping with GABA(A)Rs and inhibitory synapses and in addition is enriched in the neuronal nucleus. We also report that Maf1 interacts with a novel coiled-coil domain containing protein that we have called Macoco (for Maf1 interacting coiled-coil protein). Like Maf1, Macoco can also be found localised to inhibitory synapses and directly interacts with GABA(A)Rs. Expressing Macoco in neurons increases surface GABA(A)R levels. Our results suggest that Maf1 and Macoco are novel GABA(A)R interacting proteins important for regulating GABA(A)R surface expression and GABA(A)R signalling in the brain.


RANK, RANKL, OPG, and M-CSF expression in stromal cells during corneal wound healing.
To examine the influx of monocytes into the cornea after epithelial scrape injury and the expression of chemokines that potentially regulate monocyte phenotype in cultured corneal fibroblasts and keratocytes in situ. Monocytes were detected by immunocytochemistry for the monocyte-specific antigen CD11b, in unwounded and epithelial scrape-wounded mouse corneas. The receptor activator of NF-kappa B ligand (RANKL), osteoprotegerin (OPG), and monocyte chemotactic and stimulating factor (M-CSF) mRNAs were detected in cultured mouse stromal fibroblasts by RT-PCR and RNase protection assay. RANKL, OPG, and M-CSF proteins were detected in cultured mouse stromal fibroblasts by immunoprecipitation and Western blot analysis. RANKL, RANK, M-CSF, and OPG proteins were detected in unwounded and wounded mouse corneas by immunocytochemistry. Chimeric mice with green fluorescent protein-labeled bone marrow-derived cells underwent corneal scrape injury and were monitored by fluorescence microscopy and immunocytochemistry. A small number of cells expressing the monocyte-specific CD11b antigen were detected in the stromas of unwounded mouse corneas. A larger number of CD11b-positive cells was detected in the stroma at 24 or 48 hours after epithelial scraping injury. Experiments with chimeric mice with fluorescent green protein-labeled, bone marrow-derived cells demonstrated conclusively the origin of these CD11b(+) cells. RANKL, OPG, and M-CSF mRNAs and proteins were detected in cultured mouse stromal fibroblasts. RANKL, M-CSF, and OPG proteins were detected in unwounded corneas, but were expressed at higher levels in stromal cells during the 24- to 48-hour interval after epithelial scrape injury. RANK was detected in stromal cells presumed to be monocytes at 24 and 48 hours after epithelial injury. Cells expressing the CD11b monocyte-specific antigen appear in the corneal stroma in high numbers by 24 hours after epithelial injury and persist beyond 10 days after wounding. Cultured corneal fibroblasts and keratocytes in situ express RANKL, OPG, and M-CSF cytokines involved in regulating osteoclast differentiation from monocytes in bone. Cells expressing RANK were detected in the stroma at 24 and 48 hours after epithelial injury. The cytokine systems that regulate monocyte transition to osteoclast in bone are upregulated in the cornea in response to epithelial injury and may participate in regulating monocyte phenotype during corneal stromal wound healing.


Dicoumarol inhibits rat NAD(P)H:quinone oxidoreductase in vitro and induces its expression in vivo.
Dicoumarol is known to act as an inhibitor of quinone oxidoreductase (NQO1). This cytosolic reductase significantly contributes to the genotoxicity of the nephrotoxic and carcinogenic alkaloid aristolochic acid I (AAI). Aristolochic acid causes aristolochic acid nephropathy (AAN), and Balkan endemic nephropathy (BEN), as well as associated urothelial malignancies. NQO1 is the most efficient enzyme responsible for the reductive bioactivation of AAI to species forming covalent AAI-DNA adducts. However, it is still not known how dicoumarol influences the NQO1-mediated reductive bioactivation of AAI. AAI-DNA adduct formation was determined by 32P-postlabeling. Expression of NQO1 mRNA and NQO1 protein was determined by real-time polymerase chain reaction and Western blotting, respectively. In this study, dicoumarol inhibited AAI bioactivation to form AAI-DNA adducts mediated by rat and human NQO1 in vitro as expected. We however, demonstrated that dicoumarol acts as an inducer of NQO1 in kidney and lung of rats treated with this NQO1 inhibitor in vivo, both at protein and activity levels. This NQO1 induction increased the potency of kidney cytosol to bioactivate AAI and elevated AAI-DNA adduct levels were found in ex-vivo incubations of AAI with renal cytosols and DNA. NQO1 mRNA levels were induced in liver only by dicoumarol. Our results indicate a dual role of dicoumarol in NQO1-mediated genotoxicty of AAI. It acts both as an NQO1 inhibitor mainly in vitro and as an NQO1 inducer if administered to rats.


Serodiagnosis of La Crosse virus infections in humans by detection of immunoglobulin M class antibodies.
Sera from 92 humans with illnesses clinically compatible with those caused by California serogroup virus infections were tested for antibody to La Crosse (LAC) virus by using the immunoglobulin M (IgM) antibody-capture enzyme-linked immunosorbent assay (MAC ELISA), the IgG ELISA, and the hemagglutination inhibition (HI), complement fixation and serum dilution-plaque reduction neutralization tests. On the reported day of onset of illness in 18 individuals, 94% had IgM antibody, 50% had neutralization antibody, 33% had HI antibody, and 11% had IgG antibody. Neutralization, HI, and IgG antibody prevalence rates increased thereafter, whereas IgM antibody prevalence remained high (92% 2 or more weeks after the onset of illness). It was concluded that the MAC ELISA is a sensitive test for the presence of antibody to LAC virus. The sensitivity of the MAC ELISA and the rapidity with which it can be performed appear to provide a powerful tool for the clinically relevant serodiagnosis of LAC virus infections in humans.


Energy system contributions to the special judo fitness test.
This study investigated the energy system contributions of judo athletes to the Special Judo Fitness Test (SJFT). Fourteen male judo athletes performed the SJFT, which comprised three periods of judo activity (A = 15 s, B and C = 30 s) interspersed with 10 s rest intervals. During this test, one athlete threw two others positioned 6 m from each other using the ippon-seoi-nage technique. The fractions of the aerobic, anaerobic alactic and anaerobic lactic systems were calculated based on oxygen uptake, the fast component of excess postexercise oxygen uptake, and changes in net blood lactate, respectively. The contribution of the three energy systems was compared using a repeated measures analysis of variance and Bonferroni's multiple comparisons test. Compound symmetry, or sphericity, was determined by Mauchly's test. A level of significance of 5% (P < .05) was adopted in all analyses. The alactic energy system presented a higher (F = 20.9; P < .001; power observed = 1.0) contribution (86.8 ± 23.6 kJ; 42.3 ± 5.9%) during the test when compared with both aerobic (57.1 ± 11.3 kJ; 28.2 ± 2.9%) and lactic (58.9 ± 12.1 kJ; 29.5 ± 6.2%) energy systems (P < .001 for both comparisons). The higher alactic contribution seems to be a consequence of the high-intensity efforts performed during the test, and its intermittent nature. Thus, when using the SJFT, coaches are evaluating mainly their athletes' anaerobic alactic system, which can be considered to be the most predominant system contributing to the actions (techniques) performed in the match.


Methamphetamine-induced psychosis: Clinical features, treatment modalities and outcomes.
To investigate the clinical features, prescribing patterns and outcomes of psychiatric inpatients admitted with methamphetamine-induced psychosis. A cross-sectional, descriptive pilot study was conducted between March 2014 and August 2014 at three South African Mental Health Care Act designated hospitals prior to admission to a psychiatric hospital. Patients with methamphetamine-related psychotic symptoms according to the DSM-5 criteria were eligible. Structured face-to-face interviews were conducted and the Brief Psychiatric Rating Scale was employed as a measure of current psychopathology. Fifty-six participants were included. Positive psychotic symptoms (e.g. hallucinations) were more prominent than negative symptoms (e.g. affective blunting). Almost half the participants (43%) had previous episodes of methamphetamine-induced psychosis. Within this group, all had defaulted on the prescribed treatment prior to admission. Only 29% of the participants had received prior formal substance-use rehabilitation as treatment for their disorder. High rates of comorbid cannabis and alcohol use (51%) were recorded. Most of the participants required transfer to specialist psychiatric hospitals. The amounts of methamphetamine used were not a predictor of the persistence of psychosis; however, the pattern of use was. Clinical features correspond with other international findings. The currently employed model of sequential, non-integrated psychiatric and substance use treatment in this setting appears ineffective.


Acute pancreatitis in slender-tailed meerkats (Suricata suricatta).
Four adult, full-sibling slender-tailed meerkats (Suricata suricatta) were diagnosed with acute pancreatitis. The incident case presented with lethargy, anorexia, abdominal guarding, and a cranial abdominal mass. Serum was grossly lipemic, with elevated cholesterol and triglyceride concentrations and increased amylase and lipase activity. An exploratory laparotomy confirmed chylous peritonitis and included excision of a saponified spleno-duodenal mass, a partial pancreatectomy, and a splenectomy. Histopathology revealed severe, multifocal, subacute necrotizing and granulomatous pancreatitis. Within 13 days of the incident case, the second meerkat was identified with essentially identical clinical, surgical, and histologic findings. During subsequent physical examinations of apparently unaffected cohorts (n=12), physical and hematologic findings suggestive of pancreatitis were identified in the two remaining siblings of the first two cases. The definitive cause for these four cases is undetermined; however, common risk factors identified were obesity and hyperlipidemia, a change to a higher-fat diet, and genetic predisposition. To assess its usefulness in the diagnosis of meerkat pancreatitis, serum canine and feline pancreatic lipase immunoreactivity (cPLI and fPLI) concentrations were measured in serum samples (n=61) from two unrelated meerkat populations. Although these assays are highly sensitive and specific for the diagnosis of pancreatitis in domestic carnivores, similar correlation was not apparent for meerkats. In addition, hyperlipidemia was inconsistently present in many meerkats, with no apparent correlation to the development of clinical illness. Based on these observations, sensitive and specific diagnostic tests for pancreatitis in meerkats are currently unavailable.


The association between circulating angiotensin-converting enzyme and cardiovascular risk in the elderly: a cross-sectional study.
A polymorphism in the angiotensin-converting enzyme gene (ACE I/D polymorphism) has been associated with increased risk for cardiovascular disease (CVD). This polymorphism affects the level of circulating ACE, but there is great individual variation, even between those with the same genotype. Few previous studies have investigated the link between circulating ACE and cardiovascular risk. The aim of this study was to investigate this association, and to examine the relationship between ACE level, ACE genotype and CVD. The study population consisted of 322 men and 350 women aged 69-87. Plasma ACE level was determined using enzyme-linked immunosorbent assay (ELISA), and ACE genotype was analysed using PCR followed by gel electrophoresis. In men, ACE levels increased with increasing number of cardiovascular risk factors (p = 0.003). There was a significant association in men between increased ACE level and both diabetes (p = 0.007) and smoking (p = 0.037). This study shows that cardiovascular risk factors (such as smoking and diabetes) are associated with higher levels of circulating ACE in men. High ACE levels may represent one of the cellular mechanisms involved in producing the vascular damage associated with cardiovascular risk factors.


NFATc1 regulation of TRAIL expression in human intestinal cells.
TNF-related apoptosis-inducing ligand (TRAIL; Apo2) has been shown to promote intestinal cell differentiation. Nuclear factor of activated T cells (NFAT) participates in the regulation of a variety of cellular processes, including differentiation. Here, we examined the role of NFAT in the regulation of TRAIL in human intestinal cells. Treatment with a combination of phorbol 12-myristate 13-acetate (PMA) plus the calcium ionophore A23187 (Io) increased NFAT activation and TRAIL expression; pretreatment with the calcineurin inhibitor cyclosporine A (CsA), an antagonist of NFAT signaling, diminished NFAT activation and TRAIL induction. In addition, knockdown of NFATc1, NFATc2, NFATc3, and NFATc4 blocked PMA/Io increased TRAIL protein expression. Expression of NFATc1 activated TRAIL promoter activity and increased TRAIL mRNA and protein expression. Deletion of NFAT binding sites from the TRAIL promoter did not significantly abrogate NFATc1-increased TRAIL promoter activity, suggesting an indirect regulation of TRAIL expression by NFAT activation. Knockdown of NFATc1 increased Sp1 transcription factor binding to the TRAIL promoter and, importantly, inhibition of Sp1, by chemical inhibition or RNA interference, increased TRAIL expression. These studies identify a novel mechanism for TRAIL regulation by which activation of NFATc1 increases TRAIL expression through negative regulation of Sp1 binding to the TRAIL promoter.


Cohabiting unions, repartnering and mental health.
A considerable body of research has established that transitions out of marriage are generally deleterious for mental health and some have examined transitions out of cohabitation. In this study we depart from these established areas to investigate the effects of poor mental health on the duration and outcome of cohabitations and on the time to, and likelihood of, repartnering after both cohabitation and marriage. Samples came from the British Household Panel Survey, 1991--2001. These were: (1) 447 cohabiting spells; (2) 5571 paired person-years during cohabitation; (3) 508 spells after cohabitation; (4) 1197 person-year observations within those spells; (5) 869 spells after marriage; and (6) 2736 person-year observations within those spells. Life tables, log-rank tests, multinomial logit and proportional hazard models were used. Mental health was measured by the 12-item General Health Questionnaire. Poor mental health increased the risk of dissolving a cohabiting union for both men and women. Poor mental health reduced the risk of repartnering after a cohabiting union but had no effect on the risk of repartnering after a marriage. Other factors such as past marital status, age and parental status also had significant effects. This study provides evidence that poor mental health during a cohabiting union increases the chances of that union dissolving instead of turning into marriage and poorer mental health immediately after a transition out of a cohabiting union is associated with reduced chances of repartnering.


Association of Fitness in Young Adulthood With Survival and Cardiovascular Risk: The Coronary Artery Risk Development in Young Adults (CARDIA) Study.
Although cardiorespiratory fitness (CRF) is prognostic in older adults, the effect of CRF during early adulthood on long-term cardiovascular structure, function, and prognosis is less clear. To examine whether CRF in young adults is associated with long-term clinical outcome and subclinical cardiovascular disease (CVD). Prospective study of 4872 US adults aged 18 to 30 years who underwent treadmill exercise testing at a baseline study visit from March 25, 1985, to June 7, 1986, and 2472 individuals who underwent a second treadmill test 7 years later. Median follow-up was 26.9 years, with assessment of obesity, left ventricular mass and strain, coronary artery calcification (CAC), and vital status and incident CVD. Follow-up was complete on August 31, 2011, and data were analyzed from recruitment through the end of follow-up. The presence of CAC was assessed by computed tomography at years 15 (2000-2001), 20 (2005-2006), and 25 (2010-2011), and left ventricular mass was assessed at years 5 (1990-1991) and 25 (with global longitudinal strain). Incident CVD and all-cause mortality were adjudicated. Of the 4872 individuals, 273 (5.6%) died and 193 (4.0%) experienced CVD events during follow-up. After comprehensive adjustment, each additional minute of baseline exercise test duration was associated with a 15% lower hazard of death (hazard ratio [HR], 0.85; 95% CI, 0.80-0.91; P < .001) and a 12% lower hazard of CVD (HR, 0.88; 95% CI, 0.81-0.96; P = .002). Higher levels of baseline CRF were associated with significantly lower left ventricular mass index (β = -0.24; 95% CI, -0.45 to -0.03; P = .02) and significantly better lobal longitudinal strain (β = -0.09; 95% CI, -0.14 to -0.05; P < .001) at year 25. Fitness was not associated with CAC. A 1-minute reduction in fitness by year 7 was associated with 21% and 20% increased hazards of death (HR, 1.21; 95% CI, 1.07-1.37; P = .002) and CVD (HR, 1.20; 95% CI, 1.06-1.37; P = .006), respectively, along with a more impaired strain (β = 0.15; 95% CI, 0.08-0.23; P < .001). No association between change in fitness and CAC was found. Higher levels of fitness at baseline and improvement in fitness early in adulthood are favorably associated with lower risks for CVD and mortality. Fitness and changes in fitness are associated with myocardial hypertrophy and dysfunction but not CAC. Regular efforts to ascertain and improve CRF in young adulthood may play a critical role in promoting cardiovascular health and interrupting early CVD pathogenesis.


A study of mobile phone use among patients with noncommunicable diseases in La Paz, Bolivia: implications for mHealth research and development.
While global momentum supporting mobile health (mHealth) research and development is increasing, it is imperative to assess the potential fit of mHealth programs in local settings. We describe the penetration of mobile technologies among Bolivian patients with noncommunicable diseases (NCDs) to inform research on mHealth interventions for the Andean region as well as low- and middle-income countries more generally. Five-hundred and fifty-nine NCD patients were identified from outpatient clinics affiliated with four hospitals in the cities of La Paz and El Alto. Respondents completed surveys about their use of standard mobile phones and smartphones. Respondents also provided information about their sociodemographic characteristics, health status, and access to care. We used descriptive statistics and logistic regression to understand the variation in mobile phone use across groups defined by patient characteristics associated with health service access and socioeconomic vulnerability. Respondents were on average 52 years of age, 33% had at most a sixth grade education, and 30% spoke an indigenous language in their home. Eighty-six percent owned a mobile phone and 13% owned a smartphone. Fifty-eight percent of mobile phone users sent or received a text message at least once a week. Some mobile phone owners reported connectivity problems, such as lacking mobile signal (9%) or credit to make a call (17%). Younger age, male gender, high health literacy, more years of education, and having fewer previously diagnosed NCDs were positively related to mobile phone ownership. Among mobile phone users, respondents with lower education and other indicators of vulnerability were less likely than their counterparts to report frequent usage of texting services. Mobile phones have high penetration among NCD patients in La Paz, Bolivia, including among those who are older, less educated, and who have other socioeconomic risk factors. Smartphone use is still relatively uncommon, even among patients who are younger and more educated. While certain patient characteristics such as age or education impact patients' use of text messaging, mobile phone-based mHealth interventions are feasible strategies for increasing NCD patients' access to self-management support between face-to-face clinical encounters.


Activation of a Lotus japonicus subtilase gene during arbuscular mycorrhiza is dependent on the common symbiosis genes and two cis-active promoter regions.
The subtilisin-like serine protease SbtM1 is strongly and specifically induced during arbuscular mycorrhiza (AM) symbiosis in Lotus japonicus. Another subtilase gene, SbtS, is induced during early stages of nodulation and AM. Transcript profiling in plant symbiosis mutants revealed that the AM-induced expression of SbtM1 and the gene family members SbtM3 and SbtM4 is dependent on the common symbiosis pathway, whereas an independent pathway contributes to the activation of SbtS. We used the specific spatial expression patterns of SbtM1 promoter β-d-glucuronidase (GUS) fusions to isolate cis elements that confer AM responsiveness. A promoter deletion and substitution analysis defined two cis regions (region I and II) in the SbtM1 promoter necessary for AM-induced GUS activity. 35S minimal promoter fusions revealed that either of the two regions is sufficient for AM responsiveness when tested in tandem repeat arrangement. Sequence-related regions were found in the promoters of AM-induced subtilase genes in Medicago truncatula and rice, consistent with an ancient origin of these elements predating the divergence of the angiosperms.


Identification of novel Cryptosporidium genotypes from avian hosts.
A total of 430 avian-derived fecal specimens were randomly collected from selected Western Australian commercial aviaries, poultry farms, hatcheries, wildlife parks, and the Perth Zoo and screened for the presence of Cryptosporidium by PCR. Of these, 27 Cryptosporidium-positive isolates were detected, characterized, and compared with 11 avian-derived isolates from the Czech Republic at the 18S rRNA and actin gene loci. Sequence and phylogenetic analysis identified four genetically distinct genotypes, avian genotypes I to IV, from various avian hosts. In addition, the host range for Cryptosporidium galli was extended. Cryptosporidium muris and Cryptosporidium andersoni were also identified in a tawny frogmouth and a quail-crested wood partridge, respectively.


Mechanisms underlying increased platelet reactivity in patients with peripheral arterial disease. Preliminary results.
In peripheral arterial disease (PAD) atherosclerosis is disseminated and thrombosis risk is high. We have not only shown the platelets of PAD patients to by hyperreactive and aspirin resistant, but have recently verified them to be hypersensitive to heparin as well. In the present study we have begun to clarify the mechanisms underlying these regularly observed clinical findings. Platelet function was tested with conventional, ADP-primed aggregation and with stagnation point flow adhesio-aggregometry (SPAA). SPAA permits real time, quantitative assessment of platelet adhesion and aggregation under biologically relevant flow conditions. The platelets from a female patient with congenital afibrinogenemia, were analyzed before and after intravenous fibrinogen substitution. In 14 PAD patients and 14 controls, platelet reactivity was assessed before and after incubation with the two platelet membrane glycoprotein (GP)-IIb/IIIa inhibitors Ro 43-8857 and 7E3. Lastly, experiments were performed before and after addition of plasma aliquots stemming from 4 PAD patients to platelet rich plasma and to solutions of gel-filtered platelets (GFP) stemming from 4 healthy volunteers. Before fibrinogen substitution, the platelets of the afibrinogenemic patient were unable to adhere in the SPAA-system and maximal ADP-primed aggregability was below 10%. After substitution, normal platelet adhesion was measured and primed aggregation increased three-fold. Mean baseline adhesion in the patient collective was twice that compared to controls (p<0.001). SPAA-measured, spontaneous aggregation was observed in ten patients and in none of the controls (p<0.001). Both SPAA-measured and primed aggregation were abolished at the lowest substrate concentrations (0.1 microM Ro 43-8857, 1 microg/ml 7E3). At these concentrations adhesion was reduced by 65% and 40% (respectively) in patients, and by 55% and 25% in controls. Total abolition of adhesion in both groups was seen with 0.5 microM Ro 43-8857 and 10 microg/ml 7E3. Platelet response to inhibitory agent was similar in patients and controls, as were the differences in dose-response between aggregation and adhesion. Upon addition of patient plasma to volunteer PRP, the platelets of all 4 healthy individuals aggregated spontaneously and the mean adhesivity in the group rose three-fold. The overall ability of the GFP to adhere when re-added to their own plasma was decreased, whereas, in the presence of patient plasma, adhesion increased significantly. On the basis of these findings we conclude that: 1) SPAA measures and quantifies platelet interactions with both fluid-phase (aggregation) and immobilized (adhesion) fibrinogen, 2) these reactions are mediated by the GP, IIb/IIIa receptor complex 3) the binding affinity, metabolic pathways and signal transduction underlying platelet adhesion differ from those involved in aggregation (possibly reflecting their varying roles in hemostasis), 4) the functionally normal platelets of patients with PAD are primed in vivo by a circulating plasma constituent, which leads to enhanced recruitment of activated GP, IIb/IIIa onto the platelet surface and, thereby, to an overall increase in reactivity.


Design of financial incentive interventions to improve lifestyle behaviors and health outcomes: A systematic review.
Background: Financial incentives may improve the initiation and engagement of behaviour change that reduce the negative outcomes associated with non-communicable diseases. There is still a paucity in guidelines or recommendations that help define key aspects of incentive-oriented interventions, including the type of incentive (e.g. cash rewards, vouchers), the frequency and magnitude of the incentive, and its mode of delivery. We aimed to systematically review the literature on financial incentives that promote healthy lifestyle behaviours or improve health profiles, and focused on the methodological approach to define the incentive intervention and its delivery. The protocol was registered at PROSPERO on 26 July 2018 ( CRD42018102556). Methods: We sought studies in which a financial incentive was delivered to improve a health-related lifestyle behaviour (e.g., physical activity) or a health profile (e.g., HbA1c in people with diabetes). The search (which took place on March 3 rd 2018) was conducted using OVID (MEDLINE and Embase), CINAHL and Scopus. Results: The search yielded 7,575 results and 37 were included for synthesis. Of the total, 83.8% (31/37) of the studies were conducted in the US, and 40.5% (15/37) were randomised controlled trials. Only one study reported the background and rationale followed to develop the incentive and conducted a focus group to understand what sort of incentives would be acceptable for their study population. There was a degree of consistency across the studies in terms of the direction, form, certainty, and recipient of the financial incentives used, but the magnitude and immediacy of the incentives were heterogeneous. Conclusions: The available literature on financial incentives to improve health-related lifestyles rarely reports on the rationale or background that defines the incentive approach, the magnitude of the incentive and other relevant details of the intervention, and the reporting of this information is essential to foster its use as potential effective interventions.


Deoxysphingolipids - atypical skeletal muscle lipids related to insulin resistance in humans that decrease insulin sensitivity in vitro.
Sphingolipids are thought to promote skeletal muscle insulin resistance. 1-Deoxysphingolipids (dSL) are atypical sphingolipids that are increased in plasma of individuals with type 2 diabetes and cause β-cell dysfunction in vitro. However, their role in human skeletal muscle in unknown. We found that dSL species are significantly elevated in muscle of individuals with obesity and type 2 diabetes compared to athletes and lean individuals and are inversely related to insulin sensitivity. Furthermore, we observed a significant reduction in muscle dSL content in individuals with obesity who completed a combined weight loss and exercise intervention. Increased dSL content in primary human myotubes caused a decrease in insulin sensitivity associated with increased inflammation, decreased AMP-activated kinase (AMPK) phosphorylation, and altered insulin signaling. Our findings reveal a central role for dSL in human muscle insulin resistance and suggest dSL as therapeutic targets for the treatment and prevention of type 2 diabetes.


Swept-source optical coherence tomography microsystem with an integrated Mirau interferometer and electrothermal micro-scanner.
In the rapid evolution of gastrointestinal endomicroscopy, optical coherence tomography (OCT) has found many diverse applications. Until recently, the micro-opto-electro-mechanical systems (MOEMS) technology has been playing a key role in shaping the miniaturization of these components. We report here, to the best of our knowledge, a novel endoscopic microsystem. It is based on a spectrally tuned MOEMS Mirau micro-interferometer integrated with micro-electro-mechanical systems (MEMS) electro-thermal micro-scanner, operating in the regime of swept-source (SS) OCT imaging. This Letter validates our initial proof-of-concept toward the development of such MOEMS probe and the presentation of experimental performances of the resulting SS-OCT microsystem.


Evolution and development of inflorescence architectures.
To understand the constraints on biological diversity, we analyzed how selection and development interact to control the evolution of inflorescences, the branching structures that bear flowers. We show that a single developmental model accounts for the restricted range of inflorescence types observed in nature and that this model is supported by molecular genetic studies. The model predicts associations between inflorescence architecture, climate, and life history, which we validated empirically. Paths, or evolutionary wormholes, link different architectures in a multidimensional fitness space, but the rate of evolution along these paths is constrained by genetic and environmental factors, which explains why some evolutionary transitions are rare between closely related plant taxa.


T wave alternans and ventricular tachyarrhythmia risk stratification: a review.
Sudden cardiac death (SCD) is one of the leading causes of mortality in industrialized countries. Thus, identifying patients at high risk of SCD is an important goal. T wave alternans (TWA) is a new method for identifying patients with lethal ventricular tachyarrhythmias, and is dependent on heart rate. The maximal predictive accuracy is achieved at heart rates between 100 and 120 bpm, so that TWA is usually measured during exercise, pharmacological stress, or atrial pacing. It has been shown that TWA has high sensitivity and negative predictive value for predicting SCD after myocardial infarction and is also useful for predicting SCD in patients with nonischemic cardiomyopathy. Although the implantable cardioverter defibrillator (ICD) is now the primary therapy for preventing SCD, it is difficult to identify those patients who are susceptible to lethal ventricular tachyarrhythmias for primary prevention. In the prediction of SCD, TWA can be used as a screening test of appropriate patients for further electrophysiological examination and therapy.


Sequencing of 50 human exomes reveals adaptation to high altitude.
Residents of the Tibetan Plateau show heritable adaptations to extreme altitude. We sequenced 50 exomes of ethnic Tibetans, encompassing coding sequences of 92% of human genes, with an average coverage of 18x per individual. Genes showing population-specific allele frequency changes, which represent strong candidates for altitude adaptation, were identified. The strongest signal of natural selection came from endothelial Per-Arnt-Sim (PAS) domain protein 1 (EPAS1), a transcription factor involved in response to hypoxia. One single-nucleotide polymorphism (SNP) at EPAS1 shows a 78% frequency difference between Tibetan and Han samples, representing the fastest allele frequency change observed at any human gene to date. This SNP's association with erythrocyte abundance supports the role of EPAS1 in adaptation to hypoxia. Thus, a population genomic survey has revealed a functionally important locus in genetic adaptation to high altitude.


A randomized, placebo-controlled, multicenter study of divalproex sodium extended-release in the acute treatment of mania.
Divalproex sodium extended-release (ER) was examined for the treatment of acute mania in adults in 2 randomized, placebo-controlled clinical trials. One study demonstrated statistically significant improvements in mania symptoms compared to placebo, while an earlier study did not. Results of the earlier study are presented here. A total of 225 DSM-IV-diagnosed bipolar I disorder patients were randomly assigned in a 2:1 ratio to 21 days of double-blind treatment with divalproex ER (n = 147) or placebo (n = 78). The daily divalproex ER dosage was initiated at 20 mg/kg. The primary efficacy variable was the change from baseline to final evaluation in Mania Rating Scale (MRS) score. Subjects were discontinued from the study if they were discharged from the hospital or if they met prespecified improvement criteria. The study was conducted from May 1998 to July 1999 at centers in the United States. There was no statistically significant difference in MRS score change from baseline to final for patients treated with divalproex ER compared with those treated with placebo. With the exception of back pain and constipation, adverse event rates between placebo and divalproex ER were very similar. A large proportion of patients prematurely discontinued study treatment (divalproex ER: 83%, placebo: 82%). The mean daily dose of divalproex ER was 2,211 mg with a mean maximum serum valproic acid concentration of 77.9 microg/mL. The results of the current study did not demonstrate statistically significant improvement in mania symptoms associated with divalproex ER treatment compared to placebo. A number of methodological considerations may have contributed to the negative findings, including allowance for early study discontinuation and lower than optimal dosing. clinicaltrials.gov Identifier: NCT00060905.


Mechanical response of the tympanal membranes of the tree cricket Oecanthus henryi.
Crickets have two tympanal membranes on the tibiae of each foreleg. Among several field cricket species of the genus Gryllus (Gryllinae), the posterior tympanal membrane (PTM) is significantly larger than the anterior membrane (ATM). Laser Doppler vibrometric measurements have shown that the smaller ATM does not respond as much as the PTM to sound. Hence the PTM has been suggested to be the principal tympanal acoustic input to the auditory organ. In tree crickets (Oecanthinae), the ATM is slightly larger than the PTM. Both membranes are structurally complex, presenting a series of transverse folds on their surface, which are more pronounced on the ATM than on the PTM. The mechanical response of both membranes to acoustic stimulation was investigated using microscanning laser Doppler vibrometry. Only a small portion of the membrane surface deflects in response to sound. Both membranes exhibit similar frequency responses, and move out of phase with each other, producing compressions and rarefactions of the tracheal volume backing the tympanum. Therefore, unlike field crickets, tree crickets may have four instead of two functional tympanal membranes. This is interesting in the context of the outstanding question of the role of spiracular inputs in the auditory system of tree crickets.


Microlens-array-enabled on-chip optical trapping and sorting.
An on-chip optical trapping and sorting system composed of a microchamber and a microlens array (MLA) is demonstrated. The MLA focuses the incident light into multiple confocal spots to trap the particles within the microchamber. The SiO(2)/ZrO(2) solgel material is introduced in the fabrication of MLA for its unique optical and chemical characters. Moreover, in order to prove the effectiveness of the system, experimental demonstration of multibeam trapping and locked-in transport of micropolymer particles in the microchamber is implemented. The system may easily be integrated as microfluidic devices, offering a simple and efficient solution for optical trapping and sorting of biological particles in lab-on-a-chip technologies.


Hospitalization, inpatient burden and comorbidities associated with bullous pemphigoid in the U.S.A.
Bullous pemphigoid (BP) is associated with significant disability and comorbid health disorders that may lead to or result from hospitalization. However, little is known about the inpatient burden and comorbidities of BP. To obtain data on the inpatient burden and comorbidities of BP in the U.S.A. We analysed data from the 2002 to 2012 National Inpatient Sample, including a representative 20% sample of all hospitalizations in the U.S.A. (72 108 077 adults). The prevalence of hospitalization for BP increased from 25·84 to 32·60 cases per million inpatients from 2002 to 2012. In multivariate logistic regression models with stepwise selection, increasing age, nonwhite ethnicity, higher median household income, being insured with Medicare or Medicaid, and increasing number of chronic conditions were all associated with hospitalization for BP (P < 0·05 for all). The top three primary discharge diagnoses for patients with a secondary diagnosis of BP were septicaemia (prevalence 5·51%, 95% confidence interval 5·03-5·99), pneumonia (4·60%, 4·19-5·01) and urinary tract infection (3·52%, 3·15-3·89). Patients with BP also had numerous autoimmune, infectious, cardiovascular and other comorbidities. Interestingly, BP was associated with multiple neuropsychiatric disorders, including demyelinating disorders, dementias (presenile, senile, vascular and other), paralysis, neuropathy (diabetic, other polyneuropathy), Parkinson disease, epilepsy, psychoses and depression. The mean annual age- and sex-adjusted in-hospital mortality rate was significantly higher in patients with a secondary diagnosis of BP compared with no BP (2·9%, range 2·8-3·9% vs. 2·1%, range 1·9-2·2%). Significant predictors of mortality in patients with BP included increasing age, nonwhite ethnicity and insurance with Medicaid or other payment status (P < 0·05 for all). Hospitalization for BP increased significantly between 2002 and 2012. Moreover, there were significant ethnic and healthcare disparities with respect to hospitalization and inpatient mortality from BP.


Determinants of human papillomavirus-negative, low-grade squamous intraepithelial lesions in the atypical squamous cells of undetermined significance/low-grade squamous intraepithelial lesions triage study (ALTS).
Although low-grade squamous intraepithelial lesions (LSIL) most often are the result of infection by human papillomaviruses (HPV), a small proportion of women with LSIL have negative HPV tests. Using the Atypical Squamous Cells of Undetermined Significance/LSIL Triage Study (ALTS) population, the authors evaluated the significance of HPV-negative LSIL. Women with cytologic interpretations of LSIL by referral Papanicolaou (Pap) tests or enrollment ThinPrep tests (range, 1195-1476 women, depending on the specimen type and the reviewer) had HPV testing performed by both Hybrid Capture 2 and polymerase chain reaction (PCR)-based linear array for 27 HPV types. Using 4 independent cytologic definitions of LSIL, only 3-11% of women with LSIL were found to have HPV-negative results on both HPV tests. The demographic characteristics of women with HPV-negative LSIL were consistent with those of a low-risk population; many were age > 35 years, and many reported no or only 1 recent sexual partner. The absolute risk of a histologic diagnosis of cervical intraepithelial neoplasia (CIN) Grade 3/carcinoma during the 2-year trial was lower for women with HPV-negative LSIL (range, 2-4%) compared with the absolute risks for oncogenic HPV-positive women with LSIL (range, 13-19%). However, at the next 6-month follow-up visit, 12%-32% of the women with HPV-negative LSIL had a positive HPV test. Finally, visual inspection of cervigrams demonstrated a clear association between a larger os and negative HPV test results compared with women who had HPV-positive LSIL. This may have influenced HPV sample adequacy. Based on the ALTS data, the authors found no evidence to support the existence of HPV-negative LSIL as a distinct biologic entity related to the risk of cervical carcinoma. Such results appear to represent cytologic misinterpretations or falsely negative HPV tests.


A method for determining exercise oscillatory ventilation in heart failure: Prognostic value and practical implications.
Exercise oscillatory ventilation (EOV) has been shown to be a powerful prognostic marker in chronic heart failure (CHF). However, EOV is poorly defined, its measurement lacks standardization and it is underutilized in clinical practice. The purpose of this pilot study was to investigate the prognostic value of a modified definition of EOV in patients with CHF. Eighty-nine CHF patients (56.5±8.4years) (64% NYHA class III-IV) underwent cardiopulmonary exercise testing. EOV was defined as meeting all the following criteria: (1) ≥3 consecutive cyclic fluctuations of ventilation during exercise; (2) average amplitude over 3 ventilatory oscillations ≥5L; and (3) an average length of three oscillatory cycles 40s to 140s. Adverse cardiac events were tracked during 28±19months follow up. Cox proportional hazard analysis was used to determine the association between cardiac events and EOV. Forty-eight patients (54%) met all three criteria and were determined to have EOV. These patients exhibited significantly increased risk for adverse cardiac events [hazard ratio=2.2, 95% CI (1.2 to 4.1), p=0.011] compared to patients without EOV. After adjusting for age and established prognostic covariates (peak VO2 and VE/VCO2 slope), the modified EOV definition was the only significant variable in the multivariate model [hazard ratio=2.0, 95% CI (1.1 to 3.7), p=0.035]. The proposed method for determining EOV was independently associated with increased risk for adverse cardiac events in CHF patients. While larger prospective studies are needed, this definition provides a relatively simple and more objective characterization of EOV, suggesting its potential application in clinical practice.


Fentanyl and clonidine as adjuncts to a mixture of local anesthetics in potentiating postoperative analgesia in supraclavicular block: A randomized controlled study.
Brachial plexus block is popular for upper limb surgeries as it is effective for postoperative analgesia. The aim of the study was to compare fentanyl and clonidine as adjuncts to a mixture of local anesthetics in potentiating postoperative analgesia in the supraclavicular block. Sixty patients of the American Society of Anesthesiologist I and II undergoing upper limb surgeries lasting more than 30 min were included and randomly divided into two groups of 30 each. In clonidine (C) group, patients received 10 ml of 0.5% bupivacaine + 20 ml of 2% lignocaine with adrenaline (1:200,000) and 1 μg/kg clonidine diluted till 35 cc with normal saline. In fentanyl (F) group, patients received 10 ml of 0.5% bupivacaine + 20 ml of 2% lignocaine with adrenaline (1:200,000) and 1 μg/kg fentanyl diluted till 35 cc with normal saline. Patients were observed for onset and duration of sensory and motor blockade, duration of analgesia, postoperative pain, and adverse effects. The mean onset of sensory block was faster in Group F (8.43 ± 2.897 min) as compared to 13.17 ± 2.451 min in Group C. The difference between the two groups was statistically strongly significant (P < 0.0001). There was a significant reduction in the onset of motor block in Group F (14.67 ± 1.84 min) compared to (18.17 ± 2.45 min) Group C with P < 0.0001 (statistically strongly significant). There was a significant increase in the duration of analgesia in Group C (16.63 ± 2.04 h) compared to Group F (8.79 ± 1.50 h) with P < 0.0001. There was bradycardia (pulse did not fall below 60) in two patients of Group C (treated with atropine intravenous [i.v.]). Two patients of Group F complained of nausea and vomiting once in the early hours of surgery for which ondansetron i.v. was given. There were no significant side effects in either of the groups. Both clonidine and fentanyl establish a good safety profile. Fentanyl ensures a faster onset of sensory and motor blockade, while clonidine ensures a longer duration of sensory and motor blockade as well as prolonged analgesia.


Proteomic-based detection of a protein cluster dysregulated during cardiovascular development identifies biomarkers of congenital heart defects.
Cardiovascular development is vital for embryonic survival and growth. Early gestation embryo loss or malformation has been linked to yolk sac vasculopathy and congenital heart defects (CHDs). However, the molecular pathways that underlie these structural defects in humans remain largely unknown hindering the development of molecular-based diagnostic tools and novel therapies. Murine embryos were exposed to high glucose, a condition known to induce cardiovascular defects in both animal models and humans. We further employed a mass spectrometry-based proteomics approach to identify proteins differentially expressed in embryos with defects from those with normal cardiovascular development. The proteins detected by mass spectrometry (WNT16, ST14, Pcsk1, Jumonji, Morca2a, TRPC5, and others) were validated by Western blotting and immunoflorescent staining of the yolk sac and heart. The proteins within the proteomic dataset clustered to adhesion/migration, differentiation, transport, and insulin signaling pathways. A functional role for several proteins (WNT16, ADAM15 and NOGO-A/B) was demonstrated in an ex vivo model of heart development. Additionally, a successful application of a cluster of protein biomarkers (WNT16, ST14 and Pcsk1) as a prenatal screen for CHDs was confirmed in a study of human amniotic fluid (AF) samples from women carrying normal fetuses and those with CHDs. The novel finding that WNT16, ST14 and Pcsk1 protein levels increase in fetuses with CHDs suggests that these proteins may play a role in the etiology of human CHDs. The information gained through this bed-side to bench translational approach contributes to a more complete understanding of the protein pathways dysregulated during cardiovascular development and provides novel avenues for diagnostic and therapeutic interventions, beneficial to fetuses at risk for CHDs.


Potentially increased incidence of scaffold thrombosis in patients treated with Absorb BVS who terminated DAPT before 18 months.
The aim of this study was to investigate the impact of dual antiplatelet therapy (DAPT) termination on late and very late scaffold thrombosis (ScT) in patients treated with the Absorb bioresorbable vascular scaffold (BVS). Data from the registries of three centres were pooled (808 patients). To investigate the effect of DAPT termination on ScT after a minimum of six months, we selected a subgroup ("DAPT study cohort" with 685 patients) with known DAPT status >6 months and excluded the use of oral anticoagulants and early ScT. In this cohort, definite/probable ScT incidence for the period on DAPT was compared to ScT incidence after DAPT termination. ScT incidence was 0.83 ScT/100 py with 95% confidence interval (CI): 0.34-1.98. After DAPT termination, the incidence was higher (1.77/100 py; 95% CI: 0.66-4.72), compared to the incidence on DAPT (0.26/100 py, 95% CI: 0.04-1.86; p=0.12) and increased within the month after DAPT termination (6.57/100 py, 95% CI: 2.12-20.38; p=0.01). No very late ScT occurred in patients who continued on DAPT for a minimum of 18 months. The incidence of late and very late definite/probable ScT was acceptable. The incidence was low while on DAPT but potentially higher when DAPT was terminated before 18 months.


Induced alpha helix in the VP16 activation domain upon binding to a human TAF.
Activation domains are functional modules that enable sequence-specific DNA binding proteins to stimulate transcription. The structural basis for the function of activation domains is poorly understood. A combination of nuclear magnetic resonance (NMR) and biochemical experiments revealed that the minimal acidic activation domain of the herpes simplex virus VP16 protein undergoes an induced transition from random coil to alpha helix upon binding to its target protein, hTAFII31 (a human TFIID TATA box-binding protein-associated factor). Identification of the two hydrophobic residues that make nonpolar contacts suggests a general recognition motif of acidic activation domains for hTAFII31.


Human immune system development and survival of non-obese diabetic (NOD)-scid IL2rγ(null) (NSG) mice engrafted with human thymus and autologous haematopoietic stem cells.
Immunodeficient mice bearing targeted mutations in the IL2rg gene and engrafted with human immune systems are effective tools for the study of human haematopoiesis, immunity, infectious disease and transplantation biology. The most robust human immune model is generated by implantation of human fetal thymic and liver tissues in irradiated recipients followed by intravenous injection of autologous fetal liver haematopoietic stem cells [often referred to as the BLT (bone marrow, liver, thymus) model]. To evaluate the non-obese diabetic (NOD)-scid IL2rγ(null) (NSG)-BLT model, we have assessed various engraftment parameters and how these parameters influence the longevity of NSG-BLT mice. We observed that irradiation and subrenal capsule implantation of thymus/liver fragments was optimal for generating human immune systems. However, after 4 months, a high number of NSG-BLT mice develop a fatal graft-versus-host disease (GVHD)-like syndrome, which correlates with the activation of human T cells and increased levels of human immunoglobulin (Ig). Onset of GVHD was not delayed in NSG mice lacking murine major histocompatibility complex (MHC) classes I or II and was not associated with a loss of human regulatory T cells or absence of intrathymic cells of mouse origin (mouse CD45(+) ). Our findings demonstrate that NSG-BLT mice develop robust human immune systems, but that the experimental window for these mice may be limited by the development of GVHD-like pathological changes.


Strain Response in the Facet Joint Capsule During Physiological Joint Rotation and Translation Following a Simulated Impact Exposure: An In Vitro Porcine Model.
Low back pain (LBP) is frequently reported following rear impact collisions. Knowledge of how the facet joint capsule (FJC) mechanically behaves before and after rear impact collisions may help explain LBP development despite negative radiographic evidence of gross tissue failure. This study quantified the Green strain tensor in the facet joint capsule during rotation and translation range-of-motion tests completed before and following an in vitro simulation of a rear impact collision. Eight FSUs (4 C3-C4, 4 C5-C6) were tested. Following a preload test, FSUs were flexed and extended at 0.5 deg/s until an ±8 N·m moment was achieved. Anterior and posterior joint translation was then applied at 0.2 mm/s until a target ±400 N shear load was imposed. Markers were drawn on the facet capsule surface and their coordinates were tracked during pre- and postimpact range-of-motion tests. Strain was defined as the change in point configuration relative to the determined neutral joint posture. There were no significant differences (p > 0.05) observed in all calculated FJC strain components in rotation and translation before and after the simulated impact. Our results suggest that LBP development resulting from the initiation of strain-induced mechanoreceptors and nociceptors with the facet joint capsule is unlikely following a severe rear impact collision within the boundaries of physiological joint motion.


Contact with out-group friends as a predictor of meta-attitudinal strength and accessibility of attitudes toward gay men.
Two studies examined the effects of cross-group friendships on heterosexuals' attitudes toward gay men. In Study 1, the authors tested the effects of cross-group friendships with gay men on out-group attitudes, meta-attitudinal strength, and attitude accessibility. The authors simultaneously explored mediational effects of intergroup anxiety. Path analysis showed that cross-group friendships were associated with meta-attitudinally stronger and more accessible out-group attitudes, and the effects on all 3 criterion variables were mediated by intergroup anxiety. In Study 2, the authors sought to replicate the basic results of Study 1, while additionally exploring mediational effects of closeness of cross-group friendship and moderational effects of perceived group typicality. Structural equation modeling showed that cross-group friendships were associated with meta-attitudinally stronger and more accessible out-group attitudes; friendships had indirect effects on all 3 criterion variables, via closeness of friendship and intergroup anxiety. Closeness of friendship only predicted lower intergroup anxiety, however, when the out-group friend was perceived as highly typical. The authors emphasize the importance of considering the nature of out-group attitudes more completely when evaluating the effectiveness of intergroup contact in reducing prejudice.


Methylation-sensitive sequence-specific DNA binding by the c-Myc basic region.
The function of the c-Myc oncoprotein and its role in cell growth control is unclear. A basic region of c-Myc is structurally related to the basic motifs of helix-loop-helix (HLH) and leucine zipper proteins, which provide sequence-specific DNA binding function. The c-Myc basic region was tested for its ability to bind DNA by attaching it to the HLH dimerization interface of the E12 enhancer binding factor. Dimers of the chimeric protein, termed E6, specifically bound an E box element (GGCCACGTGACC) recognized by other HLH proteins in a manner dependent on the integrity of the c-Myc basic motif. Methylation of the core CpG in the E box recognition site specifically inhibited binding by E6, but not by two other HLH proteins. Expression of E6 (but not an E6 DNA binding mutant) suppressed the ability of c-myc to cooperate with H-ras in a rat embryo fibroblast transformation assay, suggesting that the DNA recognition specificity of E6 is related to that of c-Myc in vivo.


Exploring family risk and protective factors for adolescent problem behaviors in the Caribbean.
This paper develops measures of family risk and protective factors for adolescent problem behaviors and tests the effects of these measures on three health risk behaviors in a Caribbean nation: illegal gun ownership, gang membership, and drug use. Data are drawn from a sample of 2,376 adolescents in Trinidad and Tobago, a developing nation in the eastern Caribbean. Descriptive statistics are reported, as well as findings from exploratory and confirmatory factor analyses and structural equation models. Existing measures of family risk and protective factors have weak construct and concurrent validity when applied to a sample of youth from Trinidad and Tobago. The revised measures developed in this study have stronger construct validity and some of them have a significant influence on one or more health risk behaviors. From a methodological perspective, the findings are useful for thinking about the validity of existing measures of family risk and protective factors, especially for use in settings distant from where they were developed. From a substantive perspective, the findings outline the family correlates of three health risk behaviors known to exert a strong influence on morbidity and mortality among adolescents.


Rosiglitazone improves glucose metabolism in nondiabetic uremic patients on CAPD.
Insulin resistance, a strong risk factor for atherosclerotic vascular disease, is present in uremic patients without diabetes on continuous ambulatory peritoneal dialysis (CAPD) therapy. Amelioration of insulin resistance may reduce associated long-term cardiovascular complications. The aim of the study is to investigate the effects of rosiglitazone (ROS), an insulin sensitizer, on glucose metabolism in CAPD patients without diabetes. Fifteen uremic patients without diabetes on CAPD therapy were enrolled. All were administered ROS, 4 mg/d, for 12 weeks. A control group consisted of 15 age- and sex-matched healthy subjects. Oral glucose tolerance test (OGTT) results, fasting glucose and insulin levels, related blood biochemistry results, and C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha) levels were determined before initiation and at 4 and 12 weeks of therapy. Insulin resistance was evaluated using the homeostasis model assessment method (HOMA-IR). A whole-body insulin sensitivity index (ISI) and insulinogenic index for insulin production were calculated from OGTT results. CAPD patients showed significantly greater HOMA-IR and glucose intolerance compared with healthy controls. After 4 and 12 weeks of ROS therapy, there were no significant changes in body weight, blood pressure, dialysis adequacy, hemoglobin level, hemoglobin A(1c) level, liver function, lipid profile, or intact parathyroid hormone, CRP, IL-6, or TNF-alpha levels. There was a significant decrease in HOMA-IR (3.2 +/- 0.6, 2.2 +/- 0.4, and 2.1 +/- 0.4; P < 0.05). During the OGTT, there was a significant decrease in the area under the glucose curve and a significant increase in ISI (3.5 +/- 0.4, 5.0 +/- 0.7, and 5.3 +/- 0.7; P < 0.05), but no significant change in insulinogenic index. ROS improved insulin resistance in CAPD patients without diabetes. Whether long-term use of ROS reduces cardiovascular risk needs further study.


Colloidal lithography nanostructured Pd/PdO x core-shell sensor for ppb level H2S detection.
In this work we report on plasma oxidation of palladium (Pd) to form reliable palladium/palladium oxide (Pd/PdO x ) core-shell sensor for ppb level H2S detection and its performance improvement through nanostructuring using hole-mask colloidal lithography (HCL). The plasma oxidation parameters and the sensor operating conditions are optimized to arrive at a sensor device with high sensitivity and repeatable response for H2S. The plasma oxidized palladium/palladium oxide sensor shows a response of 43.1% at 3 ppm H2S at the optimum operating temperature of 200 °C with response and recovery times of 24 s and 155 s, respectively. The limit of detection (LoD) of the plasma oxidised beam is 10 ppb. We further integrate HCL, a bottom-up and cost-effective process, to create nanodiscs of fixed diameter of 100 nm and varying heights (10, 15 and 20 nm) on 10 nm thin Pd beam which is subsequently plasma oxidized to improve the H2S sensing characteristics. The nanostructured Pd/PdO x sensor with nanodiscs of 100 nm diameter and 10 nm height shows an enhancement in sensing performance by 11.8% at same operating temperature and gas concentration. This nanostructured sensor also shows faster response and recovery times (15 s and 100 s, respectively) compared to the unstructured Pd/PdO x counterpart together with an experimental LoD of 10 ppb and the estimated limit going all the way down to 2 ppb. Material characterization of the fabricated Pd/PdO x sensors is done using UV-vis spectroscopy and x-ray photoemission spectroscopy.


Patient acceptability, safety and access: A balancing act for selecting age-appropriate oral dosage forms for paediatric and geriatric populations.
The selection and design of age-appropriate formulations intended for use in paediatric and geriatric patients are dependent on multiple factors affecting patient acceptability, safety and access. The development of an economic and effective product relies on a balanced consideration of the risks and benefits of these factors. This review provides a comprehensive and up-to-date analysis of oral dosage forms considering key aspects of formulation design including dosage considerations, ease of use, tolerability and safety, manufacturing complexity, stability, supply and cost. Patient acceptability has been examined utilising an evidence-based approach to evaluate regulatory guidance and literature. Safety considerations including excipients and potential risk of administration errors of the different dosage forms are also discussed, together with possible manufacturing and supply challenges. Age appropriate drug product design should consider and compare i) acceptability ii) safety and iii) access, although it is important to recognise that these factors must be balanced against each other, and in some situations a compromise may need to be reached when selecting an age-appropriate formulation.


Aneurysmal wall imaging in a case of cortical superficial siderosis and multiple unruptured aneurysms.
We report a case of interhemispheric and bifrontal cortical superficial siderosis in association with two intracranial aneurysms. The patient had no clinical history suggestive of aneurysm rupture, no feature of amyloid angiopathy or other apparent etiology for cortical siderosis. We performed high resolution brain MRI with dark blood T1 sequences before and after IV contrast injection. An anterior communicating aneurysm showed partial wall enhancement on the posterior wall whereas a left posterior communicating aneurysm did not. In the light of recent reports of the association of wall enhancement with unstable aneurysms, we considered wall enhancement to be a marker of inflammation and remodeling of the aneurysm wall, resulting in chronic hemorrhagic suffusion in the subarachnoid spaces. To our knowledge, this is the first report offering proof for a possible link between apparently unruptured aneurysms and cortical siderosis.


Serological and molecular characteristics of the first Korean case of Echinococcus multilocularis.
In December 2011, we reported an autochthonous case of Echinococcus multilocularis infection in a 42-year-old woman in Korea. The diagnosis was based on histopathological findings of the surgically resected liver cyst. In the present study, we evaluated the serological and molecular characteristics of this Korean E. multilocularis case. The patient's serum strongly reacted with affinity-purified native Em18 and recombinant Em18 antigens (specific for E. multilocularis) but negative for recombinant antigen B8/1 (reactive for Echinococcus granulosus). In immunoaffinity chromatography, the serum also strongly reacted with E. multilocularis and only weakly positive for E. granulosus. We determined the whole nucleotide sequence of cox1 (1,608 bp) using the paraffin-embedded cystic tissue which was compared with E. multilocularis isolates from China, Japan, Kazakhstan, Austria, France, and Slovakia. The Korean case showed 99.8-99.9% similarity with isolates from Asia (the highest similarity with an isolate from Sichuan, China), whereas the similarity with European isolates ranged from 99.5 to 99.6%.


Healthcare reform: implications for knowledge translation in primary care.
The primary care sector represents the linchpin of many health systems. However, the translation of evidence-based practices into patient care can be difficult, particularly during healthcare reform. This can have significant implications for patients, their communities, and the public purse. This is aptly demonstrated in the area of sexual health. The aim of this paper is to determine what works to facilitate evidence-based sexual healthcare within the primary care sector. 431 clinicians (214 general practitioners and 217 practice nurses) in New South Wales, Australia, were surveyed about their awareness, their use, the perceived impact, and the factors that hindered the use of six resources to promote sexual healthcare. Descriptive statistics were calculated from the responses to the closed survey items, while responses to open-ended item were thematically analyzed. All six resources were reported to improve the delivery of evidence-based sexual healthcare. Two resources - both double-sided A4-placards - had the greatest reach and use. Barriers that hindered resource-use included limited time, limited perceived need, and limited access to, or familiarity with the resources. Furthermore, the reorganization of the primary care sector and the removal of particular medical benefits scheme items may have hampered clinician capacity to translate evidence-based practices into patient care. Findings reveal: (1) the translation of evidence-based practices into patient care is viable despite reform; (2) the potential value of a multi-modal approach; (3) the dissemination of relatively inexpensive resources might influence clinical practices; and (4) reforms to governance and/or funding arrangements may widen the void between evidence-based practices and patient care.


Phase retrieval using polychromatic illumination for transmission X-ray microscopy.
An alternative method for quantitative phase retrieval in a transmission X-ray microscope system at sub-50-nm resolution is presented. As an alternative to moving the sample in the beam direction in order to analyze the propagation-introduced phase effect, we have illuminated the TXM using X-rays of different energy without any motor movement in the TXM system. Both theoretical analysis and experimental studies have confirmed the feasibility and the advantage of our method, because energy tuning can be performed with very high energy resolution using a double crystal monochromator at a synchrotron beam line, and there is zero motor error in TXM system in our approach. High-spatial-resolution phase retrieval is accomplished using the proposed method.


Infinite-degree-corrected stochastic block model.
In stochastic block models, which are among the most prominent statistical models for cluster analysis of complex networks, clusters are defined as groups of nodes with statistically similar link probabilities within and between groups. A recent extension by Karrer and Newman [Karrer and Newman, Phys. Rev. E 83, 016107 (2011)] incorporates a node degree correction to model degree heterogeneity within each group. Although this demonstrably leads to better performance on several networks, it is not obvious whether modeling node degree is always appropriate or necessary. We formulate the degree corrected stochastic block model as a nonparametric Bayesian model, incorporating a parameter to control the amount of degree correction that can then be inferred from data. Additionally, our formulation yields principled ways of inferring the number of groups as well as predicting missing links in the network that can be used to quantify the model's predictive performance. On synthetic data we demonstrate that including the degree correction yields better performance on both recovering the true group structure and predicting missing links when degree heterogeneity is present, whereas performance is on par for data with no degree heterogeneity within clusters. On seven real networks (with no ground truth group structure available) we show that predictive performance is about equal whether or not degree correction is included; however, for some networks significantly fewer clusters are discovered when correcting for degree, indicating that the data can be more compactly explained by clusters of heterogenous degree nodes.


The low-frequency encoding disadvantage: Word frequency affects processing demands.
Low-frequency words produce more hits and fewer false alarms than high-frequency words in a recognition task. The low-frequency hit rate advantage has sometimes been attributed to processes that operate during the recognition test (e.g., L. M. Reder et al., 2000). When tasks other than recognition, such as recall, cued recall, or associative recognition, are used, the effects seem to contradict a low-frequency advantage in memory. Four experiments are presented to support the claim that in addition to the advantage of low-frequency words at retrieval, there is a low-frequency disadvantage during encoding. That is, low-frequency words require more processing resources to be encoded episodically than high-frequency words. Under encoding conditions in which processing resources are limited, low-frequency words show a larger decrement in recognition than high-frequency words. Also, studying items (pictures and words of varying frequencies) along with low-frequency words reduces performance for those stimuli.


All-In-One "Schizophrenic" Self-Assembly of Orthogonally Tuned Thermoresponsive Diblock Copolymers.
Smart, fully orthogonal switching was realized in a highly biocompatible diblock copolymer system with variable trigger-induced aqueous self-assembly. The polymers are composed of nonionic and zwitterionic blocks featuring lower and upper critical solution temperatures (LCSTs and UCSTs). In the system investigated, diblock copolymers from poly( N-isopropyl methacrylamide) (PNIPMAM) and a poly(sulfobetaine methacrylamide), systematic variation of the molar mass of the latter block allowed for shifting the UCST of the latter above the LCST of the PNIPMAM block in a salt-free condition. Thus, successive thermal switching results in "schizophrenic" micellization, in which the roles of the hydrophobic core block and the hydrophilic shell block are interchanged depending on the temperature. Furthermore, by virtue of the strong electrolyte-sensitivity of the zwitterionic polysulfobetaine block, we succeeded to shift its UCST below the LCST of the PNIPMAM block by adding small amounts of an electrolyte, thus inverting the pathway of switching. This superimposed orthogonal switching by electrolyte addition enabled us to control the switching scenarios between the two types of micelles (i) via an insoluble state, if the LCST-type cloud point is below the UCST-type cloud point, which is the case at low salt concentrations or (ii) via a molecularly dissolved state, if the LCST-type cloud point is above the UCST-type cloud point, which is the case at high salt concentrations. Systematic variation of the block lengths allowed for verifying the anticipated behavior and identifying the molecular architecture needed. The versatile and tunable self-assembly offers manifold opportunities, for example, for smart emulsifiers or for sophisticated carrier systems.


The availability of community ties predicts likelihood of peer referral for mammography: geographic constraints on viral marketing.
Engaging social networks to encourage preventive health behavior offers a supplement to conventional mass media campaigns and yet we do not fully understand the conditions that facilitate or hamper such interpersonal diffusion. One set of factors that should affect the diffusion of health campaign information involves a person's community. Variables describing geographic communities should predict the likelihood of residents accepting campaign invitations to pass along information to friends, family, and others. We investigate two aspects of a community--the availability of community ties and residential stability--as potential influences on diffusion of publicly-funded breast cancer screening in the United States in 2008-2009. In a survey study of 1515 participants living in 91 zip codes across the State of Minnesota, USA, we focus on the extent to which women refer others when given the opportunity to nominate family, friends, and peers to receive free mammograms. We predicted nomination tendency for a particular zip code would be a function of available community ties, measured as religious congregation density in that zip code, and also expected the predictive power of available ties would be greatest in communities with relatively high residential stability (meaning lower turnover in home residence). Results support our hypotheses. Congregation density positively predicted nomination tendency both in bivariate analysis and in Tobit regression models, and was most predictive in zip codes above the median in residential stability. We conclude that having a local infrastructure of social ties available in a community predicts the diffusion of available health care services in that community.


The chromatin nuclear protein NUPR1L is intrinsically disordered and binds to the same proteins as its paralogue.
NUPR1 is a protumoral multifunctional intrinsically disordered protein (IDP), which is activated during the acute phases of pancreatitis. It interacts with other IDPs such as prothymosin α, as well as with folded proteins such as the C-terminal region of RING1-B (C-RING1B) of the Polycomb complex; in all those interactions, residues around Ala33 and Thr68 (the 'hot-spot' region) of NUPR1 intervene. Its paralogue, NUPR1L, is also expressed in response to DNA damage, it is p53-regulated, and its expression down-regulates that of the NUPR1 gene. In this work, we characterized the conformational preferences of isolated NUPR1L and its possible interactions with the same molecular partners of NUPR1. Our results show that NUPR1L was an oligomeric IDP from pH 2.0 to 12.0, as judged by steady-state fluorescence, circular dichroism (CD), dynamic light scattering, 1D 1H-NMR (nuclear magnetic resonance), and as indicated by structural modelling. However, in contrast with NUPR1, there was evidence of local helical- or turn-like structures; these structures were not rigid, as judged by the lack of sigmoidal behaviour in the chemical and thermal denaturation curves obtained by CD and fluorescence. Interestingly enough, NUPR1L interacted with prothymosin α and C-RING1B, and with a similar affinity to that of NUPR1 (in the low micromolar range). Moreover, NUPR1L hetero-associated with NUPR1 with an affinity of 0.4 µM and interacted with the 'hot-spot' region of NUPR1. Thus, we suggest that the regulation of NUPR1 gene by NUPR1L does not only happen at the DNA level, but it could also involve direct interactions with NUPR1 natural partners.


Molecular Markers for Detecting Schistosoma Species by Loop-Mediated Isothermal Amplification.
Schistosomiasis is considered a neglected parasitic disease. Around 280,000 people die from it annually, and more than 779 million people are at risk of getting infected. The schistosome species which infect human beings are Schistosoma mansoni, Schistosoma haematobium, Schistosoma intercalatum, Schistosoma japonicum, Schistosoma guineensis, and Schistosoma mekongi. This disease is also of veterinary significance; the most important species being Schistosoma bovis since it causes the disease in around 160 million livestock in Africa and Asia. This work was aimed at designing and developing a genus-specific loop-mediated isothermal amplification (LAMP) method for detecting the most important schistosome species affecting humans and for the species-specific detection of S. bovis. Bioinformatics tools were used for primer design, and the LAMP method was standardised for detecting the ITS-1 region from S. intercalatum, S. haematobium, S. mansoni, S. japonicum, and S. bovis DNA (generic test) and the NADH 1 gene for specifically detecting S. bovis (at different DNA concentrations). Detection limits achieved were 1 pg DNA for S. mansoni, 0.1 pg for S. haematobium, 1 pg for S. intercalatum, and 10 pg for S. bovis. No amplification for S. japonicum DNA was obtained. The LAMP designed for the amplification of S. bovis NADH-1 worked specifically for this species, and no other DNA from other schistosome species included in the study was amplified. Two highly sensitive LAMP methods for detecting different Schistosoma species important for human and veterinary health were standardised. These methods could be very useful for the diagnosis and surveillance of schistosome infections.


Adapting a drug screening platform to discover associations of molecular targeted radiosensitizers with genomic biomarkers.
Large collections of annotated cancer cell lines are powerful tools for precisely matching targeted drugs with genomic alterations that can be tested as biomarkers in the clinic. Whether these screening platforms, which utilize short-term cell survival to assess drug responses, can be applied to precision radiation medicine is not established. To this end, 32 cancer cell lines were screened using 18 targeted therapeutic agents with known or putative radiosensitizing properties (227 combinations). The cell number remaining after drug exposure with or without radiation was assessed by nonclonogenic assays. We derived short-term radiosensitization factors (SRF2Gy) and calculated clonogenic survival assay-based dose enhancement factors (DEFSF0.1). Radiosensitization was characterized by SRF2Gy values of mostly ∼1.05 to 1.2 and significantly correlated with drug-induced changes in apoptosis and senescence frequencies. SRF2Gy was significantly correlated with DEFSF0.1, with a respective sensitivity and specificity of 91.7% and 81.5% for a 3-day endpoint, and 82.8% and 84.2% for a robotic 5-day assay. KRAS mutations (codons 12/13) were found to be a biomarker of radiosensitization by midostaurin in lung cancer, which was pronounced under conditions that enriched for stem cell-like cells. In conclusion, although short-term proliferation/survival assays cannot replace the gold-standard clonogenic survival assay for measuring cellular radiosensitivity, they capture with high accuracy the relative change in radiosensitivity that is caused by a radiosensitzing targeted agent. This study supports a paradigm shift regarding the utility of short-term assays for precision radiation medicine, which should facilitate the identification of genomic biomarkers to guide the testing of novel drug/radiation combinations.


Determinants of pregnant women's compliance with alcohol guidelines: a prospective cohort study.
In 2009, Australian alcohol guidelines for pregnancy changed from low to no alcohol intake. Previous research found a high proportion of pregnant Australian women drank during pregnancy; however, there has been limited investigation of whether pregnant women comply with 2009 alcohol guidelines. The purpose of this study was to provide an assessment of pregnant women's compliance with 2009 Australian alcohol guidelines and identify predictors of such compliance, including previous drinking behaviour. Cross-sectional analysis of prospective data from the 1973-1978 cohort of the Australian Longitudinal Study on Women's Health was conducted. Women aged 30-36 years who were pregnant at the 2009 survey and had data on alcohol use were included (n = 837). Compliance with 2009 alcohol guidelines for pregnancy was defined as no alcohol intake. Predictors of compliance were analysed using multivariate logistic regression, controlling for area of residence, in three separate models to account for multicollinearity between measures of previous alcohol intake (compliance with 2001 guidelines; frequency and quantity; bingeing). Private health insurance, household income, and illicit drug use were entered into all models and retained if significant. 72% of pregnant women did not comply with the 2009 alcohol guidelines and 82% of these women drank less than seven drinks per week, with no more than one or two drinks per drinking day. The odds of complying with abstinence increased by a factor of 3.48 (95% CI 2.39-5.05) for women who previously complied with the 2001 alcohol guidelines and decreased by a factor of 0.19 (95% CI 0.08-0.66) if household incomes were $36,400 or more. In other models the odds of complying were lower for women who consumed alcohol before pregnancy at least weekly (OR = 0.40, 95% CI 0.25-0.63) or binged (OR ≥ 0.18, 95% CI 0.10-0.31) and were higher for those who abstained (OR = 45.09; 95% CI 8.63-235.49) prior to pregnancy. Most pregnant women did not comply with alcohol guidelines promoting abstinence. Prior alcohol behaviour was the strongest predictor of compliance during pregnancy, suggesting alcohol use should be addressed in women of child-bearing age. The study is limited by the relatively short timeframe between the official introduction of the 2009 guidelines and the date the surveys were sent out. Widespread dissemination of the guidelines may be necessary to help increase guideline compliance by pregnant women.


DeltaFosB: a sustained molecular switch for addiction.
The longevity of some of the behavioral abnormalities that characterize drug addiction has suggested that regulation of neural gene expression may be involved in the process by which drugs of abuse cause a state of addiction. Increasing evidence suggests that the transcription factor DeltaFosB represents one mechanism by which drugs of abuse produce relatively stable changes in the brain that contribute to the addiction phenotype. DeltaFosB, a member of the Fos family of transcription factors, accumulates within a subset of neurons of the nucleus accumbens and dorsal striatum (brain regions important for addiction) after repeated administration of many kinds of drugs of abuse. Similar accumulation of DeltaFosB occurs after compulsive running, which suggests that DeltaFosB may accumulate in response to many types of compulsive behaviors. Importantly, DeltaFosB persists in neurons for relatively long periods of time because of its extraordinary stability. Therefore, DeltaFosB represents a molecular mechanism that could initiate and then sustain changes in gene expression that persist long after drug exposure ceases. Studies in inducible transgenic mice that overexpress either DeltaFosB or a dominant negative inhibitor of the protein provide direct evidence that DeltaFosB causes increased sensitivity to the behavioral effects of drugs of abuse and, possibly, increased drug seeking behavior. This work supports the view that DeltaFosB functions as a type of sustained "molecular switch" that gradually converts acute drug responses into relatively stable adaptations that contribute to the long-term neural and behavioral plasticity that underlies addiction.


Environmental pollution levels of lead and zinc in Ishiagu and Uburu communities of Ebonyi State, Nigeria.
Water and soil samples from the area were therefore analyzed for their lead and zinc content. Computation of pollution statuses of lead and zinc revealed topsoil lead geoaccumulation indices of -0.143 and -0.069 and zinc geoaccumulation indices of 1.168 and 0.713 for Ishiagu and Uburu respectively. The pollution indices were determined to be 0.499 and 0.3564 for soil in Ishiagu and Uburu respectively and also 5.11 and 2.42 for water in Ishiagu and Uburu communities respectively. Water/soil concentration ratio were found to be 0.0018 and 0.0014 for lead in Ishiagu and Uburu respectively. On the other hand, the water/soil concentration ratio for zinc was computed to be 0.001 and 0.0008 for Ishiagu and Uburu respectively. These results seem to suggest that the pollution of the environment by these heavy metals in the areas were as a result of the water being contaminated by lead and zinc not necessarily their concentrations in the soil.


Invited opinion: role of nitric oxide in hemorrhagic, traumatic, and anaphylactic shock and thermal injury.
The free radical nitric oxide (NO) is synthesized from the guanidino group of L-arginine by a family of enzymes termed NO synthase (NOS). Hemorrhagic shock leads to an inhibition of NO production by the calcium-dependent, endothelial NOS (ecNOS), which may lead to maldistribution of blood flow leading to, e.g., coronary, renal, and cerebral ischemia and may enhance the adhesion of neutrophil granulocytes and platelets to the endothelial surface. Prolonged periods of hemorrhagic shock are associated with the induction of a calcium-independent isoform of NOS in a variety of organs and in the vascular smooth muscle. The formation of large quantities of NO by inducible isoform of NOS (iNOS) contributes to the delayed vascular decompensation and to the hyporeactivity of the vasculature to vasoconstrictor agents. An impairment of NO formation by the ecNOS has been demonstrated in various models of traumatic shock, whereas there is good experimental evidence supporting the hypothesis that an enhanced formation of NO contributes to the pathophysiology of experimental thermal injury and anaphylactic shock. We speculate that a pharmacological modulation of NO biosynthesis which either enhances NO concentration in the vicinity of endothelium (i.e., NO donors) or inhibits NO overproduction following iNOS expression (i.e., iNOS-selective NOS inhibitors) may become novel therapies to improve the outcome of patients with circulatory shock of various etiologies.


Reconstruction of large skeletal defects due to osteomyelitis with the vascularized fibular graft in children.
Reconstruction of large skeletal defects secondary to osteomyelitis is a challenging problem. The purpose of this study was to evaluate the outcome of the use of a vascularized fibular graft to treat such defects in children. Eight patients with a mean age of seven years and a skeletal defect with a mean length of 11.8 cm (range, 6 to 17 cm) were treated with a vascularized fibular graft. A staged protocol was used for the five patients with an active infection at the time of presentation. The first procedure consisted of radical débridement, and at the second stage a free (seven patients) or pedicled (one patient) vascularized fibular graft was used. The mean follow-up time was 5.7 years. Union of the graft occurred primarily in seven of the eight patients, at a mean of 3.5 months, and after iliac crest bone-grafting in the remaining patient. There was no recurrence of deep infection. Complications developed in two patients. The mean time to full weight-bearing by the seven patients with a lower-extremity reconstruction was 8.4 months, and all patients were pain-free and able to walk without supportive devices. A vascularized fibular graft is a viable option for the management of large skeletal defects resulting from osteomyelitis in children.