Correlation of Normal Diastolic Cardiac Function With VO in the Metabolic Syndrome.
Morbid obesity and diabetes cause diastolic dysfunction that can be detected by Doppler echocardiography. Patients with the metabolic syndrome could demonstrate early diastolic dysfunction that may influence effort tolerance. A total of 32 patients (17 men) who fulfilled >/=2 of the 5 metabolic syndrome criteria were studied. The average age of patients was 37+/-2 years. All patients were overweight/obese (mean body mass index of 34.4+/-0.7 kg/m(2)), 15 had blood pressure >130/85 mm Hg, 19 had elevated triglyceride levels (>150 mg/dL), and 17 had low high-density lipoprotein cholesterol levels (men <40 mg/dL, women <50 mg/dL). Maximal exercise was performed using Bruce treadmill protocol with standard stress echocardiography and tissue Doppler. Maximal oxygen consumption (VO(2max)) was measured using indirect calorimetry. Left ventricular filling pressure was indirectly derived from dividing pulse Doppler early mitral inflow velocity (E) by tissue Doppler early diastolic mitral annular motion (E') or E/E'. The group's average treadmill time was 8.06+/-0.28 minutes, VO(2max) was 28.6+/-1.1 mL/kg/min, and 8.2+/-0.3 metabolic equivalents. None had evidence of myocardial ischemia or systolic or diastolic dysfunction with exercise. Mean "resting" E/E' and "post-exercise" E/E' were 7.01+/-0.04 and 7.41+/-0.41, respectively. There was no significant correlation between resting E/E' and VO(2max) (r=-0.266; P=.14). The post-exercise E/E' significantly correlated with VO(2max) (r=-0.483; P=.005) and metabolic equivalents (r=-0.487; P=.005). Diastolic function is preserved in early metabolic syndrome. Even in the normal diastolic function range, exercise E/E' is inversely related to VO(2max). Further longitudinal studies are needed to determine whether they develop diastolic dysfunction and related heart failure.


Gestational diabetes mellitus and risk of childhood overweight and obesity in offspring: a systematic review.
We systematically reviewed research examining the association between gestational diabetes (GDM) and childhood overweight and obesity. We identified studies from three sources: (1) a PubMed search of articles published between January 1990-January 2011, (2) reference lists of publications from the PubMed search, and (3) reference lists of review articles. We included studies that examined GDM separately from pregestational diabetes and childhood overweight or obesity defined as BMI > 85th or 95th percentile. A total of 12 studies were included in the systematic review. Crude odds ratios for the relationship between GDM and childhood overweight or obesity ranged from 0.7 to 6.3; in 8 studies, the associations were not statistically significant. In only 3 studies were results adjusted for any confounders; in the 2 that adjusted for prepregnancy obesity, the GDM and childhood overweight or obesity associations were attenuated and not statistically significant after adjustment. This paper demonstrates inconsistent evidence of an association between GDM and offspring overweight and obesity due to the methodological limitations of existing studies. Recommendations for future research are presented, which address methodological challenges.


Immobilization adjusted clock reaction in the urea-urease-H+ reaction system.
The bell-shaped reactivity-pH curve is the fundamental reason that the temporal programmable kinetic switch in clock reactions can be obtained in bio-competitive enzymatic reactions. In this work, urease was loaded on small resin particles through ionic binding. Experimental results reveal that the immobilization not only increased the stability of the enzyme and the reproducibility of the clock reaction, but also shifted the bell-shaped activity curve to lower pHs. The latter change enables the clock reaction to occur from an initial pH of 2.3, where the free enzyme had already lost its activity. Two mechanisms explain the influence of the immobilization on the clock reaction. Immobilization modified the pH sensitive functional groups on the enzyme, shifting the activity curve to a more acidic region, and reduced diffusion alters the enzyme dynamics.


Thrombomodulin and antibeta2-glycoprotein I in stroke in children.
A quantitative systematic review recently discussed the role of thrombomodulin (Thm) and antibeta2-glycoprotein I (beta2-GPI) in cerebral strokes in adults. Little is known about the problem in children. The aim of the study was to see if there is a difference in the values of Thm and beta2-GPI in children with ischemic stroke. Seventy patients were included, comprising 40 children who had had ischemic stroke of unknown etiology hospitalized from January 1995 to December 2005 at the Department of Developmental Neurology, Chair of Neurology Medical University of Gdańsk, and 30 healthy volunteers (no autoimmunologic disease or headache in interview). The concentrations of thrombomodulin (Thm) and antibeta2-glycoprotein I (beta2-GPI) in A, M, and G immunoglobulins were determined according to an immunoenzyme method (ELISA). None of the investigated subjects had elevated levels of beta2-GPI. The patients with stroke had significantly higher Thm values than the healthy group. This finding of elevated levels of thrombomodulin in cases of pediatric cerebral stroke could help in measuring the extent or duration of parenchymal brain injury, or even perhaps response to future therapeutic maneuvers. All these implications may aid not only in the diagnosis and management of acute ischemic stroke, but encourage prophylactic action to prevent probable stroke relapse.


Reduced quality and accelerated follicle loss with female reproductive aging - does decline in theca dehydroepiandrosterone (DHEA) underlie the problem?
Infertility, spontaneous abortion and conception of trisomic offspring increase exponentially with age in mammals but in women there is an apparent acceleration in the rate from about age 37. The problems mostly commonly occur when the ovarian pool of follicles is depleted to a critical level with age but are also found in low follicular reserve of other etiologies. Since recent clinical studies have indicated that dehydroepiandrosterone (DHEA) supplementation may reverse the problem of oocyte quality, this review of the literature was undertaken in an attempt to find an explanation of why this is effective? In affected ovaries, oxygenation of follicular fluid is low, ultrastructural disturbances especially of mitochondria, occur in granulosa cells and oocytes, and considerable disturbances of meiosis occur. There is, however, no evidence to date that primordial follicles are compromised. In females with normal fertility, pre-antral ovarian theca cells respond to stimulation by inhibin B to provide androgen-based support for the developing follicle. With depletion of follicle numbers, inhibin B is reduced with consequent reduction in theca DHEA. Theca cells are the sole ovarian site of synthesis of DHEA, which is both a precursor of androstenedione and an essential ligand for peroxisome proliferator-activated receptor alpha (PPARα), the key promoter of genes affecting fatty acid metabolism and fat transport and genes critical to mitochondrial function. As well as inducing a plethora of deleterious changes in follicular cytoplasmic structure and function, the omega 9 palmitate/oleate ratio is increased by lowered activity of PPARα. This provides conditions for increased ceramide synthesis and follicular loss through ceramide-induced apoptosis is accelerated. In humans critical theca DHEA synthesis occurs at about 70 days prior to ovulation thus effective supplementation needs to be undertaken about four months prior to intended conception; timing which is also suggested by successful interventions to date. In humans and primates that undergo adrenarche, the adrenal zona reticularis (ZR) is the major site of DHEA production, however this is also reduced with age. Concomitant loss in function of the ZR might account for the acceleration in the rate of aging seen in humans in the late thirties' age group.


Molecular mechanisms of the defective hepcidin inhibition in TMPRSS6 mutations associated with iron-refractory iron deficiency anemia.
Matriptase-2 is a transmembrane serine protease that negatively regulates hepcidin expression by cleaving membrane-bound hemojuvelin. Matriptase-2 has a complex ectodomain, including a C-terminal serine protease domain and its activation requires an autocatalytic cleavage. Matriptase-2 mutations have been reported in several patients with iron-refractory iron deficiency anemia. Here we describe a patient with 2 missense mutations in the second class A low-density lipoprotein receptor (LDLRA) domain. Functional studies of these 2 mutations and of a previously reported mutation in the second C1r/C1s, urchin embryonic growth factor and bone morphogenetic protein 1 (CUB) domain were performed. Transfection of mutant cDNAs showed that membrane targeting of the 2 LDLRA mutants was impaired, with Golgi retention of the variants. The activating cleavage was absent for the LDLRA mutants and reduced for the CUB mutant. All 3 mutated proteins were still able to physically interact with hemojuvelin but only partially repressed hepcidin expression compared with wild-type matriptase-2. Our results underline the importance of LDLRA and CUB domains of matriptase-2.


Three-way coexistence in obligate mutualist-exploiter interactions: the potential role of competition.
Many mutualisms host "exploiter" species that consume the benefits provided by one or both mutualists without reciprocating. Exploiters have been widely assumed to destabilize mutualisms, yet they are common. We develop models to explore conditions for local coexistence of obligate plant/pollinating seed parasite mutualisms and nonpollinating exploiters. As the larvae of both pollinators and (at a later time) exploiters consume seeds, we examine the importance of intraspecific and (asymmetric) interspecific competition among and between pollinators and exploiters for achieving three-way coexistence. With weak intra- and interspecific competition, exploiters can invade the stable mutualism and coexist with the mutualists (either stably or with oscillations), provided the exploiters' intrinsic birthrate (b(E)) slightly exceeds that of the pollinators. At higher b(E), all three species go locally extinct. When facing strong interspecific competition, exploiters cannot invade and coexist with the mutualists if intraspecific competition in pollinators and exploiters is weak. However, strong intraspecific competition in pollinators and exploiters facilitates exploiter invasion and coexistence and greatly expands the range of b(E) over which stable coexistence occurs. Our results suggest that mutualist/exploiter coexistence may be more easily achieved than previously thought, thus highlighting the need for a better understanding of competition among and between mutualists and exploiters.


Meeting American Diabetes Association guidelines in endocrinologist practice.
To determine whether American Diabetes Association (ADA) guidelines can be met in the context of routine endocrinology practice. Charts were reviewed for a group of patients who were examined in 1998, followed for > or = 1 year, and had two or more visits during that year. Process measures and metabolic outcomes were studied for patients with type 2 diabetes, and glycemic control was assessed for patients with type 1 diabetes. A total of 121 patients with type 2 diabetes had a mean age of 63 years, a mean BMI of 31 kg/m2, and a mean duration of diabetes of 12 years. Many had comorbidities or complications: 80% had hypertension, 64% had hyperlipidemia, 78% had neuropathy, 22% had retinopathy, and 21% had albuminuria. Management of type 2 diabetic patients was complex: 38% used oral hypoglycemic agents alone (54% of these were using two or more agents), 31% used oral hypoglycemic agents and insulin, and 26% used insulin alone; 42% of patients taking insulin therapy injected insulin three or more times per day. Within 12 months, 74% of patients had dilated eye examinations, 70% had lipid profiles, and 55% had urine albumin screening. Of the patients, 87% had a foot examination at their last visit. Blood pressure levels averaged 133/72 mmHg, cholesterol levels averaged 4.63 mmol/l, triglyceride levels averaged 1.99 mmol/l, HDL cholesterol levels averaged 1.24 mmol/l, and LDL cholesterol levels averaged 2.61 mmol/l. Random blood glucose levels averaged 8.0 mmol/l, and HbAlc levels averaged 6.9 +/- 0.1%. A total of 87% of patients had HbAlc levels < or = 8.0%. A total of 30 patients with type 1 diabetes had mean age of 44 years, a mean BMI of 26 kg/m2, and a mean duration of diabetes of 20 years. All type 1 diabetic patients used insulin and averaged 3.4 injections a day; their average HbAlc level was 7.1 +/- 0.2%, and 80% had HbAlc levels < or = 8.0%. Although endocrinologists must manage patients with multifaceted problems, complex treatment regimens yield glycemic control levels comparable with the Diabetes Control and Complications Trial and allow ADA guidelines to be met in a routine practice setting.


Construction of genetic linkage maps and comparative genome analysis of catfish using gene-associated markers.
A genetic linkage map of the channel catfish genome (N=29) was constructed using EST-based microsatellite and single nucleotide polymorphism (SNP) markers in an interspecific reference family. A total of 413 microsatellites and 125 SNP markers were polymorphic in the reference family. Linkage analysis using JoinMap 4.0 allowed mapping of 331 markers (259 microsatellites and 72 SNPs) to 29 linkage groups. Each linkage group contained 3-18 markers. The largest linkage group contained 18 markers and spanned 131.2 cM, while the smallest linkage group contained 14 markers and spanned only 7.9 cM. The linkage map covered a genetic distance of 1811 cM with an average marker interval of 6.0 cM. Sex-specific maps were also constructed; the recombination rate for females was 1.6 times higher than that for males. Putative conserved syntenies between catfish and zebrafish, medaka, and Tetraodon were established, but the overall levels of genome rearrangements were high among the teleost genomes. This study represents a first-generation linkage map constructed by using EST-derived microsatellites and SNPs, laying a framework for large-scale comparative genome analysis in catfish. The conserved syntenies identified here between the catfish and the three model fish species should facilitate structural genome analysis and evolutionary studies, but more importantly should facilitate functional inference of catfish genes. Given that determination of gene functions is difficult in nonmodel species such as catfish, functional genome analysis will have to rely heavily on the establishment of orthologies from model species.


Biochemical characterization of a polysialyltransferase from Mannheimia haemolytica A2 and comparison to other bacterial polysialyltransferases.
Polysialic acids are bioactive carbohydrates found in eukaryotes and some bacterial pathogens. The bacterial polysialyltransferases (PSTs), which catalyze the synthesis of polysialic acid capsules, have previously been identified in select strains of Escherichia coli and Neisseria meningitidis and are classified in the Carbohydrate-Active enZYmes Database as glycosyltransferase family GT-38. In this study using DNA sequence analysis and functional characterization we have identified a novel polysialyltransferase from the bovine/ovine pathogen Mannheimia haemolytica A2 (PSTMh). The enzyme was expressed in recombinant form as a soluble maltose-binding-protein fusion in parallel with the related PSTs from E. coli K1 and N. meningitidis group B in order to perform a side-by-side comparison. Biochemical properties including solubility, acceptor preference, reaction pH optima, thermostability, kinetics, and product chain length for the enzymes were compared using a synthetic fluorescent acceptor molecule. PSTMh exhibited biochemical properties that make it an attractive candidate for chemi-enzymatic synthesis applications of polysialic acid. The activity of PSTMh was examined on a model glycoprotein and the surface of a neuroprogenitor cell line where the results supported its development for use in applications to therapeutic protein modification and cell surface glycan remodelling to enable cell migration at implantation sites to promote wound healing. The three PSTs examined here demonstrated different properties that would each be useful to therapeutic applications.


Can personality traits and intelligence compensate for background disadvantage? Predicting status attainment in adulthood.
This study investigated the interplay of family background and individual differences, such as personality traits and intelligence (measured in a large U.S. representative sample of high school students; N = 81,000) in predicting educational attainment, annual income, and occupational prestige 11 years later. Specifically, we tested whether individual differences followed 1 of 3 patterns in relation to parental socioeconomic status (SES) when predicting attained status: (a) the independent effects hypothesis (i.e., individual differences predict attainments independent of parental SES level), (b) the resource substitution hypothesis (i.e., individual differences are stronger predictors of attainments at lower levels of parental SES), and (c) the Matthew effect hypothesis (i.e., "the rich get richer"; individual differences are stronger predictors of attainments at higher levels of parental SES). We found that personality traits and intelligence in adolescence predicted later attained status above and beyond parental SES. A standard deviation increase in individual differences translated to up to 8 additional months of education, $4,233 annually, and more prestigious occupations. Furthermore, although we did find some evidence for both the resource substitution and the Matthew effect hypotheses, the most robust pattern across all models supported the independent effects hypothesis. Intelligence was the exception, the interaction models being more robust. Finally, we found that although personality traits may help compensate for background disadvantage to a small extent, they do not usually lead to a "full catch-up" effect, unlike intelligence. This was the first longitudinal study of status attainment to test interactive models of individual differences and background factors.


Comparison of cerebral aneurysm volumes as determined by digitally measured 3D rotational angiography and approximation from three diameters.
This study compared digital measurement of aneurysm volume by 3D rotational angiography (3D-RA) with an approximation technique using three diameters of an aneurysm to re-interpret previously reported optimal packing densities (volume embolization ratio, VER) in coil embolization of intracranial aneurysms. Estimation of the volume of saccular aneurysms is important for calculation of the VER, which is in turn reported to be useful for prediction of coil compaction. The conventional formula for the volume estimation is V=4/3 π(A/2) (B/2) (C/2), where A, B, and C are the aneurysmal height, length, and width measured on 3D-RA image respectively. Using 3D rotational angiography data from 74 aneurysms, the approximated volume generated using the conventional formula was directly compared with the digitally measured volume. The digitally measured volume varied from 0.003 ml to 7.935 ml, and the dome-to-neck ratio (D/N) from 0.79 up to 4.62. We found that the conventional formula almost systematically underestimated the volume by up to 50 %, particularly when the neck was large relative to the dome (D/N<2). On average, digitally measured volume was 1.26~1.29 times larger than the approximated volume obtained using the conventional formula.Conventional 2D angiography based aneurysm volume calculation tends to underestimate an aneurysm volume, so the so-called VER (volume embolization ratio) could be overestimated.


Is there a delayed gastric emptying of patients with early-stage, untreated Parkinson's disease? An analysis using the 13C-acetate breath test.
During the pre-symptomatic stage of Parkinson's disease (PD), the idiopathic PD related abnormal synuclein immunostaining is confined to the medulla oblongata and olfactory bulb, according to Braak. In the study of the enteric nervous system of PD, it has reported that Lewy bodies were found in the Auerbach's and Meissner's plexuses. These lesions may cause dysfunction of the gastrointestinal tract (GI) as pre-clinical symptoms of PD. However, because L: -dopa therapy itself may worsen the symptoms of the digestive tract function, it is needed to evaluate the gastrointestinal tract function in patients with early-stage, untreated (de novo) PD. In the present study, using the (13)C-acetate breath test ((13)C-ABT), we investigated gastric emptying in 20 untreated, early-stage PD patients and 40 treated, advanced-stage PD patients, and 20 healthy volunteers. Gastric emptying was examined by the (13)C-ABT [the half emptying time (HET), the peak time of the (13)C% dose-excess curve (T (max))]. The T (max) and HET of gastric emptying as assessed using the (13)C-ABT was significantly delayed in untreated, early-stage PD patients as compared to the controls (P < 0.001). The T (max) and HET of gastric emptying were not significantly delayed in untreated, early-stage PD patients as compared to treated, advanced-stage PD patients. The results demonstrated that delay in gastric emptying did not differ between untreated, early-stage and treated, advanced-stage PD patients. Gastric emptying of untreated, early-stage PD is already delayed. Delayed gastric emptying may be one of markers of the pre-clinical stage of PD.


Identifying Future Drinkers: Behavioral Analysis of Monkeys Initiating Drinking to Intoxication is Predictive of Future Drinking Classification.
The Monkey Alcohol Tissue Research Resource (MATRR) is a repository and analytics platform for detailed data derived from well-documented nonhuman primate (NHP) alcohol self-administration studies. This macaque model has demonstrated categorical drinking norms reflective of human drinking populations, resulting in consumption pattern classifications of very heavy drinking (VHD), heavy drinking (HD), binge drinking (BD), and low drinking (LD) individuals. Here, we expand on previous findings that suggest ethanol drinking patterns during initial drinking to intoxication can reliably predict future drinking category assignment. The classification strategy uses a machine-learning approach to examine an extensive set of daily drinking attributes during 90 sessions of induction across 7 cohorts of 5 to 8 monkeys for a total of 50 animals. A Random Forest classifier is employed to accurately predict categorical drinking after 12 months of self-administration. Predictive outcome accuracy is approximately 78% when classes are aggregated into 2 groups, "LD and BD" and "HD and VHD." A subsequent 2-step classification model distinguishes individual LD and BD categories with 90% accuracy and between HD and VHD categories with 95% accuracy. Average 4-category classification accuracy is 74%, and provides putative distinguishing behavioral characteristics between groupings. We demonstrate that data derived from the induction phase of this ethanol self-administration protocol have significant predictive power for future ethanol consumption patterns. Importantly, numerous predictive factors are longitudinal, measuring the change of drinking patterns through 3 stages of induction. Factors during induction that predict future heavy drinkers include being younger at the time of first intoxication and developing a shorter latency to first ethanol drink. Overall, this analysis identifies predictive characteristics in future very heavy drinkers that optimize intoxication, such as having increasingly fewer bouts with more drinks. This analysis also identifies characteristic avoidance of intoxicating topographies in future low drinkers, such as increasing number of bouts and waiting longer before the first ethanol drink.


A comparison of cost effectiveness using data from randomized trials or actual clinical practice: selective cox-2 inhibitors as an example.
Data on absolute risks of outcomes and patterns of drug use in cost-effectiveness analyses are often based on randomised clinical trials (RCTs). The objective of this study was to evaluate the external validity of published cost-effectiveness studies by comparing the data used in these studies (typically based on RCTs) to observational data from actual clinical practice. Selective Cox-2 inhibitors (coxibs) were used as an example. The UK General Practice Research Database (GPRD) was used to estimate the exposure characteristics and individual probabilities of upper gastrointestinal (GI) events during current exposure to nonsteroidal anti-inflammatory drugs (NSAIDs) or coxibs. A basic cost-effectiveness model was developed evaluating two alternative strategies: prescription of a conventional NSAID or coxib. Outcomes included upper GI events as recorded in GPRD and hospitalisation for upper GI events recorded in the national registry of hospitalisations (Hospital Episode Statistics) linked to GPRD. Prescription costs were based on the prescribed number of tables as recorded in GPRD and the 2006 cost data from the British National Formulary. The study population included over 1 million patients prescribed conventional NSAIDs or coxibs. Only a minority of patients used the drugs long-term and daily (34.5% of conventional NSAIDs and 44.2% of coxibs), whereas coxib RCTs required daily use for at least 6-9 months. The mean cost of preventing one upper GI event as recorded in GPRD was US$104k (ranging from US$64k with long-term daily use to US$182k with intermittent use) and US$298k for hospitalizations. The mean costs (for GPRD events) over calendar time were US$58k during 1990-1993 and US$174k during 2002-2005. Using RCT data rather than GPRD data for event probabilities, the mean cost was US$16k with the VIGOR RCT and US$20k with the CLASS RCT. The published cost-effectiveness analyses of coxibs lacked external validity, did not represent patients in actual clinical practice, and should not have been used to inform prescribing policies. External validity should be an explicit requirement for cost-effectiveness analyses.


Rhabdomyolysis: a review, with emphasis on the pediatric population.
Rhabdomyolysis is a common clinical syndrome and accounts for 7% of all cases of acute kidney injury (AKI) in the USA. It can result from a wide variety of disorders, such as trauma, exercise, medications and infection, but in the pediatric population, infection and inherited disorders are the most common causes of rhabdomyolysis. Approximately half of patients with rhabdomyolysis present with the triad of myalgias, weakness and dark urine. The clinical suspicion, especially in the setting of trauma or drugs, is supported by elevated creatinine kinase levels and confirmed by the measurement of myoglobin levels in serum or urine. Muscle biopsy and genetic testing should be performed if rhabdomyolysis is recurrent or metabolic myopathy is suspected. Early recognition is important to prevent AKI through the use of aggressive hydration. Prevention is important in patients with inherited forms, but novel therapies may be developed with the better understanding of the pathophysiology and genetics of rhabdomyolysis.


Preclinical pharmacokinetics of a HepDirect prodrug of a novel phosphonate-containing thyroid hormone receptor agonist.
The prodrug [(2R,4S)-4-(3-chlorophenyl)-2-[(3,5-dimethyl-4-(4'-hydroxy-3'-isopropylbenzyl)phenoxy)methyl]-2-oxido-[1,3,2]-dioxaphosphonane (MB07811)] of a novel phosphonate-containing thyroid hormone receptor agonist [3,5-dimethyl-4-(4'-hydroxy-3'-isopropylbenzyl)phenoxylmethylphosphonic acid (MB07344)] is the first application of the HepDirect liver-targeting approach to a non-nucleotide agent. The disposition of MB07811 was characterized in rat, dog, and monkey to assess its liver specificity, which is essential in limiting the extrahepatic side effects associated with this class of lipid-lowering agents. MB07811 was converted to MB07344 in liver microsomes from all species tested (CL(int) 1.23-145.4 microl/min/mg). The plasma clearance and volume of distribution of MB07811 matched or exceeded 1 l/h/kg and 3 l/kg, respectively. Although absorption of prodrug was good, its absolute oral bioavailability as measured systemically was low (3-10%), an indication of an extensive hepatic first-pass effect. This effect was confirmed by comparison of systemic exposure levels of MB07811 after portal and jugular vein administration to rats, which demonstrated a hepatic extraction ratio of >0.6 with liver CYP3A-mediated conversion to MB07344 being a major component. The main route of elimination of MB07811 and MB07344 was biliary, with no evidence for enterohepatic recirculation of MB07344. Similar metabolic profiles of MB07811 were obtained in liver microsomes across the species tested. Tissue distribution and whole body autoradiography confirmed that the liver is the major target organ of MB07811 and that conversion to MB07344 was high in the liver relative to that in other tissues. Hepatic first-pass extraction and metabolism of MB07811, coupled with possible selective distribution of MB07811-derived MB07344, led to a high degree of liver targeting of MB07344.


Age-varying associations between nonmarital sexual behavior and depressive symptoms across adolescence and young adulthood.
Research has demonstrated associations between adolescent sexual behavior and depressive symptoms, but no single study has examined individuals at different ages throughout adolescence and young adulthood in order to determine at what ages sexual behavior may be associated with higher or lower levels of depressive symptoms. Using nationally representative longitudinal data and an innovative method, the time-varying effect model (TVEM), which examines how the strength of an association changes over time, this study examines how nonmarital sexual intercourse is associated with depressive symptoms at different ages, which behaviors and contexts may contribute to these associations, and whether associations differ for male and female participants. Findings indicate that sexual behavior in adolescence is associated with a higher level of depressive symptoms, particularly for female adolescents, and this association is relatively consistent across different partner types and adolescent contexts. Associations between sexual behavior and depressive symptoms in young adulthood are more dependent on partner factors and adolescent contexts; sexual behavior in young adulthood is associated with fewer depressive symptoms for women who have sex with a single partner and for men whose parents did not strongly disapprove of adolescent sexual behavior. Findings suggest that delaying sexual behavior into young adulthood may have some benefits for mental health, although contextual and relationship factors also play a role. (PsycINFO Database Record


G6PD deficiency in Latin America: systematic review on prevalence and variants.
Plasmodium vivax radical cure requires the use of primaquine (PQ), a drug that induces haemolysis in glucose-6-phosphate dehydrogenase deficient (G6PDd) individuals, which further hampers malaria control efforts. The aim of this work was to study the G6PDd prevalence and variants in Latin America (LA) and the Caribbean region. A systematic search of the published literature was undertaken in August 2013. Bibliographies of manuscripts were also searched and additional references were identified. Low prevalence rates of G6PDd were documented in Argentina, Bolivia, Mexico, Peru and Uruguay, but studies from Curaçao, Ecuador, Jamaica, Saint Lucia, Suriname and Trinidad, as well as some surveys carried out in areas of Brazil, Colombia and Cuba, have shown a high prevalence (> 10%) of G6PDd. The G6PD A-202A mutation was the variant most broadly distributed across LA and was identified in 81.1% of the deficient individuals surveyed. G6PDd is a frequent phenomenon in LA, although certain Amerindian populations may not be affected, suggesting that PQ could be safely used in these specific populations. Population-wide use of PQ as part of malaria elimination strategies in LA cannot be supported unless a rapid, accurate and field-deployable G6PDd diagnostic test is made available.


The safe passage study: design, methods, recruitment, and follow-up approach.
The Safe Passage Study is a large, prospective, multidisciplinary study designed to (1) investigate the association between prenatal alcohol exposure, sudden infant death syndrome (SIDS), and stillbirth, and (2) determine the biological basis of the spectrum of phenotypic outcomes from exposure, as modified by environmental and genetic factors that increase the risk of stillbirth, SIDS, and in surviving children, fetal alcohol spectrum disorders. The results provided are based on an interim assessment of 6004 women enrolled, out of the 12,000 projected, from the Northern Plains, US, and Cape Town, South Africa, areas known to be of high risk for maternal drinking during pregnancy. Research objectives, study design, and descriptive statistics, including consent, recruitment, and retention information, are provided. Overall visit compliance is 87%, and includes prenatal, delivery/newborn, and postnatal contacts through 1 year post-delivery. Pregnancy outcome ascertainment is 98% prior to medical chart review; less than 2% of women withdraw. Consent for the use of DNA and placental tissue exceed 94%, and consent to participate in the autopsy portion of the study is 71%. The Safe Passage Study is the first multi-site study of SIDS and stillbirth to integrate prospectively collected exposure information with multidisciplinary biological information in the same maternal and fetal/infant dyad using a common protocol. Essential components of the study design and its success are close ties to the community and rigorous systems and processes to ensure compliance with the study protocol and procedures.


Induced Forgetting Is the Result of True Forgetting, Not Shifts in Decision-making Thresholds.
Induced forgetting occurs when accessing an item in memory appears to harm memory representations of categorically related items. However, it is possible that the actual memory representations are unharmed. Instead, people may just change how they make decisions. Specifically, signal detection theory suggests this apparent forgetting may be due to participants shifting their decision criterion. Here, we used behavioral and electrophysiological measures to determine whether induced forgetting is truly due to changes in how items are represented or simply due to a shifting criterion. Participants' behavior and brain activity showed that induced forgetting was due to changes in the strength of the underlying representations, weighing against a criterion shift explanation of induced forgetting.


Temporal orienting in Parkinson's disease.
Temporal orienting of attention can affect multiple stages of processing to guide adaptive behaviour. We tested whether temporal expectation in different task contexts is compromised in individuals with Parkinson's disease (PD). In Experiment 1 two temporal-orienting tasks were used: a speeded task emphasizing motor preparation and a non-speeded task emphasizing perceptual discrimination using rapid serial visual presentation. In both tasks, auditory cues indicated the likelihood of a target appearing after a short or long interval. In the speeded-response task, participants used the cues to anticipate an easily detectable target stimulus. In the non-speeded perceptual-discrimination task, participants used the cues to help discriminate a target letter embedded in a stream of letters. Relative to healthy participants, participants with PD did not show altered temporal orienting effects in the speeded-response task. However, they were impaired in using temporal cues to improve perceptual discrimination. In Experiment 2, we tested whether the temporal-orienting deficits in the perceptual-discrimination task depended on the requirement to ignore temporally distracting stimuli. We replicated the impaired temporal orienting for perceptual discrimination in an independent group of individuals with PD, and showed the impairment was abolished when individuals were on their dopaminergic medication. In a task without any distracting letters, however, patients off or on medication benefited normally from temporal orienting cues. Our findings suggest that deficits in temporal orienting in individuals with PD interact with specific task demands, such as the requirement to select target from temporally competing distractors.


Competences in Social Media Use in the Area of Health and Healthcare.
In today's life, social media offer new working ways. People are increasingly expanding interactions from face-to-face meetings to online ways of communication, networking, searching, creating and sharing information, and furthermore taking care of patients/citizens via tweeting care, Facebook care, blogging care, vlogging care, infotainment care, gamification-care, infographic care, for instance. This chapter discusses the utilisation of social media in the healthcare domain including nursing education, practice and research. When in the current healthcare era, social media is used effectively and purposefully, it can give all of us a greater choice in how we live, how we take care of our health and how we learn and build both our professional competences and produce evidence-based, qualified data. Nurses need continuous education and proper tools to take the most of the benefits of social media, not forgetting privacy and ethical issues. This use of social media in professional nursing generates the need for new competences.


Application of sliding-window discretization and minimization of stochastic complexity for the analysis of fAFLP genotyping fingerprint patterns of Vibrionaceae.
Minimization of stochastic complexity (SC) was used as a method for classification of genotypic fingerprints. The method was applied to fluorescent amplified fragment length polymorphism (fAFLP) fingerprint patterns of 507 Vibrionaceae representatives. As the current BinClass implementation of the optimization algorithm for classification only works on binary vectors, the original fingerprints were discretized in a preliminary step using the sliding-window band-matching method, in order to maximally preserve the information content of the original band patterns. The novel classification generated using the BinClass software package was subjected to an in-depth comparison with a hierarchical classification of the same dataset, in order to acknowledge the applicability of the new classification method as a more objective algorithm for the classification of genotyping fingerprint patterns. Recent DNA-DNA hybridization and 16S rRNA gene sequence experiments proved that the classification based on SC-minimization forms separate clusters that contain the fAFLP patterns for all representatives of the species Enterovibrio norvegicus, Vibrio fortis, Vibrio diazotrophicus or Vibrio campbellii, while previous hierarchical cluster analysis had suggested more heterogeneity within the fAFLP patterns by splitting the representatives of the above-mentioned species into multiple distant clusters. As a result, the new classification methodology has highlighted some previously unseen relationships within the biodiversity of the family Vibrionaceae.


Inactivation of human SRBC, located within the 11p15.5-p15.4 tumor suppressor region, in breast and lung cancers.
A cDNA clone encoding human SRBC [serum deprivation response factor (sdr)-related gene product that binds to c-kinase] was isolated in a yeast two-hybrid screening, with amino acids 1-304 of BRCA1 as the probe. The human SRBC gene (hSRBC) was mapped to chromosome region 11p15.5-p15.4, close to marker D11S1323, at which frequent loss of heterozygosity (LOH) has been observed in sporadic breast, lung, ovarian, and other types of adult cancers as well as childhood tumors. hSRBC-coding region mutations including frame shift and truncation mutations were detected in a few ovarian and lung cancer cell lines. More significantly, the expression of hSRBC protein was down-regulated in a large fraction [30 (70%) of 43] of breast, lung, and ovarian cancer cell lines, whereas strong expression of hSRBC protein was detected in normal mammary and lung epithelial cells. The down-regulation of hSRBC expression in cancer cells was associated with hypermethylation of CpG dinucleotides in its promoter region, and 3 (60%) of 5 primary breast tumors and 11 (79%) of 14 primary lung tumors were also found to be hypermethylated. Treatment of breast cancer MCF7 cells with 5'azacytidine and Trichostatin A resulted in expression of hSRBC, confirming DNA methylation as the mode of inactivation. Our results suggest that epigenetic or mutational inactivation of hSRBC may contribute to the pathogenesis of several types of human cancers, marking hSRBC as a candidate tumor suppressor gene.


The effect of an integrated perceived competence and motor intervention in children with developmental coordination disorder.
Children with DCD have lower self-perceptions and are less physically active than typically developing children. The aim of this quasi-experimental study was to investigate whether an integrated perceived competence and motor intervention affects DCD children's motor performance, self-perceptions, and physical activity compared with a motor intervention only. The intervention group consisted of 20 children and the care-as-usual group consisted of 11 children, all aged 7-10 years. The perceived competence component of the intervention focused primarily on providing positive, specific, and progress feedback to enhance self-perceptions. We assessed children at baseline, after 12 treatment sessions (trial end-point), and at 3-month follow-up. Mixed linear models revealed no differences between the intervention and the care-as-usual group on any of the outcome measures. Children improved their motor performance and increased their perceived athletic competence, global self-esteem, and perceived motor competence after 12 treatment sessions. This improvement was maintained at 3-month follow-up. Motor task values and physical activity remained unchanged for all children. A perceived competence and motor intervention is as effective as care-as-usual in children with DCD. Future research should focus on improving physical activity in children with DCD. This is the first study that has investigated the effect of an integrated perceived competence and motor intervention (intervention group) on motor performance, self-perceptions, and physical activity compared with a motor intervention (care-as-usual group) in children with DCD. We made the perceived competence component explicit by providing positive, specific, and progress feedback to enhance children's self-perceptions. Also, this is one of the first studies that has investigated the effect after both 12 treatment sessions (trial end-point) and after 3 months of no intervention (3-month follow-up). We found no differences between the intervention and the care-as-usual group, but children improved their motor performance and increased (most) of their self-perceptions after 12 treatment sessions, while physical activity remained the same. The improvement was still present at the 3-month follow-up. We also benchmarked our results about self-perceptions and physical activity to a group of typically developing children. Self-perceptions in children with DCD had improved to the level of typically developing children after 12 treatment sessions, but their physical activity levels remained significantly lower. This result was the same at the 3-month follow-up, except for perceived athletic competence, which was lower in children with DCD at the 3-month follow-up. In accordance with previous intervention studies that have investigated children with DCD, we found large intra-group variability in the change in motor performance and self-perceptions in children with DCD. We argue that we need to better understand why some children with DCD improve and others do not after a motor intervention.


Expanding the obesity research paradigm to reach African American communities.
Obesity is more prevalent among African Americans and other racial and ethnic minority populations than among whites. The behaviors that determine weight status are embedded in the core social and cultural processes and environments of day-to-day life in these populations. Therefore, identifying effective, sustainable solutions to obesity requires an ecological model that is inclusive of relevant contextual variables. Race and ethnicity are potent stratification variables in U.S. society and strongly influence life contexts, including many aspects that relate to eating and physical activity behaviors. This article describes a synthesis initiated by the African American Collaborative Obesity Research Network (AACORN) to build and broaden the obesity research paradigm. The focus is on African Americans, but the expanded paradigm has broader implications and may apply to other populations of color. The synthesis involves both community and researcher perspectives, drawing on and integrating insights from an expanded set of knowledge domains to promote a deeper understanding of relevant contexts. To augment the traditional, biomedical focus on energy balance, the expanded paradigm includes insights from family sociology, literature, philosophy, transcultural psychology, marketing, economics, and studies of the built environment. We also emphasize the need for more attention to tensions that may affect African American or other researchers who identify or are identified as members of the communities they study. This expanded paradigm, for which development is ongoing, poses new challenges for researchers who focus on obesity and obesity-related health disparities but also promises discovery of new directions that can lead to new solutions.


Tailoring of the free spectral range and geometrical cavity dispersion of a microsphere by a coating layer.
The modal dispersion of a whispering gallery mode (WGM) resonator is a very important parameter for use in all nonlinear optics applications. In order to tailor the WGM modal dispersion of a microsphere, we have coated a silica microsphere with a high-refractive-index coating in order to study its effect on the WGM modal dispersion. We used Er(3+) ions as a probe for a modal dispersion assessment. We found that, by varying the coating thickness, the geometrical cavity dispersion can be used to shift overall modal dispersion in a very wide range in both the normal and anomalous dispersion regime.


The Genome of Artemisia annua Provides Insight into the Evolution of Asteraceae Family and Artemisinin Biosynthesis.
Artemisia annua, commonly known as sweet wormwood or Qinghao, is a shrub native to China and has long been used for medicinal purposes. A. annua is now cultivated globally as the only natural source of a potent anti-malarial compound, artemisinin. Here, we report a high-quality draft assembly of the 1.74-gigabase genome of A. annua, which is highly heterozygous, rich in repetitive sequences, and contains 63 226 protein-coding genes, one of the largest numbers among the sequenced plant species. We found that, as one of a few sequenced genomes in the Asteraceae, the A. annua genome contains a large number of genes specific to this large angiosperm clade. Notably, the expansion and functional diversification of genes encoding enzymes involved in terpene biosynthesis are consistent with the evolution of the artemisinin biosynthetic pathway. We further revealed by transcriptome profiling that A. annua has evolved the sophisticated transcriptional regulatory networks underlying artemisinin biosynthesis. Based on comprehensive genomic and transcriptomic analyses we generated transgenic A. annua lines producing high levels of artemisinin, which are now ready for large-scale production and thereby will help meet the challenge of increasing global demand of artemisinin.


Phonological neighborhood effects in spoken word production: an fMRI study.
The current study examined the neural systems underlying lexically conditioned phonetic variation in spoken word production. Participants were asked to read aloud singly presented words, which either had a voiced minimal pair (MP) neighbor (e.g., cape) or lacked a minimal pair (NMP) neighbor (e.g., cake). The voiced neighbor never appeared in the stimulus set. Behavioral results showed longer voice-onset time for MP target words, replicating earlier behavioral results [Baese-Berk, M., & Goldrick, M. Mechanisms of interaction in speech production. Language and Cognitive Processes, 24, 527-554, 2009]. fMRI results revealed reduced activation for MP words compared to NMP words in a network including left posterior superior temporal gyrus, the supramarginal gyrus, inferior frontal gyrus, and precentral gyrus. These findings support cascade models of spoken word production and show that neural activation at the lexical level modulates activation in those brain regions involved in lexical selection, phonological planning, and, ultimately, motor plans for production. The facilitatory effects for words with MP neighbors suggest that competition effects reflect the overlap inherent in the phonological representation of the target word and its MP neighbor.


Flow changes caused by the sequential placement of stents across the neck of sidewall cerebral aneurysms.
The goal of this study was to quantify the reduction in velocity, vorticity, and shear stresses resulting from the sequential placement of stents across the neck of sidewall cerebral aneurysms. A digital particle image velocimetry (DPIV) system was used to measure the pulsatile velocity field within a flexible silicone sidewall intracranial aneurysm model and at the aneurysm neck-parent artery interface in this model. The DPIV system is capable of providing an instantaneous, quantitative two-dimensional measurement of the velocity vector field of "blood" flow inside the aneurysm pouch and the parent vessel, and its changes at varying stages of the cardiac cycle. The corresponding vorticity and shear stress fields are then computed from the velocity field data. Three Neuroform stents (Boston Scientific/Target), each with a strut thickness between 60 and 65 microm, were subsequently placed across the neck of the aneurysm model and measurements were obtained after each stent had been placed. The authors measured a consistent decrease in the values of the maximal averaged velocity, vorticity, and shear stress after placing one, two, and three stents. Measurements of the circulation inside the sac demonstrated a systematic reduction in the strength of the vortex due to the stent placement. The decrease in the magnitude of the aforementioned quantities after the first stent was placed was remarkable. Placement of two or three stents led to a less significant reduction than placement of the first stent. The use of multiple flexible intravascular stents effectively reduces the strength of the vortex forming in an aneurysm sac and results in a decrease in the magnitude of stresses acting on the aneurysm wall.


Exploring the use of cognitive intervention for children with acquired brain injury.
Children with acquired brain injury (ABI) often experience cognitive, motor, and psychosocial deficits that affect participation in everyday activities. Cognitive Orientation to Daily Occupational Performance (CO-OP) is an individualized treatment that teaches cognitive strategies necessary to support successful performance. This study explores the use of CO-OP with children with ABI. Children with ABI, experiencing school and self-care difficulties, were identified from a previous study. Six children, aged 6-15 years, completed 10 weekly intervention sessions with occupational therapists. Children and parents rated the child's performance of challenging everyday tasks and their satisfaction with this performance. Task performance was also evaluated objectively through videotape analysis. Participants showed significant improvement in their ability to perform child-chosen tasks and maintained this performance 4 months later. However, they had difficulty applying the executive problem-solving strategy and discovering cognitive strategies on their own. Issues related to the use of CO-OP with this population are discussed.


Chronically ill Canadians' experiences of being unattached to a family doctor: a qualitative study of marginalized patients in British Columbia.
Unattached patients do not have a regular primary care provider. Initiatives are being developed to increase attachment rates across Canada. Most existing attention paid to patient unattachment has focused on quantifying the problem and health system costs. Our purpose is to qualitatively identify the implications of chronically ill patients' experiences of unattachment for health policy and planning to provide policy-relevant insights for Canadian attachment initiatives. Three focus groups were conducted with marginalized chronically ill individuals residing in a mid-sized city in British Columbia who are unattached to a family doctor. We use the term marginalized as a descriptor to acknowledge that by virtue of their low socio-economic status and lack of attachment the participants are marginalized in Canada's health care system Focus groups were structured as an open conversation organized around a series of probing questions. They were digitally recorded and transcribed verbatim. Thematic analysis was employed. Twenty-six individuals participated in the focus groups. The most common chronic illnesses reported were active drug addiction or recovery (and their associated symptoms), depression, arthritis, and hepatitis C. Participants identified life transitions as being the root cause for not having a family doctor. There was a strong sense that unsuccessful attempts to get a family doctor reflected that they were undesirable patients. Participants wanted to experience having a trusting relationship with a regular family doctor as they believed it would encourage greater honesty and transparency. One of the main health concerns regarding lack of access to a regular family doctor is that participants lacked access to preventative care. Participants were also concerned about having a discontinuous medical record due to unattachment. Participants perceived that there are many benefits to be had by having attachment to a regular family doctor and that experiencing unattachment challenged their health and access to health care. We encourage more research to be done on the lived experience of unattachment in order to provide on-the-ground insights that policy-makers require in order to develop responsive, patient-centred supports and programs.


Adult-type pulmonary tuberculosis in children 10-14 years of age.
We report 8 children (10-14 years of age) who were diagnosed with tuberculosis at their local primary health care clinic from July to September 2004, after routine sputum testing was extended to all children older than 10 years of age with suspected tuberculosis. This case series emphasizes that older children develop adult-type cavitating disease, which can be diagnosed by sputum smear microscopy, in contrast to younger children for whom smear microscopy has very little diagnostic value.


Isoquinoline and quinazoline urea analogues as antagonists for the human adenosine A(3) receptor.
Isoquinoline and quinazoline urea derivatives were found to bind to human adenosine A(3) receptors. Series of N-phenyl-N'-quinazolin-4-ylurea derivatives and N-phenyl-N'-isoquinolin-1-ylurea derivatives were synthesized and tested in radioligand binding assays on their adenosine receptor affinities. A structure-affinity analysis indicated that on the 2-position of the quinazoline ring or the equivalent 3-position of the isoquinoline ring a phenyl or heteroaryl substituent increased the adenosine A(3) receptor affinity in comparison to unsubstituted or aliphatic derivatives. Furthermore, the structure-affinity relationship of substituted phenylurea analogues was investigated. Substituents such as electron-withdrawing or electron-donating groups were introduced at different positions of the benzene ring to probe electronic and positional effects of substitution. Substitution on the 3- or 4-position of the phenyl ring decreased the adenosine A(3) receptor affinity. Substitution at position 2 with an electron-donating substituent, such as methyl or methoxy, increased human adenosine A(3) receptor affinity, whereas substitution on the 2-position with an electron-withdrawing substituent did not influence affinity. Combination of the optimal substituents in the two series had an additive effect, which led to the potent human adenosine A(3) receptor antagonist N-(2-methoxyphenyl)-N'-(2-(3-pyridyl)quinazolin-4-yl)urea (VUF5574, 10a) showing a K(i) value of 4 nM and being at least 2500-fold selective vs A(1) and A(2A) receptors. Compound 10a competitively antagonized the effect of an agonist in a functional A(3) receptor assay, i.e., inhibition of cAMP production in cells expressing the human adenosine A(3) receptor; a pA(2) value of 8.1 was derived from a Schild plot. In conclusion, compound 10a is a potent and selective human adenosine A(3) receptor antagonist and might be a useful tool in further characterization of the human A(3) receptor.


Landscape position influences microbial composition and function via redistribution of soil water across a watershed.
Subalpine forest ecosystems influence global carbon cycling. However, little is known about the compositions of their soil microbial communities and how these may vary with soil environmental conditions. The goal of this study was to characterize the soil microbial communities in a subalpine forest watershed in central Montana (Stringer Creek Watershed within the Tenderfoot Creek Experimental Forest) and to investigate their relationships with environmental conditions and soil carbonaceous gases. As assessed by tagged Illumina sequencing of the 16S rRNA gene, community composition and structure differed significantly among three landscape positions: high upland zones (HUZ), low upland zones (LUZ), and riparian zones (RZ). Soil depth effects on phylogenetic diversity and β-diversity varied across landscape positions, being more evident in RZ than in HUZ. Mantel tests revealed significant correlations between microbial community assembly patterns and the soil environmental factors tested (water content, temperature, oxygen, and pH) and soil carbonaceous gases (carbon dioxide concentration and efflux and methane concentration). With one exception, methanogens were detected only in RZ soils. In contrast, methanotrophs were detected in all three landscape positions. Type I methanotrophs dominated RZ soils, while type II methanotrophs dominated LUZ and HUZ soils. The relative abundances of methanotroph populations correlated positively with soil water content (R = 0.72, P < 0.001) and negatively with soil oxygen (R = -0.53, P = 0.008). Our results suggest the coherence of soil microbial communities within and differences in communities between landscape positions in a subalpine forested watershed that reflect historical and contemporary environmental conditions.


PTHR1 polymorphisms influence BMD variation through effects on the growing skeleton.
We investigated whether polymorphisms in PTHR1 are associated with bone mineral density (BMD), to determine whether the association of this gene with BMD was due to effects on attainment of peak bone mass or effects on subsequent bone loss. The PTHR1 gene, including its 14 exons, their exon-intron boundaries, and 1,500 bp of its promoter region, was screened for polymorphisms by denaturing high-performance liquid chromatography (dHPLC) and sequencing in 36 osteoporotic cases. Eleven single-nucleotide polymorphisms (SNPs), one tetranucleotide repeat, and one tetranucleotide deletion were identified. A cohort of 634 families, including 1,236 men (39%) and 1,926 women (61%) ascertained with probands with low BMD (Z< -2.0) and the Children in Focus subset of the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort (785 unrelated individuals, mean age 118 months), were genotyped for the five most informative SNPs (minor allele frequency >5%) and the tetranucleotide repeat. In our osteoporosis families, association was noted between lumbar spine BMD and alleles of a known functional tetranucleotide repeat (U4) in the PTHR1 promoter region (P = 0.042) and between two and three marker haplotypes of PTHR1 polymorphisms with lumbar spine, femoral neck, and total hip BMD (P = 0.021-0.047). This association was restricted to the youngest tertile of the population (age 16-39 years, P = 0.013-0.048). A similar association was found for the ALSPAC cohort: two marker haplotypes of SNPs A48609T and C52813T were associated with height (P = 0.006) and total body less head BMD (P = 0.02), corrected for age and gender, confirming the family findings. These findings suggest a role for PTHR1 variation in determining peak BMD.


Progress towards universal health coverage in Myanmar: a national and subnational assessment.
Attainment of universal health coverage is a global health priority. The Myanmar Government has committed to attainment of universal health coverage by 2030, but progress so far has not been assessed. We aimed to estimate national and subnational health service coverage and financial risk protection. We used nationally representative data from the Myanmar Demographic and Health Survey (2016) and the Integrated Household Living Condition Assessment (2010) to examine 26 health service indicators and explored the incidence of catastrophic health payment and impoverishment caused by out-of-pocket payments. We used logistic regression models of inequalities in, and risk factors for, indicators of universal health coverage. Nationally, the coverage of health service indicators ranged from 18·4% (95% CI 14·9-21·9) to 96·2% (95·9-96·5). Coverage of most health services indicators was below the universal health coverage target of 80%. 14·6% (95% CI 13·9-15·3) of households that used health services faced catastrophic health-care payments. 2·0% (95% CI 1·7-2·3) of non-poor households became poor because of out-of-pocket payments for health. Health service coverage and financial risk protection varied substantially by region. Although the richest quintiles had better access to health services than the poorest quintiles, they also had a higher incidence of financial catastrophe as a result of payments for health care. Of the indicators included in the study, coverage of adequate sanitation, no indoor use of solid fuels, at least four antenatal care visits, postnatal care for mothers, skilled birth attendance, and institutional delivery were the most inequitable by wealth quintile. Attainment of universal health coverage in Myanmar in the immediate future will be very challenging as a result of the low health service coverage, high financial risk, and inequalities in access to care. Health service coverage and financial risk protection for vulnerable, disadvantaged populations should be prioritised. Japanese Ministry of Health, Labour and Welfare, Ministry of Education, Culture, Sports, Science and Technology of Japan.


Differential effects of the Glasgow Coma Scale Score and its Components: An analysis of 54,069 patients with traumatic brain injury.
The Glasgow Coma Scale (GCS) is widely used in the assessment of clinical severity and prediction of outcome after traumatic brain injury (TBI). The sum score is frequently applied, but the differential influence of the components infrequently addressed. We aimed to investigate the contribution of the GCS components to the sum score, floor and ceiling effects of the components, and their prognostic effects. Data on adult TBI patients were gathered from three data repositories: TARN (n=50,064), VSTR (n=14,062), and CRASH (n=9,941). Data on initial hospital GCS-assessment and discharge mortality were extracted. A descriptive analysis was performed to identify floor and ceiling effects. The relation between GCS and outcome was studied by comparing case fatality rates (CFR) between different component-profiles adding up to identical sum scores using Chi2-tests, and by quantifying the prognostic value of each component and sum score with Nagelkerke's R2 derived from logistic regression analyses across TBI severities. In the range 3-7, the sum score is primarily determined by the motor component, as the verbal and eye components show floor-effects at sum scores 7 and 8, respectively. In the range 8-12, the effect of the motor component attenuates and the verbal and eye components become more relevant. The motor, eye and verbal scores reach their ceiling-effects at sum 13, 14 and 15, respectively. Significant variations were exposed in CFR between different component-profiles despite identical sum scores, except in sum scores 6 and 7. Regression analysis showed that the motor score had highest R2 values in severe TBI patients, whereas the other components were more relevant at higher sum scores. The prognostic value of the three components combined was consistently higher than that of the sum score alone. The GCS-components contribute differentially across the spectrum of consciousness to the sum score, each having floor and ceiling effects. The specific component-profile is related to outcome and the three components combined contain higher prognostic value than the sum score across different TBI severities. We, therefore, recommend a multidimensional use of the three-component GCS both in clinical practice, and in prognostic studies.


Reasons That Dutch Dentists and Dental Hygienists Oppose or Support an Extended Scope of Practice for Dental Hygienists.
In the Netherlands, the scope of dental hygiene practice was expanded in 2006. The objective of this study was to explore reasons among dentists and dental hygienists for supporting or opposing an extended scope of practice and to find explanatory factors. A questionnaire containing pre-defined reasons and an open-ended question was distributed among 1,674 randomly selected members of two Dutch professional associations (874 dentists, 800 dental hygienists). Data were analyzed with binary logistic regression with Bayesian information criterion (BIC) model selection. Response were obtained from 541 practitioners (32.3%): i.e., 233 dentists (43.1%) and 308 dental hygienists (56.9%). Non-response analysis revealed no differences, and representativeness analysis showed similarities between samples and target populations. Most often, dentists reported flexible collaboration (50.2%) and dental hygienists indicated task variation (71.1%) as supportive reasons. As opposing reasons, dentists generally reported quality of care (41.2%) and dental hygienists' self-competence (22.7%). Reasons were explained by profession, gender, and new-style practitioners. Dentists and dental hygienists conveyed different reasons for supporting or opposing an extended scope of dental hygiene practice. Outcomes can be categorized as reasons related to economic, professional status, quality, job satisfaction, and flexible collaboration and are not only explained by profession.


The relationship between HIV and prevalence of disabilities in sub-Saharan Africa: systematic review (FA).
To systematically review evidence on the prevalence and risk of disabilities among children and adults living with HIV in sub-Saharan Africa. Articles were identified from 1980 to June 2013 through searching seven electronic databases. Epidemiological studies conducted in sub-Saharan Africa that explored the association between HIV status and general disability or specific impairments, with or without an HIV-uninfected comparison group, were eligible for inclusion. Of 12 867 records initially identified, 61 papers were deemed eligible for inclusion. The prevalence of disability was high across age groups, impairment types and study locations. Furthermore, 73% of studies using an HIV- comparator found significantly lower levels of functioning in people living with HIV (PLHIV). By disability type, the results were as follows: (i) for studies measuring physical impairments (n = 14), median prevalence of limitations in mobility and motor function among PLHIV was 25.0% (95% CI: 21.8-28.2%). Five of eight comparator studies found significantly reduced functioning among PLHIV; for arthritis, two of three studies which used an HIV- comparison group found significantly increased prevalence among PLHIV; (ii) for sensory impairment studies (n = 17), median prevalence of visual impairment was 11.2% (95%CI: 9.5-13.1%) and hearing impairment was 24.1% (95%CI: 19.2-29.0%) in PLHIV. Significantly increased prevalence among PLHIV was found in one of four (vision) and three of three studies (hearing) with comparators; (iii) for cognitive impairment in adults (n = 30), median prevalence for dementia was 25.3% (95% CI: 22.0-28.6%) and 40.9% (95% CI: 37.7-44.1%) for general cognitive impairment. Across all types of cognitive impairment, twelve of fourteen studies found a significant detrimental effect of HIV infection; (iv) for developmental delay in children with HIV (n = 20), median prevalence of motor delay was 67.7% (95% CI: 62.2-73.2%). All nine studies that included a comparator found a significant difference between PLHIV and controls; for cognitive development and global delay, a significant detrimental effect of HIV was found in five of six and one of two studies, respectively. In the nine cohort studies comparing vertically infected and uninfected children, eight showed a significant gap in development over time in children with HIV. Finally, fifteen of thirty-one (48%) studies found a statistically significant dose-response relationship between indicators of disease progression (CD4 or WHO stage) and disability. HIV is widespread in sub-Saharan Africa and the evidence suggests that it is linked to disabilities, affecting a range of body structures and functions. More research is needed to better understand the implications of HIV-related disability for individuals, their families as well as those working in the fields of disability and HIV so that appropriate interventions can be developed.


Vascular lesions in hypertensive rats under salt loading: kidney renin and lysosomal enzymes.
1. Renal and cerebral vascular lesions occurred more often and earlier in spontaneously hypertensive rats (SHR) given a high salt diet than in SHR given a normal diet. 2. Kidney renin activity was low during high salt loading; the kidney renin activity of rats with hypertensive renal vascular lesions was moderately elevated. Kidney renin activity or cathepsin D activities were higher in stroke-prone SHR (SHRSP) aged 9 months than in stroke-resistant SHR (SHRSR). 3. beta-Glucuronidase, cathepsin D and deoxyribonuclease activities were greater in the kidney of Wistar/Kyoto (WK) rats or SHR when there were hypertensive vascular lesions. These three enzyme activities were also greater in the aorta of SHR aged 13-14 months than in the aorta of WK rats. 4. It was supposed that kidney renin activity and lysosomal enzyme activities were related to hypertensive vascular lesions.


A self-organizing model of perisaccadic visual receptive field dynamics in primate visual and oculomotor system.
We propose and examine a model for how perisaccadic visual receptive field dynamics, observed in a range of primate brain areas such as LIP, FEF, SC, V3, V3A, V2, and V1, may develop through a biologically plausible process of unsupervised visually guided learning. These dynamics are associated with remapping, which is the phenomenon where receptive fields anticipate the consequences of saccadic eye movements. We find that a neural network model using a local associative synaptic learning rule, when exposed to visual scenes in conjunction with saccades, can account for a range of associated phenomena. In particular, our model demonstrates predictive and pre-saccadic remapping, responsiveness shifts around the time of saccades, and remapping from multiple directions.


Grandparents caring for grandchildren in rural China: consequences for emotional and cognitive health in later life.
In rural China, where families serve as critical safety-nets for their vulnerable members, grandparents play an essential role caring for the offspring of their migrant children. Evidence is mixed as to whether caring for grandchildren provides health benefits or incurs health risks. In this article, we used six waves of data from a study in rural China to examine the impact of caregiving for grandchildren on grandparents' emotional and cognitive health. Further, we examined financial transfers from adult children as a resource that potentially moderates the impact of high intensity caregiving on these outcomes. Data derived from six waves (2001-2015) of the Longitudinal Study of Older Adults in Anhui Province, China. We constructed 2,835 person-interval observations derived from 1,067 grandparents to examine lagged change in depressive symptoms and cognitive ability. Results show that caregiving frequency is not by itself harmful or beneficial to the emotional and cognitive health of grandparents, but it does appear to be harmful in the context of custodial care that is less economically supported by adult children. These results are discussed in terms of their relevance to intergenerational reciprocity in a filial culture, time-for-money exchange expectations, and the need for financial resources among caregiving grandparents in rural China.


Ancient feeding ecology inferred from stable isotopic evidence from fossil horses in South America over the past 3 Ma.
Stable isotope ratios (13C/12C and 18O/16O) in fossil teeth and bone provide key archives for understanding the ecology of extinct horses during the Plio-Pleistocene in South America; however, what happened in areas of sympatry between Equus (Amerhippus) and Hippidion is less understood. Here, we use stable carbon and oxygen isotopes preserved in 67 fossil tooth and bone samples for seven species of horses from 25 different localities to document the magnitude of the dietary shifts of horses and ancient floral change during the Plio-Pleistocene. Dietary reconstructions inferred from stable isotopes of both genera of horses present in South America document dietary separation and environmental changes in ancient ecosystems, including C3/C4 transitions. Stable isotope data demonstrate changes in C4 grass consumption, inter-species dietary partitioning and variation in isotopic niche breadth of mixed feeders with latitudinal gradient. The data for Hippidion indicate a preference varying from C3 plants to mixed C3-C4 plants in their diet. Equus (Amerhippus) shows three different patterns of dietary partitioning Equus (A.) neogeus from the province of Buenos Aires indicate a preference for C3 plants in the diet. Equus (A.) andium from Ecuador and Equus (A.) insulatus from Bolivia show a preference for to a diet of mixed C3-C4 plants, while Equus (A.) santaeelenae from La Carolina (sea level of Ecuador) and Brazil are mostly C4 feeders. These results confirm that ancient feeding ecology cannot always be inferred from dental morphology. While the carbon isotope composition of horses skeletal material decreased as latitude increased, we found evidence of boundary between a mixed C3/C4 diet signal and a pure C4 signal around 32° S and a change from a mixed diet signal to an exclusively C3 signal around 35°S.We found that the horses living at high altitudes and at low to middle latitude still have a C4 component in their diet, except the specimens from 4000 m, which have a pure C3 diet. The change in altitudinal vegetation gradients during the Pleistocene is one of several possibilities to explain the C4 dietary component in horses living at high altitudes. Other alternative explanations imply that the horses fed partially at lower altitudes.


Dose Equivalents for Second-Generation Antipsychotic Drugs: The Classical Mean Dose Method.
The concept of dose equivalence is important for many purposes. The classical approach published by Davis in 1974 subsequently dominated textbooks for several decades. It was based on the assumption that the mean doses found in flexible-dose trials reflect the average optimum dose which can be used for the calculation of dose equivalence. We are the first to apply the method to second-generation antipsychotics. We searched for randomized, double-blind, flexible-dose trials in acutely ill patients with schizophrenia that examined 13 oral second-generation antipsychotics, haloperidol, and chlorpromazine (last search June 2014). We calculated the mean doses of each drug weighted by sample size and divided them by the weighted mean olanzapine dose to obtain olanzapine equivalents. We included 75 studies with 16 555 participants. The doses equivalent to 1 mg/d olanzapine were: amisulpride 38.3 mg/d, aripiprazole 1.4 mg/d, asenapine 0.9 mg/d, chlorpromazine 38.9 mg/d, clozapine 30.6 mg/d, haloperidol 0.7 mg/d, quetiapine 32.3mg/d, risperidone 0.4 mg/d, sertindole 1.1 mg/d, ziprasidone 7.9 mg/d, zotepine 13.2 mg/d. For iloperidone, lurasidone, and paliperidone no data were available. The classical mean dose method is not reliant on the limited availability of fixed-dose data at the lower end of the effective dose range, which is the major limitation of "minimum effective dose methods" and "dose-response curve methods." In contrast, the mean doses found by the current approach may have in part depended on the dose ranges chosen for the original trials. Ultimate conclusions on dose equivalence of antipsychotics will need to be based on a review of various methods.


Preventing the next 'SARS' - European healthcare workers' attitudes towards monitoring their health for the surveillance of newly emerging infections: qualitative study.
Hospitals are often the epicentres of newly circulating infections. Healthcare workers (HCWs) are at high risk of acquiring infectious diseases and may be among the first to contract emerging infections. This study aims to explore European HCWs' perceptions and attitudes towards monitoring their absence and symptom reports for surveillance of newly circulating infections. A qualitative study with thematic analysis was conducted using focus group methodology. Forty-nine hospital-based HCWs from 12 hospitals were recruited to six focus groups; two each in England and Hungary and one each in Germany and Greece. HCWs perceived risk factors for occupationally acquired infectious diseases to be 1.) exposure to patients with undiagnosed infections 2.) break-down in infection control procedures 3.) immuno-naïvety and 4.) symptomatic colleagues. They were concerned that a lack of monitoring and guidelines for infectious HCWs posed a risk to staff and patients and felt employers failed to take a positive interest in their health. Staffing demands and loss of income were noted as pressures to attend work when unwell. In the UK, Hungary and Greece participants felt monitoring staff absence and the routine disclosure of symptoms could be appropriate provided the effectiveness and efficiency of such a system were demonstrable. In Germany, legislation, privacy and confidentiality were identified as barriers. All HCWs highlighted the need for knowledge and structural improvements for timelier recognition of emerging infections. These included increased suspicion and awareness among staff and standardised, homogenous absence reporting systems. Monitoring absence and infectious disease symptom reports among HCWs may be a feasible means of surveillance for emerging infections in some settings. A pre-requisite will be tackling the drivers for symptomatic HCWs to attend work.


Proopiomelanocortin Processing in the Hypothalamus Is Directly Regulated by Saturated Fat: Implications for the Development of Obesity.
In outbred mice, susceptibility or resistance to diet-induced obesity is associated with rapid changes in hypothalamic proopiomelanocortin (POMC) levels. Here, we evaluated 3 hypotheses that potentially explain the development of the different obesity phenotypes in outbred Swiss mice. First, rapid and differential changes in the gut microbiota in obesity-prone (OP) and obesity-resistant (OR) mice fed on a high-fat diet (HFD) might cause differential efficiencies in fatty acid harvesting leading to changes in systemic fatty acid concentrations that in turn affect POMC expression and processing. Second, independently of the gut microbiota, OP mice might have increased blood fatty acid levels after the introduction of a HFD, which could affect POMC expression and processing. Third, fatty acids might act directly in the hypothalamus to differentially regulate POMC expression and/or processing in OP and OR mice. We evaluated OP and OR male Swiss mice using 16S rRNA sequencing for the determination of gut microbiota; gas chromatography for blood lipid determination; and immunoblot and real-time polymerase chain reaction for protein and transcript determination and indirect calorimetry. Some experiments were performed with human pluripotent stem cells differentiated into hypothalamic neurons. We did not find evidence supporting the first 2 hypotheses. However, we found that in OP but not in OR mice, palmitate induces a rapid increase in hypothalamic POMC, which is followed by increased expression of proprotein convertase subtilisin/kexin type 1 PC1/3. Lentiviral inhibition of hypothalamic PC1/3 increased caloric intake and body mass in both OP and OR mice. In human stem cell-derived hypothalamic cells, we found that palmitate potently suppressed the production of POMC-derived peptides. Palmitate directly regulates PC1/3 in OP mice and likely has a functional impact on POMC processing.


Optimal Timing and Outcome of Transforaminal Epidural Steroid Injection for the Management of Radicular Pain due to Extruded Lumbar Disc Herniation.
To evaluate the optimal timing and outcome of fluoroscopically guided transforaminal epidural steroid injections (TFESI) for the management of radicular pain due to extruded lumbar disc herniation (LDH). In this clinical study, 305 individuals received fluoroscopically guided TFESI for the management of radicular pain due to extruded LDH. Preprocedural and 12-week postprocedural Visual Analog Scale (VAS) scores measuring radicular pain were statistically compared. The neurological conditions of the patients and the complications of the procedure were also recorded. The intensity of radicular pain evaluated by the mean preprocedural and 12-week postprocedural VASs were 8.765 ± 0.559 and 2.281 ± 0.401, respectively (p=0.001, and t=119.01). A correlation was noted between the short duration of symptoms before the procedure and the effectiveness of the procedure. After 12 weeks of the procedure, 32 of the 58 patients showed improvement in terms of neurological deficit. There was no major complication. Nine patients required lumbar disc surgery after the procedure. This clinical research demonstrated that TFESI for the management of extruded LDH may alleviate radicular pain and may decrease the neurological deficit and that it is more effective when performed at the earliest possible time point.


Operative management of sacral chordoma.
Sacrococcygeal chordoma presents a difficult diagnostic and therapeutic problem, with a high rate of local recurrence. The purpose of this report is to define the importance of adequate surgical treatment for optimum outcome and survival. Fifty-two patients underwent surgical treatment for sacrococcygeal chordoma between 1980 and 2001. The series included eighteen female patients and thirty-four male patients, with an average age of fifty-six years (range, thirteen to seventy-six years) at the time of the diagnosis. The surgical approach depended on the level and extent of the lesion, with a posterior approach performed in twenty-two patients and a combined anteroposterior approach used in thirty. A wide surgical margin was achieved in twenty-one patients. At an average of 7.8 years (range, 2.1 to twenty-three years) postoperatively, twenty-three patients were alive with no evidence of disease. Twenty-three patients (44%) had local recurrence. The rate of recurrence-free survival was 59% at five years and 46% at ten years. The overall survival rates were 74%, 52%, and 47% at five years, ten years, and fifteen years, respectively. The most important predictor of survival was a wide margin. All patients with a wide margin survived, and this survival rate was significantly different from that for patients who had had either marginal or intralesional excision (p = 0.0001). Of the twenty-one patients with a wide margin, seventeen (81%) had undergone a combined anteroposterior approach and only four had been treated with a posterior approach. A wide surgical margin is the most important predictor of survival and of local recurrence in patients with sacrococcygeal chordoma. Use of a combined anteroposterior approach increases the likelihood of obtaining a wide margin. Therapeutic Level IV.


B lymphocyte reconstitution after human bone marrow transplantation. Leu-1 antigen defines a distinct population of B lymphocytes.
Differences in the expression of Leu-1 (CD5) define two populations of recovering B cells after human marrow transplantation, Leu-1+ and Leu-1- B cells. The Leu-1+ B cells were polyclonal, of donor origin, and did not express detectable interleukin 2 receptor. Leu-1+ B cells generally appeared 2-4 wk after marrow grafting and often preceded the recovery of Leu-1- B cells. Acute and chronic graft vs. host disease (GvHD) resulted in the recovery of significantly fewer Leu-1+ B cells, whereas Leu-1- B cells were only decreased in acute GvHD. Multivariate analysis showed no significant effect of age, disease, prednisone or azathioprine, or ex vivo treatment of the marrow with anti-Leu-1 and complement on recovery of Leu-1+ and Leu-1- B cells, independent of the effects of GvHD. Leu-1+ B cells are a major lymphocyte population posttransplant. They may reflect a stage of differentiation of normal B cells or a separate B cell lineage.


Chronic cough due to gastroesophageal reflux disease: ACCP evidence-based clinical practice guidelines.
To critically review and summarize the literature on cough and gastroesophageal reflux disease (GERD), and to make evidence-based recommendations regarding the diagnosis and treatment of chronic cough due to GERD. Ovid MEDLINE literature review (through March 2004) for all studies published in the English language and selected articles published in other languages such as French since 1963 using the medical subject heading terms "cough," "gastroesophageal reflux," and "gastroesophageal reflux disease." GERD, singly or in combination with other conditions, is one of the most common causes of chronic cough. In patients with normal chest radiographic findings, GERD most likely causes cough by stimulation of an esophageal-bronchial reflex. When GERD causes cough, there may be no GI symptoms up to 75% of the time. While 24-h esophageal pH monitoring is the most sensitive and specific test in linking GERD and cough in a cause-effect relationship, it has its limitations. In addition, there is no general agreement on how to best interpret the test, and it cannot detect non-acid reflux events. Therefore, when patients fit the clinical profile that has a high likelihood of predicting that GERD is the cause of cough, antireflux medical therapy should be empirically instituted. While some patients improve with minimal medical therapy, others require more intensive regimens. When empiric treatment fails, it cannot be assumed that GERD has been ruled out as a cause of chronic cough. Rather, an objective investigation for GERD is then recommended because the empiric therapy may not have been intensive enough or medical therapy may have failed. Surgery may be efficacious when intensive medical therapy has failed in selected patients who have undergone an extensive objective GERD evaluation. Accurately diagnosing and successfully treating chronic cough due to GERD can be a major challenge.


Medical comorbidity in polycystic ovary syndrome with special focus on cardiometabolic, autoimmune, hepatic and cancer diseases: an updated review.
Polycystic ovary syndrome (PCOS) is defined by hyperandrogenism, irregular menses and polycystic ovaries when other causes are excluded. The possible implication of increased morbidity in PCOS for screening and follow-up is uncertain and is reviewed in this article. The increased risk of type 2 diabetes and cardiovascular disease in PCOS is closely associated with BMI. Women with PCOS should be screened for the elements of the metabolic syndrome upon diagnosis. Measurement of HbA1c and the lipid accumulation product could be important tools to differentiate women with high metabolic risk. The immune function in PCOS is impaired with increased secretion of autoantibodies and increased risk of type 1 diabetes, asthma and thyroid disease. The occurrence of thyroid disease could be modified by BMI and D-vitamin status. Screening for diabetes and thyroid disease is part of routine evaluation for endocrine diseases at baseline in PCOS, whereas the necessity of prospective screening for thyroid disease awaits future studies. Especially obese women with PCOS are at an increased risk of nonalcoholic fatty liver disease, gall bladder disease and endometrial cancer. Recent data support that screening and follow-up in patients with PCOS should be stratified according to BMI.


Local and distant products from modularity.
In this study, the local and distant distribution of solid and soluble products of corrosion from the head and neck junction of modular femoral total hip prosthetic components were characterized. Particulate corrosion products from retrieved implants and surrounding tissues were analyzed. Serum transport and urinary excretion of metal was measured in correlation with the degree of corrosion at the head and neck junction. Particles of metal oxides, metal chlorides, and chromium phosphate corrosion products were identified on implants of 10 designs from 6 manufacturers. The most abundant solid corrosion product on the implant and within the periprosthetic tissues (size range, < 1-200 micrometers) was an amorphous chromium orthophosphate hydrate-rich material. Serum cobalt and urine chromium concentrations were elevated significantly in patients with implants that had moderate to severe corrosion in comparison with those with no to mild corrosion. Solid corrosion products from modular femoral stems may accelerate articular wear via a 3-body mechanism. Phagocytosable particles of these corrosion products may stimulate macrophage-mediated periprosthetic bone loss. Systemic dissemination of metallic corrosion products raises the issue of systemic toxicity; however, no overt evidence of metal toxicity was observed in this study.


Differential expression of the muscarinic m2 acetylcholine receptor by small and large motoneurons of the rat spinal cord.
The purpose of this study was to determine if motoneurons in the spinal ventral horn express the muscarinic m2 acetylcholine receptor. Motoneurons were retrogradely labelled in adult rats by intramuscular injection of Fluorogold and examined with confocal microscopy for evidence of immunoreactivity for the receptor. The cells were also double-labelled for choline acetyltransferase to determine if they were contacted by cholinergic axons. Almost all large motoneurons (diameters greater than 35 microm) displayed intense immunoreactivity for the receptor which was evenly distributed along the plasma membrane. Small cells were immunonegative for the receptor or weakly labelled. As large cells probably correspond to alpha-motoneurons and receive many cholinergic contacts, it is concluded that acetylcholine can influence this type of motoneuron by acting through the m2 receptor.


Olive oil exhibits osteoprotection in ovariectomized rats without estrogenic effects.
The present study was designed to evaluate the effect of olive oil on bone and uterus in ovariectomized rats. A total of 34 surgically ovariectomized or sham-operated virgin Sprague-Dawley rats were divided into four groups: i) Sham-operated control rats (sham group); ii) Ovariectomized rats (OVX group); iii) Olive oil-supplemented ovariectomized rats (olive group); and iv) Diethylstilbestrol-supplemented ovariectomized rats (E2 group). At 12 weeks following left ventricular blood sacrificed to detect plasma estradiol (E2), interleukin-1β (IL-1β) and IL-6 levels. Bone mineral density (BMD) of the lumbar spine was evaluated using dual-energy X-ray absorptiometry, and the left femur proximal 1/3 slices were observed using transmission electron microscopy. Uterine wet weight and the uterus index (ratio of uterine wet weight and body weight) were compared, and the uterine endometrium was observed using a light microscope. In the OVX group, serum E2 was significantly lower and IL-1β and IL-6 levels were significantly higher compared with the sham group. By contrast, serum E2 levels increased and IL-1β levels decreased in the olive group, but showed no significant difference compared with the sham group. The lumbar spine BMD in the olive group was increased compared with OVX group. Electron microscopy revealed sparse collagen fibers in the OVX group, with decreased density and multi-cavity, showing pathological features of osteoporosis. By contrast, the situation was improved in the E2 and olive groups, in which organelles such as the rough endoplasmic reticulum, mitochondria and Golgi apparatus were visible and active. Compared with the sham group rats, the uterine wet weight and uterine index decreased in the OVX and olive groups; however, no statistically significant difference was observed in the E2 group. Furthermore, endometrial hyperplasia was not observed in the olive group, which were apparently different from E2 group. The present results suggest that olive oil can effectively reduce bone loss in ovariectomized rats, and with no or only mild effects on the uterine endothelium.


Learning the ABCs of pregnancy and newborn care through mobile technology.
The diffusion of mobile phones in low- and middle-income countries has taken place faster than any other infrastructural development. Mobile Midwife, a mobile application implemented in Ghana in 2010, sends timely messages in local languages to registered expectant mothers and new parents. The field of mobile health (mHealth) is severely underresearched, yet it can be an alternative for improving health systems and the ways in which health services are delivered. Our goal was to investigate the role that Mobile Midwife technology has played in the lives of pregnant and nursing mothers in Awutu Senya District, Ghana. A total of three focus group discussions and 19 individual interviews were conducted. Discussions and interviews were recorded, transcribed verbatim from the local language to English, and analyzed by means of qualitative content analysis at the manifest and latent levels. The main findings show that while oscillating between modern and traditional practices, women gradually gained trust in Mobile Midwife's counselling and attempted to balance between myths and reality regarding nutrition in pregnancy. In addition, their decisions to seek essential obstetric care were enhanced by Mobile Midwife's advice. Women also felt strengthened in their understanding of the importance of seeking professional care during pregnancy and childbirth as well as recognizing signs of ill health in the newborn. The findings indicate that Mobile Midwife could be an excellent tool in working towards the improvement of maternal health. Mobile Midwife will hopefully contribute to the stepwise achievement of the Sustainable Development Goals extended from the Millennium Development Goals, which expire at the end of 2015. There is a need for strong political will from key stakeholders, to embark in the field of mHealth as a complementary means to strengthen health systems.


Phenotypic heterogeneity and evolution of melanoma cells associated with targeted therapy resistance.
Phenotypic plasticity is associated with non-genetic drug tolerance in several cancers. Such plasticity can arise from chromatin remodeling, transcriptomic reprogramming, and/or protein signaling rewiring, and is characterized as a cell state transition in response to molecular or physical perturbations. This, in turn, can confound interpretations of drug responses and resistance development. Using BRAF-mutant melanoma cell lines as the prototype, we report on a joint theoretical and experimental investigation of the cell-state transition dynamics associated with BRAF inhibitor drug tolerance. Thermodynamically motivated surprisal analysis of transcriptome data was used to treat the cell population as an entropy maximizing system under the influence of time-dependent constraints. This permits the extraction of an epigenetic potential landscape for drug-induced phenotypic evolution. Single-cell flow cytometry data of the same system were modeled with a modified Fokker-Planck-type kinetic model. The two approaches yield a consistent picture that accounts for the phenotypic heterogeneity observed over the course of drug tolerance development. The results reveal that, in certain plastic cancers, the population heterogeneity and evolution of cell phenotypes may be understood by accounting for the competing interactions of the epigenetic potential landscape and state-dependent cell proliferation. Accounting for such competition permits accurate, experimentally verifiable predictions that can potentially guide the design of effective treatment strategies.