A quantitative analysis of the supply and demand of veterinary manpower in India: implications for policy decisions.
The objective of this study was to estimate and forecastthe supply and demand of veterinary manpower in India. Intake numbers of veterinary students and numbers of graduates and postgraduates were collected for the period 1997 to 2007. Based on the annual growth rate, the demand and supply for the years 2015 and 2020 were predicted. Between 1997 and 2002 the average annual number of veterinary graduates was 1,675. This increased to 1,707 between 2002 and 2007, with a marginal growth rate of 1.87%. With a growth rate of 1.87% in graduates, and 4.5% growth rate in the Indian livestock sector, the number of additional graduates required to fill the gap between supply and demand for the years 2015 and 2020 would be 1,710 and 2,364, respectively. The annual postgraduate requirement for education and research and development is 310. However, between 2002 and 2007 the average annual number of veterinary postgraduates was 995, with a growth rate of 5.3% when compared with the period between 1997 and 2002, indicating a more than three-fold surplus. With a 5.3% growth rate in postgraduates and 4.5% growth rate in the livestock sector, the surplus postgraduates available by 2015 and 2020 will be 1,027 and 1,316, respectively. The study revealed that India is training fewer veterinary graduates and more postgraduates than the system requires. Therefore, it is recommended that attention and resources be directed to the expansion of professional undergraduate veterinary education, while postgraduate veterinary education should be contained and consolidated.


Use of nonsteroidal anti-inflammatory drugs and bladder cancer risk: a meta-analysis of epidemiologic studies.
Several epidemiologic studies have evaluated the association between nonsteroidal anti-inflammatory drugs (NSAIDs) and bladder cancer risk and the results were varied. Thus, we conducted a comprehensive meta-analysis of studies exclusively dedicated to the relationship between the 3 most commonly used analgesics and bladder cancer risk. A systematic literature search up to November 2012 was performed in PubMed database for 3 categories of analgesics: acetaminophen, aspirin or non-aspirin NSAIDs. Study-specific risk estimates were pooled using a random-effects model. Seventeen studies (8 cohort and 9 case-control studies), involving a total of 10,618 bladder cancer cases, were contributed to the analysis. We found that acetaminophen (relative risk [RR] 1.01, 95% confidence interval [CI] 0.88-1.17) and aspirin (RR 1.02, 95% CI 0.91-1.14) were not associated with bladder cancer risk. Although non-aspirin NSAIDs was statistically significantly associated with reduced risk of bladder cancer among case-control studies (but not cohort studies), the overall risk was not statistically significant (RR 0.87, 95% CI 0.73-1.05). Furthermore, we also found that non-aspirin NSAIDs use was significantly associated with a 43% reduction in bladder cancer risk among nonsmokers (RR 0.57, 95% CI 0.43-0.76), but not among current smokers. The results of our meta-analysis suggest that there is no association between use of acetaminophen, aspirin or non-aspirin NSAIDs and bladder cancer risk. However, non-aspirin NSAIDs use might be associated with a reduction in risk of bladder cancer for nonsmokers.


A nicked beta-subunit of human chorionic gonadotropin purified from pregnancy urine.
Human chorionic gonadotropin (hCG) is a glycoprotein hormone composed of two dissimilar subunits (alpha and beta) and normally excreted in urine of pregnant women. An uncommon beta-subunit of hCG was purified from fresh early normal pregnancy urine by Sepralyte C8, resin adsorption. Sephadex G-100 column chromatography, and reverse-phase HPLC. SDS-PAGE under non-reducing conditions showed that the apparent molecular weight (39,000) of this beta-subunit was extremely similar to that of the native beta-subunit, which is known to consist of 145 amino acid residues and carbohydrates. However, SDS-PAGE, under reducing conditions, resulted in two bands with apparent molecular weights of 22,000 and 18,000, indicating that it consisted of two peptide fragments connected with disulfide bridge(s). These two peptide fragments, separated and purified from the reduced and carboxymethylated protein, were subjected to amino acid and N-terminal sequence analyses. It was found that this beta-subunit consisted of two polypeptide chains composed of residues 1-47 disulfide-bridged to residues 48-145 of the beta-subunit, which may be produced by nicking of the beta-subunit at the one site (Gly47-Val48). This beta-subunit was termed a nicked beta-subunit of hCG (N-hCG beta). It was also found that N-hCG beta was present in urine as an alpha beta dimer, indicating that an intrachain nicking of this site in the beta-subunit does not inhibit alpha beta dimer formation.(ABSTRACT TRUNCATED AT 250 WORDS)


β-adrenoceptor regulates miRNA expression in rat heart.
MicroRNAs (miRNAs) are noncoding RNAs of 18-25 nucleotides that post-transcriptionally regulate gene expression and are involved in a wide range of physiological and pathological conditions. The β-adrenergic signaling pathway plays a fundamental role in regulation of heart function. The present study was designed to investigate the expression profile of miRNAs and functional implications under conditions of β-adrenoceptor activation or inhibition in rat heart. Hemodynamic parameters were measured to assess heart function in Wistar rats treated with isoproterenol (ISO) or propranolol (PRO). miRNA expression was analyzed by miRNA Microarray and confirmed by real-time quantitative reverse transcription PCR (real-time qRT-PCR). Isoproterenol (ISO, a β-adrenoceptor activator) and propranolol (PRO, a β-adrenoceptor inhibitor) induced differential miRNA expression profiles. Out of 349 miRNAs measured, 43 were upregulated and nine downregulated in the ISO group, while five miRNAs were upregulated and 28 downregulated in PRO group. Among these altered miRNAs in both PRO and ISO groups, 11 were cardiac abundant and 11 showed opposite profiles between the PRO and ISO groups. The recognized anti-hypertrophic miRNAs miR-1, miR-21 and miR-27b, and the pro-hypertrophic miRNAs miR-22, miR-24, miR-199a, miR-212 and miR-214, were upregulated in the ISO group. In the PRO group, pro-hypertrophic miRNA miR-30c was upregulated, whereas miR-212 was downregulated. β-adrenoceptor intervention alters miRNA expression profile, and miRNAs may be involved in the β-adrenoceptor signaling pathway. Cardiomyocyte hypertrophy is a balanced process between pro-hypertrophic and anti-hypertrophic regulation and involves, at the very least, miRNA participation.


Prognostic relevance of MOG antibodies in children with an acquired demyelinating syndrome.
To assess the prognostic value of MOG antibodies (abs) in the differential diagnosis of acquired demyelinating syndromes (ADS). Clinical course, MRI, MOG-abs, AQP4-abs, and CSF cells and oligoclonal bands (OCB) in children with ADS and 24 months of follow-up were reviewed in this observational prospective multicenter hospital-based study. Two hundred ten children with ADS were included and diagnosed with acute disseminated encephalomyelitis (ADEM) (n = 60), neuromyelitis optica spectrum disorder (NMOSD) (n = 12), clinically isolated syndrome (CIS) (n = 101), and multiple sclerosis (MS) (n = 37) after the first episode. MOG-abs were predominantly found in ADEM (57%) and less frequently in NMOSD (25%), CIS (25%), or MS (8%). Increased MOG-ab titers were associated with younger age (p = 0.0001), diagnosis of ADEM (p = 0.005), increased CSF cell counts (p = 0.011), and negative OCB (p = 0.012). At 24-month follow-up, 96 children had no further relapses. Thirty-five children developed recurrent non-MS episodes (63% MOG-, 17% AQP4-abs at onset). Seventy-nine children developed MS (4% MOG-abs at onset). Recurrent non-MS episodes were associated with high MOG-ab titers (p = 0.0003) and older age at onset (p = 0.024). MS was predicted by MS-like MRI (p < 0.0001) and OCB (p = 0.007). An MOG-ab cutoff titer ≥1:1,280 predicted a non-MS course with a sensitivity of 47% and a specificity of 100% and a recurrent non-MS course with a sensitivity of 46% and a specificity of 86%. Our results show that the presence of MOG-abs strongly depends on the age at disease onset and that high MOG-ab titers were associated with a recurrent non-MS disease course.


Use of bivalirudin to prevent thrombosis following orthotopic liver transplantation in a patient with Budd-Chiari syndrome and a history of heparin-induced thrombocytopenia.
Type II heparin-induced thrombocytopenia (HIT) is an immune-mediated syndrome that may arise in a time-dependent manner following heparin therapy, placing patients at significant risk for thromboembolic events. Therapy includes anticoagulation with a direct thrombin inhibitor and avoidance of heparin. We report a patient with Budd-Chiari syndrome and a history of heparin-induced thrombocytopenia who presented for orthotopic liver transplant and required postoperative anticoagulation with bivalirudin. During the post-transplant graft function improvement, we observed a significant dose-effect alteration manifested by an increased bivalirudin dose requirement as factor V activity increased. This observation is an important consideration in the attempt to maintain an optimal balance between effective anticoagulation and a reduced risk of postoperative bleeding.


The influence of expansion rates on mandibular distraction osteogenesis: a computational analysis.
Mandibular distraction osteogenesis is a clinical procedure used for modifying the mandibular geometry when problems of dental overcrowding and arch shrinkage occur. The objective of this study is to use a computational model of tissue differentiation to examine the influence of the rate of distraction on bone re-growth within the fracture callus of a human mandible submitted to symphyseal distraction osteogenesis. A 3D model of the mandible is reconstructed from CT scan data and meshed into finite elements. Two different mastication loadings have been investigated: a 'full' mastication load and a 'reduced' mastication load where the action of each muscle was reduced by 70%. Four different distraction rates were analyzed: 0.6, 1.2, 2, and 3 mm/day, allowing a total displacement of 6 mm. In the early stages of the distraction process it is predicted that there is a decrease in the amount of bone tissue forming within the center of the fracture gap for all distraction rates. After the initial phases of expansion, the bone tissue within the callus increases for the slower rate of distraction or continues to decrease at the faster rates of distraction. At the end of the simulated maturation period, 47% of the distracted callus was predicted to consist of bone tissue for a distraction rate of 0.6 mm/day, decreasing to 22% for a distraction rate of 3 mm/day. Significantly higher amounts of bone formation were predicted for all distraction rates for the case of reduced mastication loading. Disparities between the model predictions and what is observed in vivo were found. For instance, during the latency period, the distraction period and beyond, the model is predicting larger than expected amounts of cartilage tissue formation within the callus. This and other limitations of the proposed model are discussed and possible specific explanations for these disparities are provided in the paper. The model predicts a distraction rate of around 1.2 mm/day to be optimal as higher rates produce less bone tissue while the risk of a premature bone union is greater at slower rates of distraction because in the latter stages of the distraction process bone tissue is predicted to form between the left and right side of the bone callus.


Anti-podoplanin Monoclonal Antibody LpMab-7 Detects Metastatic Lesions of Osteosarcoma.
Osteosarcoma is the most common primary malignant bone tumor and is highly metastatic to the lungs. Therefore, the development of a novel molecular targeting therapy against metastasis of osteosarcoma is necessary. A platelet aggregation-inducing factor, podoplanin/aggrus, is involved in tumor metastasis. Furthermore, podoplanin expression was reported to be involved in the poor prognosis of osteosarcoma patients. However, the association between podoplanin expression and metastasis of osteosarcoma remains unclear because of the lack of highly sensitive anti-podoplanin monoclonal antibodies (MAbs). In this study, we used a novel anti-podoplanin MAb, LpMab-7, which is more sensitive than well-known anti-podoplanin MAbs in immunohistochemistry. Immunohistochemical analysis using LpMab-7 showed that podoplanin expression at primary lesions is observed in 15 out of 16 (93.8%) cases. Furthermore, podoplanin expression at metastatic lesions was higher compared with primary lesions in three out of four (75%) cases with lung metastasis. Because LpMab-7 has high sensitivity against podoplanin, it is expected to be useful for molecular targeting therapy for osteosarcomas.


Characterization of "Campylobacter pyloridis" by culture, enzymatic profile, and protein content.
"Campylobacter pyloridis" has been recently described as a gastritis-associated bacterium. We studied 20 strains. The bacteria had most of the characteristics of Campylobacter spp. strains. They were hippurate negative and tolerant to triphenyl tetrazolium chloride (at 0.4 and 1 mg/ml). They grew on all the media commonly used in laboratories, although chocolate agar was the most effective for isolation. They grew in a microaerophilic atmosphere as well as in an atmosphere enriched in CO2 and when incubated at 37 degrees C but not at 30 or 42 degrees C. A total of 31 enzymes were present among the 78 studied. gamma-Glutamyl-transpeptidase activity was, in addition to urea hydrolysis, an interesting feature for the identification of these bacteria. The protein profiles of the 20 strains were similar.


Central connections of the ovine olfactory bulb formation identified using wheat germ agglutinin-conjugated horseradish peroxidase.
Pheromonal stimuli elicit rapid behavioral and reproductive endocrine changes in the ewe. The neural pathways responsible for these effects in sheep are unknown, in part, because the olfactory bulb projections have not been examined in this species. Using the anterograde and retrograde neuronal tracer, wheat germ agglutinin-conjugated horseradish peroxidase (WGA-HRP), we describe the afferent and efferent olfactory bulb connections of the Suffolk ewe. Injections of WGA-HRP limited to the main olfactory bulb resulted in retrograde labeling of cells in numerous telencephalic, diencephalic, and metencephalic regions. Terminal labeling was limited to layer la of ipsilateral cortical structures extending rostrally from the anterior olfactory nucleus (AON), piriform cortex, anterior-, and posterolateral-cortical amygdaloid nuclei to lateral entorhinal cortex caudally. Injections involving the accessory olfactory bulb and AON produced additional labeling of cells within the bed nucleus of the stria terminalis (BNST), medial nucleus of the amygdala, and a few cells in the posteromedial cortical nucleus of the amygdala. Terminal labeling included a small dorsomedial quadrant of BNST and also extended to the far lateral portions of the supraoptic nucleus. A clearly defined accessory olfactory tract and nucleus was not evident, perhaps due to limitations in the sensitivity of the method. With this possible exception, the afferent and efferent olfactory connections in the sheep appear similar to those reported for other species.


Chronic scrotal pain and microsurgical spermatic cord denervation: tricks of the trade.
Every practicing urologist encounters patients complaining of chronic scrotal content pain (CSCP). This condition can be equally frustrating for both patients and clinicians as there are no clear treatment guidelines, or pathways, for urologists to follow. As a result, most patients typically seek out multiple providers without improvements in their symptoms. Fortunately, microsurgical spermatic cord denervation (MSCD) is becoming an accepted, reliable and reproducible technique for definitively addressing CSCP in select patients. This manuscript reviews the background, effectiveness and current practice guidelines for scrotal pain in general, and MSCD in particular. Technical insights into how this technique can be performed both safely, and efficaciously, are provided. Finally, the manuscript presents a simple, yet detailed, easy to follow treatment algorithm to aid all urologists in the management of patients presenting with chronic pain.


Social stress induces autoimmune responses against the brain.
Clinical studies have revealed a high comorbidity between autoimmune diseases and psychiatric disorders, including major depressive disorder (MDD). However, the mechanisms connecting autoimmunity and depression remain unclear. Here, we aim to identify the processes by which stress impacts the adaptive immune system and the implications of such responses to depression. To examine this relationship, we analyzed antibody responses and autoimmunity in the chronic social defeat stress (CSDS) model in mice, and in clinical samples from patients with MDD. We show that socially stressed mice have elevated serum antibody concentrations. We also confirm that social stress leads to the expansion of specific T and B cell populations within the cervical lymph nodes, where brain-derived antigens are preferentially delivered. Sera from stress-susceptible (SUS) mice exhibited high reactivity against brain tissue, and brain-reactive immunoglobulin G (IgG) antibody levels positively correlated with social avoidance behavior. IgG antibody concentrations in the brain were significantly higher in SUS mice than in unstressed mice, and positively correlated with social avoidance. Similarly, in humans, increased peripheral levels of brain-reactive IgG antibodies were associated with increased anhedonia. In vivo assessment of IgG antibodies showed they largely accumulate around blood vessels in the brain only in SUS mice. B cell-depleted mice exhibited stress resilience following CSDS, confirming the contribution of antibody-producing cells to social avoidance behavior. This study provides mechanistic insights connecting stress-induced autoimmune reactions against the brain and stress susceptibility. Therapeutic strategies targeting autoimmune responses might aid in the treatment of patients with MDD featuring immune abnormalities.


Development and Validation of the American Heart Association Predicting Risk of Cardiovascular Disease EVENTs (PREVENT) Equations.
Background: Multivariable equations are recommended by primary prevention guidelines to assess absolute risk of cardiovascular disease (CVD). However, current equations have several limitations. Therefore, we developed and validated the AHA Predicting Risk of CVD EVENTs (PREVENT) equations among US adults aged 30-79 years without known CVD. Methods: The derivation sample included individual-level participant data from 25 datasets (N=3,281,919) between 1992-2017. The primary outcome was CVD (atherosclerotic CVD [ASCVD] and heart failure [HF]). Predictors included traditional risk factors (smoking status, systolic blood pressure, cholesterol, anti-hypertensive or statin use, diabetes) and estimated glomerular filtration rate [eGFR]. Models were sex-specific, race-free, developed on the age-scale, and adjusted for competing risk of non-CVD death. Analyses were conducted in each dataset and meta-analyzed. Discrimination was assessed using Harrell's C-statistic. Calibration was calculated as the slope of the observed vs. predicted risk by decile. Additional equations to predict each CVD subtype (ASCVD, HF) and include optional predictors (urine albumin-to-creatinine ratio [UACR], hemoglobin A1c [HbA1c]), and social deprivation index [SDI]) were also developed. External validation was performed in 3,330,085 participants from 21 additional datasets. Results: Among 6,612,004 adults included, mean (SD) age was 53 (12) years and 56% were female. Over a mean (SD) follow-up of 4.8 (3.1) years, there were 211,515 incident total CVD events. The median C-statistics in external validation for CVD were 0.794 (interquartile interval [IQI]: 0.763-0.809) in female and 0.757 (0.727-0.778) in male participants. The calibration slopes were 1.03 (IQI 0.81 -1.16) and 0.94 (0.81-1.13) among females and males, respectively. Similar estimates for discrimination and calibration were observed for ASCVD- and HF-specific models. The improvement in discrimination was small but statistically significant when UACR, HbA1c, and SDI were added together to the base model to total CVD (ΔC-statistic [IQI] 0.004 [0.004, 0.005] and 0.005 [0.004, 0.007] among females and males, respectively). Calibration improved significantly when UACR was added to the base model among those with marked albuminuria (>300mg/g) (1.05 [0.84-1.20] vs. 1.39 [1.14-1.65], p=0.01). Conclusions: PREVENT equations accurately and precisely predicted risk for incident CVD and CVD subtypes in a large, diverse, and contemporary sample of US adults using routinely available clinical variables.


Reconstitution of human beta-globin locus control region hypersensitive sites in the absence of chromatin assembly.
The human beta-globin genes are regulated by the locus control region (LCR), an element composed of multiple DNase I-hypersensitive sites (HS sites) located 5' to the genes. Various functional studies indicate that the LCR confers high-level, position-independent, and copy number-dependent expression to linked globin genes in transgenic mice. However, the structural basis for LCR function is unknown. Here we show that LCR HS sites can be reconstituted in an erythroid cell-specific manner on chromatin-assembled LCR templates in vitro. Surprisingly, HS2 and HS3 are also formed with erythroid proteins in the absence of chromatin assembly, indicating that sensitivity to nucleases is not simply a consequence of nucleosome reorganization. The generation of LCR HS sites in the absence of chromatin assembly leads to the formation of S1- and KMnO(4)-sensitive regions in HS2 and HS3. These sites are also sensitive to S1 nuclease in erythroid cells in vivo, suggesting a distorted DNA structure in the LCR core enhancer elements. Finally, we show that RNA polymerase II initiates transcription in the HS2 and HS3 core enhancer regions in vitro. Transcription in both HS2 and HS3 proceeds in a unidirectional manner. Taken together, the data suggest that erythroid proteins interact with the core enhancer elements, distort the DNA structure, and recruit polymerase II transcription complexes. These results further our understanding of the structural basis for LCR function and provide an explanation for why the LCR core regions are so extremely sensitive to nucleases in erythroid cells.


A Novel Model for Predicting Rehospitalization Risk Incorporating Physical Function, Cognitive Status, and Psychosocial Support Using Natural Language Processing.
With the increasing focus on reducing hospital readmissions in the United States, numerous readmissions risk prediction models have been proposed, mostly developed through analyses of structured data fields in electronic medical records and administrative databases. Three areas that may have an impact on readmission but are poorly captured using structured data sources are patients' physical function, cognitive status, and psychosocial environment and support. The objective of the study was to build a discriminative model using information germane to these 3 areas to identify hospitalized patients' risk for 30-day all cause readmissions. We conducted clinician focus groups to identify language used in the clinical record regarding these 3 areas. We then created a dataset including 30,000 inpatients, 10,000 from each of 3 hospitals, and searched those records for the focus group-derived language using natural language processing. A 30-day readmission prediction model was developed on 75% of the dataset and validated on the other 25% and also on hospital specific subsets. Focus group language was aggregated into 35 variables. The final model had 16 variables, a validated C-statistic of 0.74, and was well calibrated. Subset validation of the model by hospital yielded C-statistics of 0.70-0.75. Deriving a 30-day readmission risk prediction model through identification of physical, cognitive, and psychosocial issues using natural language processing yielded a model that performs similarly to the better performing models previously published with the added advantage of being based on clinically relevant factors and also automated and scalable. Because of the clinical relevance of the variables in the model, future research may be able to test if targeting interventions to identified risks results in reductions in readmissions.


Chirality selective metamaterial absorber with dual bands.
In this paper, a sensitive chirality selective metamaterial absorber (CSMA) is constructed by using 'I-shaped' resonator with asymmetric twisted metallic wires. Absorption of 95.18% and 91.77% at two resonant frequencies can be achieved for left-handed circularly polarized (LCP) incident wave, with little loss of right-handed circularly polarized (RCP) incident wave, which results in significant absorptive circular dichroism. Not only can the CSMA intensely absorb LCP illumination with dual bands, but also circularly polarized (CP) conversion for RCP wave is achieved over a broad bandwidth. The spin-dependent absorption, closely linked to chiral symmetry breaking, is investigated through oblique incidence, power loss distribution and scanning parameters optimization. The proposed strategy is further demonstrated in mid-infrared band which could advance the applications in polarization manipulation to circularly polarized detectors/lasers, chiral sensing/bolometers, and molecular spectroscopy.


Basal ganglia neuropeptides show abnormal processing associated with L-DOPA-induced dyskinesia.
L-DOPA administration is the primary treatment for Parkinson's disease (PD) but long-term administration is usually accompanied by hyperkinetic side-effects called L-DOPA-induced dyskinesia (LID). Signaling neuropeptides of the basal ganglia are affected in LID and changes in the expression of neuropeptide precursors have been described, but the final products formed from these precursors have not been well defined and regionally mapped. We therefore used mass spectrometry imaging to visualize and quantify neuropeptides in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine exposed parkinsonian and LID Macaca mulatta brain samples. We found that dyskinesia severity correlated with the levels of some abnormally processed peptides - notably, des-tyrosine dynorphins, substance P (1-7), and substance P (1-9) - in multiple brain regions. Levels of the active neuropeptides; dynorphin B, dynorphin A (1-8), α-neoendorphin, substance P (1-11), and neurokinin A, in the globus pallidus and substantia nigra correlated with putaminal levels of L-DOPA. Our results demonstrate that the abundance of selected active neuropeptides is associated with L-DOPA concentrations in the putamen, emphasizing their sensitivity to L-DOPA. Additionally, levels of truncated neuropeptides (which generally exhibit reduced or altered receptor affinity) correlate with dyskinesia severity, particularly for peptides associated with the direct pathway (i.e., dynorphins and tachykinins). The increases in tone of the tachykinin, enkephalin, and dynorphin neuropeptides in LID result in abnormal processing of neuropeptides with different biological activity and may constitute a functional compensatory mechanism for balancing the increased L-DOPA levels across the whole basal ganglia.


Warm-started wavefront reconstruction for adaptive optics.
Future extreme adaptive optics (ExAO) systems have been suggested with up to 10(5) sensors and actuators. We analyze the computational speed of iterative reconstruction algorithms for such large systems. We compare a total of 15 different scalable methods, including multigrid, preconditioned conjugate-gradient, and several new variants of these. Simulations on a 128x128 square sensor/actuator geometry using Taylor frozen-flow dynamics are carried out using both open-loop and closed-loop measurements, and algorithms are compared on a basis of the mean squared error and floating-point multiplications required. We also investigate the use of warm starting, where the most recent estimate is used to initialize the iterative scheme. In open-loop estimation or pseudo-open-loop control, warm starting provides a significant computational speedup; almost every algorithm tested converges in one iteration. In a standard closed-loop implementation, using a single iteration per time step, most algorithms give the minimum error even in cold start, and every algorithm gives the minimum error if warm started. The best algorithm is therefore the one with the smallest computational cost per iteration, not necessarily the one with the best quasi-static performance.


Hormonal profiles of callipyge and normal sheep.
Five sheep expressing the callipyge gene, which causes muscle hypertrophy, were compared with five normal sheep to determine whether endocrine differences existed between genotypes. Blood samples were taken at 15-min intervals for 6 h to measure serum concentrations of growth hormone and insulin. Thyroxine and IGF-I levels were determined in single samples. No differences were found in mean serum growth hormone concentrations, growth hormone pulse amplitude, or pulse frequency (P > .3). Insulin concentrations were not different between genotypes before or after feeding (4.5 +/- 1.3 ng/mL callipyge vs 4.9 +/- 1.7 ng/mL normal, P > .4). The IGF-I concentrations did not differ (273.8 +/- 17.6 ng/mL callipyge vs 261.4 +/- 12.3 ng/mL normal). Serum thyroxine concentrations also were not different (5.9 +/- 2.3 microg/mL for callipyge vs 5.1 +/- 2.1 microg/mL normal, P > .3). In a separate experiment, five ewe lambs with and five without the callipyge gene were stressed to determine whether the adrenocortical response to stress differed between genotypes. Blood samples were taken at 15-min intervals for 2 h before, during, and after restraint stress. Restraint increased serum cortisol concentrations in both groups (P < .001), but genotypes did not differ at any time (P > .3). These results suggest that differences in muscling are not due to differences in systemic hormone secretion. The results of the second experiment indicate that callipyge and normal sheep have similar adrenocortical responses to stress.


Cardiocerebral protective effects of dexmedetomidine as anesthetic in colorectal cancer surgery.
To explore the cardiocerebral protective effect of dexmedetomidine as an anesthetic in colorectal cancer surgery. A total of 246 colorectal cancer patients were enrolled in this retrospective analysis. Those patients were admitted to the Affiliated Hospital of Qingdao University and underwent surgery from July 2014 to July 2016. The patients were divided into observation group and control group according to the anesthetic used in surgery. The conventional anesthetic was administered to patients in control group, whereas conventional anesthetic supplemented with dexmedetomidine was administered to patients in the observation group. The heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP), jugular venous oxygen saturation (Sj-vO2), cerebral oxygen extraction ratio (ERO2), and cerebral arterial partial pressure of oxygen (PaO2) were recorded before dexmedetomidine administration (T0), 30 min after start of surgery (T1), and 2 h after surgery (T2). Central venous blood (4 ml) was withdrawn 6 hours and 24 hours after surgery. Following centrifugation, the serum was collected and stored at -70°C. After collection of all the blood samples, concentrations of creatine kinase (CK-MB), troponin I (cTnI), TNF-α and S100β in serum were measured using ELISA, and differences between the two groups were compared. Differences of the parameters measured at T0 were not statistically significant between observation group and control group (p>0.05), whereas the parameters measured at T1 and T2 were significantly better in the observation group than those in the control group (p<0.05). The post-surgery blood test showed that indicators of cardiocerebral hemodynamics were better in the observation group than those in the control group (p<0.05). Administration of dexmedetomidine in colorectal cancer surgery can provide effective cardiocerebral protection and it is worth popularizing in clinical practice.


The epidemiology of schistosomiasis in Egypt: Minya Governorate.
Risk factors, prevalence, and intensity of infection with Schistosoma sp. and prevalence and magnitude of morbidity caused by schistosomiasis was assessed in a stratified random sample of 16,433 subjects from 2,409 households in 33 rural communities in Minya Governorate, Egypt. The prevalence of S. haematobium ranged from 1.9% to 32.7% among the communities and averaged 8.9%. The average intensity of infection was a geometric mean egg count (GMEC) of 8.5 per 10 ml of urine and ranged from 1.6 to 30.9. Prevalence was maximum (18-20%) in those 10-20 years of age and higher in males than in females. Intensity of infection followed the same pattern. Infection with S. mansoni was present almost exclusively in a single village, confirming spread of this species up the Nile River and its focality in Minya. Risk factors for S. haematobium infection were an age from 11 to 20; male gender; males bathing in, women washing clothing or utensils in, and children swimming or playing in canals; and a history of, or treatment for, schistosomiasis. Recent history of burning micturition was associated with infection in children but not in adults, while a history of blood in urine correlated with S. haematobium infection in both age groups. Reagent strip-detected hematuria and proteinuria were highly associated, particularly in children, with S. haematobium infection. The presence of hepatomegaly or splenomegaly on physical examination was not associated with S. haematobium ova in the urine. Hepatomegaly, as measured by ultrasonography in the midclavicular line or the midsternal line, or ultrasonography-detected splenomegaly were not present more frequently in infected subjects than in uninfected subjects. Schistosoma ova were not detected more frequently in urine of subjects with ultrasonography-detected periportal fibrosis than in the urine from subjects without this finding. Ultrasonography-detected urinary bladder wall lesions were detected in only 6 (0.3%) subjects and obstructive uropathy was observed in 54 (2.7%) subjects. The absence of an association between prevalence of urinary tract morbidity and S. haematobium infections was surprising. Two possible explanations are 1) that repeated chemotherapy has reduced the prevalence of urinary tract morbidity and 2) that morbidity was not being detected by the ultrasonographic operators.


Comparison of Single and Combined Treatment with Exercise Therapy and Collagen Supplementation on Early Knee Arthritis among Athletes-A Quasi-Randomized Trial.
Athletic injuries are commonly implicated in the development of early osteoarthritic (EOA) changes in the knee. These changes have a significant impact on athletic performance, and therefore the early detection of EOA is paramount. The objective of the study is to assess the impact of different interventions on individuals with EOA, particularly focusing on recreational athletes. The study aims to evaluate the effectiveness of three treatment groups in improving various aspects related to knee EOA, including pain, range of motion, strength, and function. A study was undertaken with 48 recreational athletes with EOA who were assigned to one of three groups by the referring orthopedic surgeon: collagen (Col), exercise (Ex), or collagen and exercise (ColEx) groups. All the participants received their respective group-based intervention for 12 weeks. Visual analog scale (VAS), knee flexion range of motion (ROM) knee flexors and extensors strength, and KOOS were assessed at baseline, and after 4 weeks, 8 weeks, and 12 weeks of intervention. VAS for activity improved in all treatment groups, with no difference between groups. The between-group analysis for knee ROM revealed a significant difference (p = 0.022) in the Col vs. Ex group at 12 weeks. The knee flexor and extensor strength and the KOOS scores improved considerably in the Ex and the ColEx group (p < 0.05) at 12 weeks. Exercise therapy improved pain, strength and function in subjects with EOA, whereas the association of collagen seems to have accentuated the effects of exercise in bringing about clinical improvements.


An ELISA-based approach to optimize elution conditions for obtaining hapten-specific antibodies.
The correct choice of the elution conditions to break an affinity interaction is important for the successful purification of biomolecules. The optimal elution buffer liberates the bound substance in a minimum volume and maintains the activity of the purified material. The present study demonstrates an enzyme-linked immunosorbent assay (ELISA)-based approach for selection of specific elution conditions for eluting antibodies against a small molecule (atrazine) from pooled sera. Six different elution conditions were tried for the removal of antibodies from the complex. Large-scale purification of anti-atrazine antibodies from the sera was done with a hapten-specific column using an amino-terminal crosslinked agarose gel. Efficacy in terms of total amount of recovery and binding affinities of eluted antibodies from the column were further investigated by ELISA. Results indicate that the ELISA-based elution approach is ideal for the selection of suitable elution buffer that can subsequently be utilized for affinity purification applications.


Genomic analysis reveals an exogenous viral symbiont with dual functionality in parasitoid wasps and their hosts.
Insects are known to host a wide variety of beneficial microbes that are fundamental to many aspects of their biology and have substantially shaped their evolution. Notably, parasitoid wasps have repeatedly evolved beneficial associations with viruses that enable developing wasps to survive as parasites that feed from other insects. Ongoing genomic sequencing efforts have revealed that most of these virus-derived entities are fully integrated into the genomes of parasitoid wasp lineages, representing endogenous viral elements (EVEs) that retain the ability to produce virus or virus-like particles within wasp reproductive tissues. All documented parasitoid EVEs have undergone similar genomic rearrangements compared to their viral ancestors characterized by viral genes scattered across wasp genomes and specific viral gene losses. The recurrent presence of viral endogenization and genomic reorganization in beneficial virus systems identified to date suggest that these features are crucial to forming heritable alliances between parasitoid wasps and viruses. Here, our genomic characterization of a mutualistic poxvirus associated with the wasp Diachasmimorpha longicaudata, known as Diachasmimorpha longicaudata entomopoxvirus (DlEPV), has uncovered the first instance of beneficial virus evolution that does not conform to the genomic architecture shared by parasitoid EVEs with which it displays evolutionary convergence. Rather, DlEPV retains the exogenous viral genome of its poxvirus ancestor and the majority of conserved poxvirus core genes. Additional comparative analyses indicate that DlEPV is related to a fly pathogen and contains a novel gene expansion that may be adaptive to its symbiotic role. Finally, differential expression analysis during virus replication in wasps and fly hosts demonstrates a unique mechanism of functional partitioning that allows DlEPV to persist within and provide benefit to its parasitoid wasp host.


Influence of obesity on clinical outcomes in hospitalized children: a systematic review.
Obesity is prevalent among hospitalized children. Knowledge of the relationship between obesity and outcomes in hospitalized children will enhance nutrition assessment and provide opportunities for interventions. To systematically review the existing literature concerning the impact of obesity on clinical outcomes in hospitalized children. PubMed, Web of Science, and EMBASE databases were searched for studies of hospitalized children aged 2 to 18 years with identified obesity and at least 1 of the following clinical outcomes: all-cause mortality, incidence of infections, and length of hospital stay. Cohort and case-control studies were included. Cross-sectional studies, studies of healthy children, and those without defined criteria for classifying weight status were excluded. The Newcastle-Ottawa Scale was used to assess study quality. Twenty-eight studies (26 retrospective; 24 cohort and 4 case-control) were included. Of the 21 studies that included mortality as an outcome, 10 reported a significant positive relationship between obesity and mortality. The incidence of infections was assessed in 8 of the 28 studies; 2 reported significantly more infections in obese compared with nonobese patients. Of the 11 studies that examined length of stay, 5 reported significantly longer lengths of hospital stay for obese children. Fifteen studies (53%) had a high quality score. Larger studies observed significant relationships between obesity and outcomes. Studies of critically ill, oncologic or stem cell transplant, and solid organ transplant patients showed a relationship between obesity and mortality. The available literature on the relationship between obesity and clinical outcomes is limited by subject heterogeneity, variations in criteria for defining obesity, and outcomes examined. Childhood obesity may be a risk factor for higher mortality in hospitalized children with critical illness, oncologic diagnoses, or transplants. Further examination of the relationship between obesity and clinical outcomes in this subgroup of hospitalized children is needed.


Insulin increases glucose transfer across the blood-brain barrier in man.
The influence of insulin on unidirectional flux of glucose across the blood-brain barrier and on net uptake of glucose by the brain was investigated in seven fasting patients. The unidirectional extraction, E, of [14C]D-glucose was determined using 36Cl- as an intravascular reference, by the indicator dilution method. 0.4 U insulin/kg body wt was infused intravenously over 30 min while blood glucose was maintained constant by glucose infusion. Six determinations were made in each patient, two before, two during insulin infusion, and two after. In connection with each blood-brain barrier study, arterial and cerebral venous samples were taken for measurement of glucose, oxygen, insulin, K+, and phosphate. Cerebral blood flow (CBF) was measured in each patient. The main finding was an increased extraction of glucose from 14 to 21% and a highly significant increase in unidirectional flux (CBF X unidirectional extraction X arterial glucose concentration) from 0.46 to 0.66 mumol/g X min during insulin infusion (plasma insulin approximately 1,500 microU/ml). The net brain uptake of glucose (CBF X arterio-venous difference for glucose) as unaltered during the investigation period of 45 min, which is too short a time for insulin to penetrate the barrier. It follows that the backflux of glucose from the brain was increased during insulin application. The effect of insulin might be a speeding up of the glucose carrier in analogy to heart muscle.


PsSAK1, a stress-activated MAP kinase of Phytophthora sojae, is required for zoospore viability and infection of soybean.
Mitogen-activated protein kinase (MAPK) pathways are universal and evolutionarily conserved signal transduction modules in all eukaryotic cells. In this study, PsSAK1, which encodes a stress-activated MAPK of Phytophthora sojae, was identified. PsSAK1 is highly conserved in oomycetes, and it represents a novel group of MAPK due to its pleckstrin homology domain. Reverse-transcription polymerase chain reaction analysis showed that PsSAK1 expression was upregulated in zoospores and cysts and during early infection. In addition, its expression was induced by osmotic and oxidative stress mediated by NaCl and H(2)O(2), respectively. To elucidate the function, the expression of PsSAK1 was silenced using stable transformation of P. sojae. The silencing of PsSAK1 did not impair hyphal growth, sporulation, or oospore production but severely hindered zoospore development, in that the silenced strains showed quicker encystment and a lower germination ratio than the wild type. PsSAK1-silenced mutants produced much longer germ tubes and could not colonize either wounded or unwounded soybean leaves. Our results indicate that PsSAK1 is an important regulator of zoospore development and pathogenicity in P. sojae.


Intermediate filament proteins in classic and variant types of small cell lung carcinoma cell lines: a biochemical and immunochemical analysis using a panel of monoclonal and polyclonal antibodies.
The intermediate filament protein (IFP) characteristics of a panel of lung cancer cell lines including adenocarcinoma (two cell lines) and small cell lung cancer (SCLC, three classic and three variant cell lines) were examined using one- and two-dimensional gel electrophoretic techniques, immunocytochemical techniques and immunoblotting assays. A panel of 28 monoclonal and polyclonal antibodies to the five different types of IFP were used. The results of our studies indicate that these human lung adenocarcinoma, classic SCLC and variant SCLC cell lines can be differentiated on the basis of their pattern of IFP. The main conclusions from this study can be summarized as follows. The two adenocarcinoma cell lines contain cytokeratins 7, 8, 18, and sometimes 19, next to vimentin intermediate filament (IF). The three classic-type SCLC cell lines contain only cytokeratin IFs but not vimentin IF or neurofilaments (NFs). Cytokeratin polypeptides 7, 8, 18 and 19 could be detected. All three variant-type SCLC cell lines do not contain detectable amounts of cytokeratins. In contrast, two out of three variant SCLC cell lines contain neurofilament proteins. All three variant-type SCLC cell lines contain vimentin IF. Using immunoblotting assays with monoclonal and polyclonal antibodies to defined NF proteins the presence of the 68 X 10(3) Mr and the 160 X 10(3) Mr NF polypeptide could be demonstrated in two variant SCLC cell lines. As patients with SCLC-variant phenotype have a poorer prognosis after cytotoxic therapy than patients with 'pure' SCLC, the use of antibodies to IFP in staining fresh lung tumours, especially anaplastic ones, may differentiate the two subtypes of SCLC. Such a distinction would have a major impact on therapy selections and may be of prognostic importance.


Do distributions of diamondoid hydrocarbons accumulated in oil-contaminated fish tissues help to identify the sources of oil?
Identifying the sources of environmental oil contamination can be challenging, especially for oil in motile organisms such as fish. Lipophilic hydrocarbons from oil can bioaccumulate in fish adipose tissue and potentially provide a forensic "fingerprint" of the original oil. Herein, diamondoid hydrocarbon distributions were employed to provide such fingerprints. Indices produced from diamondoids were used to compare extracts from fish adipose tissues and the crude and fuel oils to which the fish were exposed under laboratory conditions. A suite of 20 diamondoids was found to have bioaccumulated in the dietary-exposed fish. Cross-plots of indices between fish and exposure oils were close to the ideal 1:1 relationship. Comparisons with diamondoid distributions of non-exposure oils produced overall, but not exclusively, weaker correlations. Linear Discriminatory Analysis on a combined set of 15 diamondoid and bicyclane molecular ratios was able to identify the exposure oils, so a use of both compound classes is preferable.


Developments in microarray technologies.
The focus of high-throughput drug discovery has progressed through the genome and the transcriptome and is now moving towards more difficult problems in assessing the proteome, glycome and metabolome. Microarrays are currently the major tool in the assessment of gene expression via cDNA or RNA analysis; however, they are also used to screen libraries of proteins and small molecules. Microarrays have helped to extract more information from smaller sample volumes and enabled the incorporation of low-cost high-throughput assays in the drug discovery process. The technology continues to develop and is being rapidly transferred into more challenging areas, with the potential to further aid and enhance the drug discovery process through the development of, for example, proteomic, glycomic and tissue arrays.


[Spermograms of healthy young subjects living in Arica, Chile].
Semen analysis is one of the parameters used to predict male fertility. Semen can be altered by environmental pollutants; therefore it could be used as a biological marker of exposure in contaminated areas. To analyze the spermogram values in a sample of healthy young males, residing in Arica, Chile. One hundred and two healthy university students volunteers aged 18 to 30 years answered a questionnaire about fertility, habits and andrologic diseases and provided a semen sample. Within three hours after ejaculation, semen volume, pH, sperm concentration, motility and morphology were analyzed. Six percent of volunteers had offspring, 1% declared to be infertile, 32% smoked and 78% consumed alcohol. Semen pH was 7.6 ± 0.5, volume, 2.9 ± 1.6 ml, sperm concentration, 62.8 ± 62.3 x 10(6)/ml, normal morphology, 15.0 ± 7.9%, overall motility, 42.2 ± 23.2 % and grade A motility, 19.2 ± 18.6%. The percentage of subjects that had normal semen values was 82% for total sperm count, 76% for sperm concentration, 72% for volume, 64% for vitality, 63% for pH, 57% for morphology, 38% for overall motility and 26% for grade A motility. This sample of healthy young males had a normal sperm count in comparison with international reports. However it is necessary to characterize the spermogram in uncontaminated areas of Chile to ensure that our results are within the expected values for the country.


Social deprivation and breast cancer.
This cross-sectional study was carried out in a population-based setting in Worcestershire to investigate the relationship between social deprivation and other potential prognostic factors. A total of 762 female patients diagnosed with primary breast cancer between 1 January 1998 and 31 December 1999 were selected. Breast cancer included all new cases of primary invasive breast cancer and ductal carcinoma in situ. A total of 753 patients were matched by their postcode of residence to enumeration district Townsend score and then divided into three groups based on Townsend quintiles (affluent n = 478; middle n = 157; deprived n = 118). Main outcome measures were relationships between social deprivation and tumour type, stage at presentation, oestrogen receptor status, tumour grade and treatment type. Compared with the most deprived women, affluent women were less likely to present with invasive ductal tumours (70.8 per cent versus 85.9 per cent, chi2 linear trend = 6.757, p = 0.009), tumours of higher grade (36.0 per cent versus 44.7 per cent, chi2 linear trend = 4.201, p = 0.040), and oestrogen receptor negative tumours (22.4 per cent versus 33.3 per cent, chi2 linear trend = 3.501, p = 0.061). There was no significant difference in stage or tumour size at presentation between deprivation groups. More deprived women with invasive tumours of less than 20 mm maximum diameter were significantly more likely to have mastectomies than affluent women (47.8 per cent versus 32.1 per cent, chi2 linear trend = 4.091, p = 0.043). This study suggests that level of social deprivation is associated with tumour type, grade and oestrogen receptor status. There was also a suggestion that increased level of deprivation was associated with increased risk of potentially unnecessary mastectomies.


RhoA/Rho kinase mediates TGF-β1-induced kidney myofibroblast activation through Poldip2/Nox4-derived reactive oxygen species.
The small G proteins Rac1 and RhoA regulate actin cytoskeleton, cell shape, adhesion, migration, and proliferation. Recent studies in our laboratory have shown that NADPH oxidase Nox4-derived ROS are involved in transforming growth factor (TGF)-β1-induced rat kidney myofibroblast differentiation assessed by the acquisition of an α-smooth muscle actin (α-SMA) phenotype and expression of an alternatively spliced fibronectin variant (Fn-EIIIA). Rac1 and RhoA are essential in signaling by some Nox homologs, but their role as effectors of Nox4 in kidney myofibroblast differentiation is not known. In the present study, we explored a link among Rac1 and RhoA and Nox4-dependent ROS generation in TGF-β1-induced kidney myofibroblast activation. TGF-β1 stimulated an increase in Nox4 protein expression, NADPH oxidase activity, and abundant α-SMA and Fn-EIIIA expression. RhoA but not Rac1 was involved in TGF-β1 induction of Nox4 signaling of kidney myofibroblast activation. TGF-β1 stimulated active RhoA-GTP and increased Rho kinase (ROCK). Inhibition of RhoA with small interfering RNA and ROCK using Y-27632 significantly reduced TGF-β1-induced stimulation of Nox4 protein, NADPH oxidase activity, and α-SMA and Fn-EIIIA expression. Treatment with diphenyleneiodonium, an inhibitor of NADPH oxidase, did not decrease RhoA activation but inhibited TGF-β1-induced α-SMA and Fn-EIIIA expression, indicating that RhoA is upstream of ROS generation. RhoA/ROCK also regulated polymerase (DNA-directed) δ-interacting protein 2 (Poldip2), a newly discovered Nox4 enhancer protein. Collectively, these data indicate that RhoA/ROCK is upstream of Poldip2-dependent Nox4 regulation and ROS production and induces redox signaling of kidney myofibroblast activation and may broader implications in the pathophysiology of renal fibrosis.


Aromatase in colon carcinoma.
Aromatase is one of the key estrogen-producing enzymes and is regarded as one of the therapeutic targets in estrogen receptor-positive breast cancer patients. Human colon carcinoma has also been recently proposed as being an estrogen-responsive malignancy, but the detailed status of aromatase has not yet been reported. Therefore, in this study, we evaluated the aromatase expression in colon carcinoma using immunohistochemistry and real-time polymerase chain reaction. Aromatase mRNA was significantly higher (p=0.03) in colon carcinoma than in the corresponding non-neoplastic mucosa (n=31). Aromatase immunoreactivity tended to be positively associated with the intratumoral concentration of estrogens (n=53), and in particular, the concentration of estradiol was significantly higher (p=0.02) in aromatase-positive cases in men. Aromatase immunoreactivity was detected in the cytoplasm of the carcinoma cells in 217/328 (65%) examined colon carcinoma cases. Aromatase immunoreactivity was significantly positively correlated with tubular differentiation, and inversely correlated with Ki-67 labeling index, although not necessarily correlated with the clinical outcome of the patients. All these results demonstrate that colon carcinoma expresses functional aromatase, and that estrogens are locally synthesized in the tumor tissues. The findings reported here could contribute to a better understanding of the actions of estrogen in colon carcinoma.


[The public-private mix in the Brazilian Health System: financing, delivery and utilization of health services].
This paper analyzes the public-private mix in the Brazilian Health System from the perspective of health care delivery, utilization and financing. Moreover, this quantitative study based on secondary data from official databases contemplates the subsidies granted by the government to the private sector. It shows the existence of some inequalities favoring the population having private health plans, a result of the peculiar participation of the private sector in the Brazilian Health System not only offering supplementary care but duplicating the coverage offered by the public system (called SUS). The analysis is made on the basis of the classification of public-private mix in Health Systems developed by the OECD in 2004, that helps understanding the kinds of inequalities occurring in each type of public-private mix. The inequalities that occur in the Brazilian system must be understood as the result of the duplicated coverage offered by the private market and of the weak public funding for the SUS while granting important subsidies to the private sector.


Alpha chain of HLA-DR transplantation antigens is a member of the same protein superfamily as the immunoglobulins.
Four cDNA clones, pDR-alpha-1, pDR-alpha-2, pDR-alpha-3 and pDR-alpha-4, corresponding to the alpha chain of HLA-DR antigens, have been sequenced. Restriction maps and sequences suggest that all clones are identical apart from a single-base substitution present in pDR-alpha-1. Amino acid sequence data, together with the nucleotide sequence data, allowed the complete amino acid sequence to be predicted. The alpha chain is composed of 229 amino acids, of which 191 are exposed on the outside of the plasma membrane. The membrane-embedded portion of the chain consists of 23 hydrophobic amino acids. The succeeding 15 amino acids form the cytoplasmically localized hydrophilic tail. The extracellular portion, with carbohydrate moieties linked to Asn78 and Asn118, seems to be organized into two domains. The second domain, which contains the only disulfide bond of the alpha chain, displays amino acid sequence homology to immunoglobulin constant regions, to the second domain of the beta chain of a class II antigen, to the third domain of heavy chains of class I antigens and to beta 2-microglobulin. Thus the subunits of immunoglobulins, class I antigens and class II antigens are related evolutionarily.


Evaluation of the thermal antinociceptive effects of hydromorphone hydrochloride after intramuscular administration to orange-winged Amazon parrots (Amazona amazonica).
To evaluate the thermal antinociceptive effects of hydromorphone hydrochloride after IM administration to orange-winged Amazon parrots (Amazona amazonica). 8 healthy adult parrots (4 males and 4 females). In a randomized crossover study, each bird received hydromorphone (0.1, 1, and 2 mg/kg) and saline (0.9% NaCl) solution (1 mL/kg; control) IM, with a 7-day interval between treatments. Each bird was assigned an agitation-sedation score, and the thermal foot withdrawal threshold (TFWT) was measured at predetermined times before and after treatment administration. Adverse effects were also monitored. The TFWT, agitation-sedation score, and proportion of birds that developed adverse effects were compared among treatments over time. Compared with the mean TFWT for the control treatment, the mean TFWT was significantly increased at 0.5, 1.5, and 3 hours and 1.5, 3, and 6 hours after administration of the 1- and 2-mg/kg hydromorphone doses, respectively. Significant agitation was observed at 0.5, 1.5, and 3 hours after administration of the 1 - and 2-mg/kg hydromorphone doses. Other adverse effects observed after administration of the 1- and 2-mg/kg doses included miosis, ataxia, and nausea-like behavior (opening the beak and moving the tongue back and forth). Although the 1- and 2-mg/kg hydromorphone doses appeared to have antinociceptive effects, they also caused agitation, signs of nausea, and ataxia. Further research is necessary to evaluate administration of lower doses of hydromorphone and other types of stimulation to better elucidate the analgesic and adverse effects of the drug in psittacine species.


Mosquito feeding-induced enhancement of Cache Valley Virus (Bunyaviridae) infection in mice.
Cache-Valley (CV) virus, an arthropod-borne bunyavirus, recently has emerged as a significant veterinary pathogen causing infertility and congenital malformations in North American ruminants. To investigate the role of vector feeding on CV infection, adult mice were injected subcutaneously with CV, CV and vector thorax extract (a source of vector saliva), or CV into the site of intense, noninfected-mosquito feeding. Mice did not become infected after injection of CV or CV and vector saliva, nor did they produce antibodies to CV. However, injection of CV into sites of mosquito feeding resulted in viremia and production of anti-CV antibody by 2 wk after infection. This enhancement of CV infection resulted after feeding by Aedes triseriatus (Say), Ae. aegypti (L.), or Culex pipiens (L.). Enhancement occurred when injection was delayed up to 4 h after mosquito feeding, but it was not observed when virus injection was performed at a site distant from mosquito feeding. These results indicate that arbovirus infection may be enhanced by mosquito-vertebrate host interactions and that replication of arboviruses in arthropod vectors may not be responsible for increased virulence of infections mediated by infected arthropods. Enhanced CV infection in pregnant mice did not result in infertility or malformed pups, indicating that the mouse is not a suitable model to study CV-induced malformations.


Poly(glycoamidoamine) Brushes Formulated Nanomaterials for Systemic siRNA and mRNA Delivery in Vivo.
Safe and effective delivery is required for siRNA and mRNA-based therapeutics to reach their potential. Here, we report on the development of poly(glycoamidoamine) brush nanoparticles as delivery vehicles for siRNA and mRNA. These polymers were capable of significant delivery of siRNA against FVII and mRNA-encoding erythropoietin (EPO) in mice. Importantly, these nanoparticles were well-tolerated at their effective dose based on analysis of tissue histology, systemic cytokine levels, and liver enzyme chemistry. The polymer brush nanoparticles reported here are promising for therapeutic applications.


Application of competitive enzyme-linked immunosorbent assay for the quantification of imidacloprid titers in xylem fluid extracted from grapevines.
A competitive enzyme-linked immunosorbent assay (ELISA) technique was evaluated for quantifying titers of imidacloprid in xylem fluid extracted from Vitis vinifera L. grapevines that were treated with systemic applications of the neonicotinoid insecticide Admire. Evidence of matrix effects, factors that compromise the precision and accuracy of the ELISA, was present in assays with undiluted xylem fluid. These effects could be eliminated by dilution of extracts in water, resulting in a lower sensitivity of the assay of 4 microg liter(-1). In a field trial conducted in a commercial vineyard, there was an excellent correlation between Admire application rates and xylem fluid concentrations of imidacloprid. At an Admire application rate of 1.17 liter ha(-1) (16 fl oz per acre), uptake of imidacloprid into vines was rapid. Imidacloprid was consistently detected in the xylem for up to 3 mo after application at concentrations known to be effective at managing populations of the sharpshooter Homalodisca coagulata Say, an important vector of Xylella fastidiosa Wells in California vineyards. The ELISA is a sensitive technique that can be used to study the behavior of systemic insecticides within crop systems and their impact on pest populations.


Advances in pediatric restless legs syndrome: Iron, genetics, diagnosis and treatment.
A substantial literature characterizes pediatric restless legs syndrome (RLS), which occurs in about 1.9% of individuals between 8 and 18years of age. Diagnostic interview techniques and an updated inventory of pediatric RLS mimics are presented. Evidence for comorbidity of pediatric RLS with attention-deficit/hyperactivity disorder, depression, and anxiety is reviewed as is the relationship to periodic limb movements in sleep and periodic limb movement disorder. The role of relative iron deficiency in pediatric RLS is discussed, along with new data indicating the benefit of iron therapy in reducing symptoms. Five genetic variants have been linked to RLS, an important finding in a condition that is highly familial in early-onset cases. Numerous case reports and case series indicate benefit for moderate to severe pediatric RLS with medication. However, to date, there have been no double-blind, placebo-controlled studies of therapy for pediatric RLS published. These and other recent advances relevant to pediatric RLS research are reviewed.


[Validity and reproducibility of a questionnaire on physical activity and non-activity for school children in Mexico City].
To assess the validity and reproducibility of a self-reported questionnaire on physical activity and inactivity, developed for children aged 10-14 in Mexico City. Between May and December 1996, a self-reported physical activity and inactivity questionnaire was developed and applied twice to a sample of 114 students aged 10 to 14, from a low and middle income population of Mexico City. The children's mothers completed the same questionnaire, and two 24-hour recalls of physical activity were used for comparison. Statistical analysis consisted of central tendency and dispersion measures and Pearson's correlation coefficient. Correlations between hours per day spent in physical activity and inactivity from the children's questionnaire and the 24-hour recall data, were 0.03 for moderate activity, 0.15 for vigorous activity, and 0.51 (p = 0.001) for watching television, adjusted by age, gender, town, and illness prior to the administration of the questionnaire. Compared to the 24-hour recall data, the questionnaire overestimated the time spent watching television, reading or participating in vigorous activity, and underestimated the time engaged in moderate activity. Statistically significant (p < 0.05) six-month reproducibility values were observed for watching television (r = 0.53), sleeping (r = 0.40), moderate (r = 0.38), and vigorous activity (r = 0.55). Among children of Mexico City aged 10-14, the questionnaire showed acceptable validity in estimating the time watching television, and acceptable reproducibility of the time watching television, vigorous and moderate activity.


Long-term structural and symptomatic effects of intra-articular sprifermin in patients with knee osteoarthritis: 5-year results from the FORWARD study.
The FORWARD (FGF-18 Osteoarthritis Randomized Trial with Administration of Repeated Doses) trial assessed efficacy and safety of the potential disease-modifying osteoarthritis drug (DMOAD) sprifermin in patients with knee osteoarthritis. Here, we report 5-year efficacy and safety results. Patients were randomised to intra-articular sprifermin 100 µg or 30 µg every 6 months (q6mo) or 12 months, or placebo, for 18 months. The primary analysis was at year 2, with follow-up at years 3, 4 and 5. Additional post hoc exploratory analyses were conducted in patients with baseline minimum radiographic joint space width 1.5-3.5 mm and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain 40-90, a subgroup at risk (SAR) of progression. 378 (69%) patients completed the 5-year follow-up. A significant dose-response in total femorotibial joint cartilage thickness with sprifermin (trend test, p<0.001) and a 0.05 mm mean difference with sprifermin 100 µg q6mo versus placebo (95% CI 0.00 to 0.10; p=0.015) were sustained to year 5. WOMAC pain scores improved ~50% from baseline in all groups. No patient in the 100 µg q6mo group had replacement of the treated knee. 96%-98% of patients receiving sprifermin and 98% placebo reported adverse events, most were mild or moderate and deemed unrelated to treatment. Adverse event-related study withdrawals were <10%. Differentiation in WOMAC pain between sprifermin 100 µg q6mo and placebo in the SAR (n=161) at year 3 was maintained to year 5 (-10.08; 95% CI -25.68 to 5.53). In the longest DMOAD trial reported to date, sprifermin maintained long-term structural modification of articular cartilage over 3.5 years post-treatment. Potential translation to clinical benefit was observed in the SAR. NCT01919164.


Recurrent asthma induced by toluene diisocyanate.
A worker developed toluene diisocyanate induced asthma in 1974. On reassessment, 11 years after leaving the chemical plant where toluene diisocyanate was produced, he had no respiratory symptoms and normal bronchial reactivity in response to methacholine, and showed no reaction when challenged with a subirritant concentration of toluene diisocyanate. He developed asthma within five months of returning to the workplace. Repeat challenge testing showed bronchial hyperreactivity to methacholine and to the specific sensitising agent, toluene diisocyanate. This clinical pattern could be due to underlying toluene diisocyanate sensitivity with resolution and reappearance of hyperresponsiveness to methacholine and toluene diisocyanate reactivity associated with workplace toluene diisocyanate exposure. Alternatively, this worker may have developed sensitisation to toluene diisocyanate anew.


Effect of treatment dose reductions in the setting of hand-foot syndrome on survival outcomes in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor receptor inhibitors.
Purpose Hand-foot syndrome is a common dose limiting toxicity of vascular endothelial growth factor receptor tyrosine kinase inhibitors used for treatment of patients with metastatic renal cell carcinoma. The effect of treatment dose reductions, in the context of hand-foot syndrome, on survival outcomes is reported. Methods This was a retrospective case series of patients receiving vascular endothelial growth factor receptor tyrosine kinase inhibitors from 1 January 2004 to 31 October 2013. The main outcomes were progression-free and overall survival in these patients experiencing hand-foot syndrome and undergoing treatment dose reductions. Univariate and multivariate analyses were conducted utilizing Kaplan-Meier method and COX Proportional Hazard model with landmark analyses at 2 months. Results Of the 120 patients evaluated, treatment dose reductions for any reason were required in 68 (56.7%) patients. The most common reasons for treatment dose reductions were mucositis, hand-foot syndrome, and fatigue. The median progression-free survival and overall survival were significantly longer in patients with hand-foot syndrome with or without treatment dose reductions as compared to those without hand-foot syndrome. Conclusions An improvement in survival outcomes was observed in metastatic renal cell carcinoma patients with treatment-associated hand-foot syndrome despite treatment dose reductions. These data need validation in a larger cohort to confirm the hypothesis that treatment dose reductions in the setting of hand-foot syndrome do not negatively impatient survival.


Insights into the mechanism of onabotulinumtoxinA in chronic migraine.
OnabotulinumtoxinA has recently been approved by regulatory agencies in the UK and United States for treatment of chronic migraine based on data generated from the PREEMPT studies. As such, onabotulinumtoxinA is the only prophylactic therapy specifically approved for chronic migraine. Most headache clinicians would agree that acute episodic migraine and chronic migraine differ in their pathophysiology, etiology, diagnosis, and response to pharmacological as well as nonpharmacological therapies. Of the 7 botulinum neurotoxin serotypes, botulinum neurotoxin type A (onabotulinumtoxinA) has been the most thoroughly investigated in preclinical and clinical studies. Based on preclinical studies, onabotulinumtoxinA is known to inhibit the release of excitatory neurotransmitters from both motor and sensory neurons by preventing vesicle fusion to the cell membrane. In addition to the well-documented myorelaxant effects of this neurotoxin, onabotulinumtoxinA can exert a direct analgesic effect that likely involves inhibition of primary and secondary nociceptive neurons. The inhibitory effects of onabotulinumtoxinA are also likely to involve suppressing the activity of myogenic trigger points and decreasing the persistent nociceptive barrage that promotes and maintains central sensitization. This article describes possible mechanisms to explain how onabotulinumtoxinA functions as a therapy for chronic migraine and considers why treatment with the neurotoxin is not effective in some chronic migraineurs.


Sex difference in nitric oxide synthase-dependent dilatation of cerebral arterioles during long-term alcohol consumption.
Although long-term alcohol consumption impairs both endothelial nitric oxide synthase (NOS) (eNOS)-dependent and neuronal NOS (nNOS)-dependent reactivity of cerebral arterioles in male rats, the influence of sex on alcohol consumption-induced impairment of NOS-dependent cerebral vasodilation has not been examined. Therefore, the authors' first goal was to determine whether long-term alcohol consumption alters eNOS-dependent and nNOS-dependent reactivity of pial arterioles in female rats. Their second goal was to examine potential mechanisms for impaired responses of pial arterioles during long-term alcohol consumption. Male and female rats were fed liquid diets with or without alcohol for 2-3 months. The authors measured the in vivo diameter of pial arterioles in response to eNOS-dependent agonists (acetylcholine and ADP), nNOS-dependent agonists (kainate and NMDA), and NOS-independent agonists (nitroglycerin and diethylaminodiazen (NONOate)) in the absence and presence of tetrahydrobiopterin (BH4). Topical application of acetylcholine (1.0 and 10 microM), ADP (10 and 100 microM), kainate (100 and 300 microM), and NMDA (100 and 300 microM) produced dose-related dilatation of pial arterioles. However, the magnitude of vasodilation in response to acetylcholine and ADP was significantly less in alcohol-fed male and female rats, and the magnitude of vasodilation in response to kainate and NMDA was significantly less in alcohol-fed male rats. Nitroglycerin and NONOate produced similar vasodilation in non-alcohol-fed and alcohol-fed male and female rats. Application of BH4 did not alter vasodilation in non-alcohol-fed rats but improved impaired eNOS-dependent vasodilation in alcohol-fed male and female rats. Our findings suggest that long-term alcohol consumption impairs eNOS-dependent but not nNOS-dependent dilatation of cerebral arterioles in female rats and that impaired eNOS-dependent vasodilation may be related to a deficiency or alteration in the utilization of BH4.


The role of viral evolution in rabies host shifts and emergence.
Despite its ability to infect all mammals, Rabies virus persists in numerous species-specific cycles that rarely sustain transmission in alternative species. The determinants of these species-associations and the adaptive significance of genetic divergence between host-associated viruses are poorly understood. One explanation is that epidemiological separation between reservoirs causes neutral genetic differentiation. Indeed, recent studies attributed host shifts to ecological factors and selection of 'preadapted' viral variants from the existing viral community. However, phenotypic differences between isolates and broad scale comparative and molecular evolutionary analyses indicate multiple barriers that Rabies virus must overcome through adaptation. This review assesses various lines of evidence and proposes a synthetic hypothesis for the respective roles of ecology and evolution in Rabies virus host shifts.


Baclofen Toxicity in a Patient with End-stage Renal Disease on Maintenance Dialysis.
Baclofen is a β-(p-chlorophenyl) derivative of the neurotransmitter y-aminobutyrio acid (GABA). This centrally-acting GABA agonist is prescribed as therapy for spasticity in the spinal cord region. The drug is predominantly excreted by the kidney, thus making patients with kidney disease susceptible to side effects. We report on a patient with end-stage renal disease who developed baclofen toxicity, which was successfully treated with intense hemodialysis.


Physician nurse care: A new use of UMLS to measure professional contribution: Are we talking about the same patient a new graph matching algorithm?
Physician and nurses have worked together for generations; however, their language and training are vastly different; comparing and contrasting their work and their joint impact on patient outcomes is difficult in light of this difference. At the same time, the EHR only includes the physician perspective via the physician-authored discharge summary, but not nurse documentation. Prior research in this area has focused on collaboration and the usage of similar terminology. The objective of the study is to gain insight into interprofessional care by developing a computational metric to identify similarities, related concepts and differences in physician and nurse work. 58 physician discharge summaries and the corresponding nurse plans of care were transformed into Unified Medical Language System (UMLS) Concept Unique Identifiers (CUIs). MedLEE, a Natural Language Processing (NLP) program, extracted "physician terms" from free-text physician summaries. The nursing plans of care were constructed using the HANDS© nursing documentation software. HANDS© utilizes structured terminologies: nursing diagnosis (NANDA-I), outcomes (NOC), and interventions (NIC) to create "nursing terms". The physician's and nurse's terms were compared using the UMLS network for relatedness, overlaying the physician and nurse terms for comparison. Our overarching goal is to provide insight into the care, by innovatively applying graph algorithms to the UMLS network. We reveal the relationships between the care provided by each professional that is specific to the patient level. We found that only 26% of patients had synonyms (identical UMLS CUIs) between the two professions' documentation. On average, physicians' discharge summaries contain 27 terms and nurses' documentation, 18. Traversing the UMLS network, we found an average of 4 terms related (distance less than 2) between the professions, leaving most concepts as unrelated between nurse and physician care. Our hypothesis that physician's and nurse's practice domains are markedly different is supported by the preliminary, quantitative evidence we found. Leveraging the UMLS network and graph traversal algorithms, allows us to compare and contrast nursing and physician care on a single patient, enabling a more complete picture of patient care. We can differentiate professional contributions to patient outcomes and related and divergent concepts by each profession.


Use of impregnated catheters to decrease colonization rates in neonates - A randomized controlled pilot trial.
Nosocomial infections increase mortality and morbidity in preterm infants. Central venous line colonization is a major risk factor for the development of such infections. In adults and children, antibiotic and antimycotic impregnated catheters have been demonstrated to reduce colonization. However, recently published data showed no significant difference in bloodstream infection in neonates when an impregnated catheter was used. We investigated the effect of impregnation of percutaneously inserted micro-catheters (PICC) on colonization in preterm and sick term infants in our unit. Neonates were randomly assigned to receive either a standard (S-PICC; n = 34) or antibiotic and antimycotic impregnated (IP-PICC; n = 37) PICC. Catheters were placed and removed according to a standard procedure and subsequently examined by roll-out culture. The primary outcome was the rate of colonization defined as >15 colony-forming-units/ml. Additional outcomes were catheter associated or systemic infections. The rate of colonization was lower in neonates who received an IP-PICC as compared to S-PICC (5.6% vs. 12.1% respectively; p = 0.42). However, the difference was not significant. In IP-PICC vs S-PICC, catheter related local infection (CRI) although lower was not statistically significant (2.9% vs. 6.1%; p = 0.60). We observed no difference in catheter related systemic infection (CR-SI) (0% vs. 3.1%, p = 0.48). The neonates whose catheters were colonized were predominantly of a lower gestational age (median 254/7, p = 0.05) and males (100%, p = 0.01). In addition, the median colony count in the colonized IP-PICC catheters was lower as compared to S- PICC group (53 vs 250, p = 0.06). The use of antibiotic and antimycotic impregnated PICC-lines in neonates tended to decrease colonization rates in neonates in our centers but this difference was not significant. Lower gestational age and male sex are risk factors for catheter colonization.


Comparison of outcomes of primary and secondary implantation of scleral fixated posterior chamber intraocular lens.
To assess and compare the results of primary and secondary implantation of scleral fixated posterior chamber intraocular lens (SFIOL). The medical records of a consecutive series of 55 eyes of 55 patients with SFIOLs implanted during (group 1) or after (group 2) complicated senile cataract surgery were retrospectively reviewed and analysed. There were 30 and 25 eyes in group 1 and 2, respectively. Follow up was from 6 to 36 months. Mean logMAR postoperative best corrected visual acuity in group 1 was not significantly different (0.50 (SD 0.36)) from that of group 2 (0.36 (0.21)) (p=0.109). Postoperative best corrected visual acuity of 6/12 or better was achieved in 58.6% and 76.0% in group 1 and 2, respectively. The difference was not statistically significant (p=0.177). In group 1, 25 (83.3%) eyes had a total of 55 early complications, while in group 2, 16 (64%) eyes had 26 early complications (p=0.028). The difference in early complication was statistically significant. For late complication after 1 month, 21 (70.0%) eyes had a total of 37 complications in group 1, while 13 eyes (52.0%) had 19 complications in group 2 (p=0.077). The difference in late complication was not statistically significant. Secondary implantation of SFIOL after cataract extraction seems to have a lower early complication rate than primary implantation in complicated cataract extraction although the final visual acuity and late complication rate are not significantly different.


Interventions for alcohol and drug problems in outpatient settings: a systematic review.
Research evidence indicates a high prevalence of substance abuse among patients presenting in general hospital settings. Such misuse of alcohol and illicit drugs has a major impact on population health and on costs to health services and to society at large. This review aimed to identify the interventions for alcohol or illicit drug misuse problems that have been evaluated for hospital outpatient populations. Thirteen electronic databases including MEDLINE, EMBASE and PsycInfo were searched for published and unpublished studies in any language up to August 2011. Reference lists of included studies and reviews were also hand-searched. We included randomised and controlled clinical trials of any intervention for adult participants identified as having alcohol and/or drug problems presenting to hospital outpatient settings other than addiction or psychiatric units. Participants could be attending hospital for any reason other than treatment for substance abuse. A narrative synthesis was conducted. There is some evidence to suggest that interventions based on motivational techniques might be effective in treatment of alcohol misuse in oral-maxillofacial clinics but not in general outpatient departments. The evidence is insufficient to allow any conclusions to be derived on the effectiveness of interventions in the treatment of drug misuse and combined alcohol-drug misuse in outpatient settings. Further research is needed to investigate interventions for alcohol and drug misuse in outpatient settings. Additionally, problems remain in terms of study quality. Procedures to ensure the rigour of a study were often poorly reported.


Incretin mimetics and dipeptidyl peptidase-4 inhibitors: innovative treatment therapies for type 2 diabetes.
The prevalence of diabetes and impaired glucose tolerance is predicted to dramatically increase over the next two decades. Clinical therapies for type 2 diabetes mellitus (T2DM) have traditionally included lifestyle modification, oral anti-diabetic agents, and ultimately insulin initiation. In this report, we review the clinical trial results of two innovative T2DM treatment therapies that are based on the glucoregulatory effects of incretin hormones. Incretin mimetics are peptide drugs that mimic several of the actions of glucagon-like peptide-1 (GLP-1) and have been shown to lower glycated hemoglobin (A1C) levels in patients with T2DM. Additionally, incretin mimetics lower postprandial and fasting glucose, suppress elevated glucagon release, and are associated with progressive weight reduction. Dipeptidyl peptidase-4 (DPP-4) inhibitors increase endogenous GLP-1 levels by inhibiting the enzymatic degradation of GLP-1. Clinical studies in patients with T2DM have shown that DPP-4 inhibitors reduce elevated A1C, lower postprandial and fasting glucose, suppress glucagon release, and are weight neutral. Collectively, these new drugs, given in combination with other antidiabetic agents, such as metformin, sulfonylureas, and/or thiazolidinediones, can help restore glucose homeostasis in poorly controlled patients with T2DM.


High-Content Screening in hPSC-Neural Progenitors Identifies Drug Candidates that Inhibit Zika Virus Infection in Fetal-like Organoids and Adult Brain.
Zika virus (ZIKV) infects fetal and adult human brain and is associated with serious neurological complications. To date, no therapeutic treatment is available to treat ZIKV-infected patients. We performed a high-content chemical screen using human pluripotent stem cell-derived cortical neural progenitor cells (hNPCs) and found that hippeastrine hydrobromide (HH) and amodiaquine dihydrochloride dihydrate (AQ) can inhibit ZIKV infection in hNPCs. Further validation showed that HH also rescues ZIKV-induced growth and differentiation defects in hNPCs and human fetal-like forebrain organoids. Finally, HH and AQ inhibit ZIKV infection in adult mouse brain in vivo. Strikingly, HH suppresses viral propagation when administered to adult mice with active ZIKV infection, highlighting its therapeutic potential. Our approach highlights the power of stem cell-based screens and validation in human forebrain organoids and mouse models in identifying drug candidates for treating ZIKV infection and related neurological complications in fetal and adult patients.


Pharmacokinetics of oral and intravenous cannabidiol and its antidepressant-like effects in chronic mild stress mouse model.
Cannabidiol (CBD) exhibits significant efficacy in mental and inflammatory diseases. Several studies have recently reported on the rapid antidepressant-like effects of CBD, suggesting that CBD is a potential anti-depressant or anti-stress drug. However, CBD is mainly administered orally or by inhalation with poor bioavailability, resulting in high costs. We aim to explore the efficacy of long-term periodic administration of CBD in chronic mild stress (CMS) via two routes and its pharmacokinetics. We treated ICR mice with CBD administered orally and intravenously and then determined the kinetic constants. A single bolus intravenous injection of CBD resulted in a half-life of 3.9 h, mean residence time of 3.3 h, and oral bioavailability of about 8.6%. The antidepressant-like effects of periodically administered CBD on the chronic mild stress mouse model are evaluated. Results demonstrated that such treatment at a high dose of 100 mg/kg CBD (p.o.) or a low dose of 10 mg/kg CBD (i.v.), elicited significant antidepressant-like behavioral effects in forced swim test, following increased mRNA expression of brain-derived neurotrophic factor (BDNF) and synaptophysin in the prefrontal cortex and the hippocampus. Our findings are expected to provide a reference for the development of intravenous antidepressant formulations of CBD.


Genetic variation in the folate metabolic pathway and risk of childhood leukemia.
Studies of childhood leukemia and the potential etiologic role of genetic variation in folate metabolism have produced conflicting findings and have often been based on small numbers. We investigated the association between polymorphisms in key folate metabolism enzymes (MTHFR 677 C>T, MTHFR 1298 A>C, SHMT1 1420 C>T, MTR 2756 A>G, TS 1494del6, and TS 28bp repeat) in 939 cases of childhood acute lymphoblastic leukemia (ALL) and 89 cases of acute myeloid leukemia (AML) recruited into the United Kingdom Childhood Cancer Study. We also examined the maternal genotypes of 752 of these cases. Data from 824 noncancer controls recruited were used for comparison. No evidence of an association with MTHFR 677 was observed for ALL or AML, either in children or their mothers. However, in children an increased risk of ALL (odds ratio [OR] = 1.88; 95% confidence interval [CI], 1.16-3.07; P = .010) and AML (OR = 2.74; 95% CI, 1.07-7.01; P = .036) was observed with the MTR 2756 GG genotype; the association was most pronounced for cases with the MLL translocation (OR = 4.90; 95% CI, 1.30-18.45; P = .019). These data suggest that genetic variation in methionine synthase could mediate risk of childhood leukemia, either via effects on DNA methylation or via effects on fetal growth and development.


Prostacyclin synthesis by vascular tissue. Effect of extracellular Ca2+.
Prostacyclin (PGI2) synthesis in vascular tissue is stimulated by free Ca2+. Concentrations in excess of 4 mM result in a sustained release of PGI2, but not other prostanoids, from rat aorta. This effect arises by increased synthesis of PGI2 and not through the inhibition of its metabolism. Physico-chemical examination of serum and plasma extract has indicated that much of the PGI2-stimulating activity reported for human serum derives from the presence of free Ca2+.


Age at marriage in Sri Lanka: stabilizing or declining?
Over the last four decades in Sri Lanka, age at first marriage for males increased marginally, and for females it rose considerably, but there has been no recent increase in female age at marriage. Among the younger cohorts, estimated ages at which some married indeed show a declining mean age at marriage. Coale-McNeil estimates indicate that there is no real decline in female age at marriage in Sri Lanka. Marriages were delayed as a result of economic hardship or increased mortality to the mid-1970s, but once the overall economy improved after 1977, more marriages took place. Female age at marriage in Sri Lanka remained slightly below 24 years, the age which is anticipated by younger cohorts, and this level is likely to persist for some time.


The ATR-Activation Domain of TopBP1 Is Required for the Suppression of Origin Firing during the S Phase.
The mammalian DNA replication program is controlled at two phases, the licensing of potential origins of DNA replication in early gap 1 (G1), and the selective firing of a subset of licenced origins in the synthesis (S) phase. Upon entry into the S phase, serine/threonine-protein kinase ATR (ATR) is required for successful completion of the DNA replication program by limiting unnecessary dormant origin activation. Equally important is its activator, DNA topoisomerase 2-binding protein 1 (TopBP1), which is also required for the initiation of DNA replication after a rise in S-phase kinase levels. However, it is unknown how the ATR activation domain of TopBP1 affects DNA replication dynamics. Using human cells conditionally expressing a TopBP1 mutant deficient for ATR activation, we show that functional TopBP1 is required in suppressing local dormant origin activation. Our results demonstrate a regulatory role for TopBP1 in the local balancing of replication fork firing within the S phase.


Protein NMR recall, precision, and F-measure scores (RPF scores): structure quality assessment measures based on information retrieval statistics.
One of the most important challenges in modern protein NMR is the development of fast and sensitive structure quality assessment measures that can be used to evaluate the "goodness-of-fit" of the 3D structure with NOESY data, to indicate the correctness of the fold and accuracy of the resulting structure. Quality assessment is especially critical for automated NOESY interpretation and structure determination approaches. This paper describes new NMR quality assessment scores, including Recall, Precision, and F-measure scores (referred to here are "NMR RPF" scores), which quickly provide global measures of the goodness-of-fit of the 3D structures with NOESY peak lists using methods from information retrieval statistics. The sensitivity of the F-measure is improved using a scaled Fold Discriminating Power (DP) score. These statistical RPF scores are quite rapid to compute since NOE assignments and complete relaxation matrix calculations are not required. A graphical method for site-specific assessment of structure quality based on the Precision statistic is also described. These statistical measures are demonstrated to be valuable for assessing protein NMR structure accuracy. Their relationships to other proposed NMR "R-factors" and structure quality assessment scores are also discussed.


Adolescents perception of reproductive health care services in Sri Lanka.
Adolescent health needs, behaviours and expectations are unique and routine health care services are not well geared to provide these services. The purpose of this study was to explore the perceived reproductive health problems, health seeking behaviors, knowledge about available services and barriers to reach services among a group of adolescents in Sri Lanka in order to improve reproductive health service delivery. This qualitative study was conducted in a semi urban setting in Sri Lanka. A convenient sample of 32 adolescents between 17-19 years of age participated in four focus group discussions. Participants were selected from four midwife areas. A pre-tested focus group guide was used for data collection. Male and female facilitators conducted discussions separately with young males and females. All tape-recorded data was fully transcribed and thematic analysis was done. Psychological distresses due to various reasons and problems regarding menstrual cycle and masturbation were reported as the commonest health problems. Knowledge on existing services was very poor and boys were totally unaware of youth health services available through the public health system. On reproductive Health Matters, girls mainly sought help from friends whereas boys did not want to discuss their problems with anyone. Lack of availability of services was pointed out as the most important barrier in reaching the adolescent needs. Lack of access to reproductive health knowledge was an important reason for poor self-confidence among adolescents to discuss these matters. Lack of confidentiality, youth friendliness and accessibility of available services were other barriers discussed. Adolescents were happy to accept available services through public clinics and other health infrastructure for their services rather than other organizations. A demand was made for separate youth friendly services through medical practitioners. Adolescent health services are inadequate and available services are not being delivered in an acceptable manner. Proper training of health care providers on youth friendly service provision is essential. A National level integrated health care program is needed for the adolescents.


Epigenetic alterations in gastric carcinogenesis.
Gastric cancer is believed to result in part from the accumulation of multiple genetic alterations leading to oncogene overexpression and tumor suppressor loss. Epigenetic alterations as a distinct and crucial mechanism to silence a variety of methylated tissue-specific and imprinted genes, have been extensively studied in gastric carcinoma and play important roles in gastric carcinogenesis. This review will briefly discuss the basic aspects of DNA methylation and CpG island methylation, in particular the epigenetic alterations of certain critical genes implicated in gastric carcinogenesis and its relevance of clinical implications.


Why Is Hyperparathyroidism Underdiagnosed and Undertreated in Older Adults?
Hyperparathyroidism significantly decreases quality of life, yet elderly patients are underdiagnosed and undertreated even though parathyroidectomy offers definitive cure with minimal morbidity. The purpose of this study is to determine why older patients with hyperparathyroidism are not appropriately diagnosed and referred for parathyroidectomy. We reviewed charts for a random sample of 25 patients aged 75 and older who had hyperparathyroidism and were referred for surgical evaluation, and 25 who were not referred. Two reviewers independently evaluated medical records to identify reasons for delayed diagnosis of hyperparathyroidism and reasons for nonreferral for parathyroidectomy. The median age of our cohort was 84 (80-96) years, 90% were women, 60% were white, and median follow-up was 5.5 (1-17) years. In 58% of all patients, an elevated serum calcium was not acknowledged. Even when calcium and parathyroid hormone levels were both elevated, the diagnosis was missed in 28% of patients, and 16% with clear symptoms of hyperparathyroidism remained undiagnosed. For 42% of patients, a nonsurgeon informed them that surgery offered no benefit. Surgery was also rejected as a treatment for 36% of patients despite the development of new symptoms or rising calcium. Substantial gaps exist in processes for diagnosis and referral of patients with hyperparathyroidism that lead to underdiagnosis and undertreatment. To improve rates of diagnosis and treatment, strategies are needed to educate nonsurgeons and patients about the benefits of surgery and to modify care processes to more efficiently diagnose and refer patients.