title stringlengths 0 1.13k | abstract stringlengths 1 15.7k | PMID int64 22 36.5M |
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Tuberous sclerosis complex: a case report. | Tuberous Sclerosis Complex (TSC) was first described in the late 1800s as a relative of neurofibromatosis, but it has since been identified as a discrete disorder. Patients with TSC typically present with facial adenomas, seizure disorder, and a developmental disability. The syndrome is caused by mutations in either chromosomes 9 or 16, both of which code for cell development and maturation. This case report describes the unique findings of TSC, and suggests areas for future study. By understanding the dental and medical implications of TSC, early intervention may vastly improve a patient's overall quality of life. | 18,782,197 |
Australasian emergency physicians: A learning and educational needs analysis. Part six: differences in confidence, exposure to learning and expressed learning needs by subgroups of Australasian emergency physicians. | To determine differences in the confidence and learning needs between subgroups of Fellows of the Australasian College for Emergency Medicine (FACEM), according to sex, type of hospital of principal employment, region of practice in Australasia, year of obtaining the fellowship and percentage of hours worked clinically. Mailed survey of all FACEM with multiple Likert scale options. Male emergency physicians (EP) more often expressed confidence in 14 of 58 tasks, but female EP more often expressed a strong desire for continuing professional development (CPD) in 8. EP working in private hospitals were more likely to find lack of conference in their contracts a barrier to participation in CPD (28% [CI 14.1-47.8]vs 7.3% [CI 5.2-10.1]; P = 0.003). EP obtaining their fellowship before 1990 were more confident in 13 of 25 non-clinical tasks than others but had similar confidence in clinical skills. Although EP who spent 30% or less on clinical work expressed confidence more frequently in a range of non-clinical skills, they were less confident for paediatric emergencies, central lines, orthopaedics and tube thoracostomy. There were few variations between Australian states and territories and New Zealand in confidence of EP. EP in regional and rural centres nominated geographical factors (31.3% [CI 21.2-43.4]vs 17.2% [CI 13.9-21.3]; P = 0.012), other colleagues being at the same conference (46.9% [CI 35.2-58.9]vs 28.3% [CI 24.2-32.9]; P = 0.005) and inability to use their conference leave (48.4% [CI 36.6-60.4]vs 33.1% [CI 28.7-37.8]; P = 0.024) as significant barriers more frequently than their city colleagues. These findings might assist planning CPD for EP. | 18,782,208 |
PI3K/Akt signaling as a key regulatory pathway for chondrocyte terminal differentiation. | Chondrogenesis is a well-coordinated multi-step differentiation process in which resting chondrocytes produce terminally differentiated hypertrophic chondrocytes through a proliferative stage. Here we show that phosphoinositide-3 kinase (PI3K) and its major downstream molecule, Akt, a serine-threonine kinase, play pivotal roles in this process. Akt signaling was activated in resting and proliferative chondrocytes but was reduced during terminal differentiation. We adopted two chondrocyte differentiation systems to investigate the roles of PI3K/Akt signaling in chondrogenesis. First, we employed an embryonic forelimb organ culture of transgenic mice expressing an Akt-Mer (a ligand-binding domain of a mutated estrogen receptor) fusion protein whose kinase activity was conditionally activated by treatment with 4-hydroxytamoxifen (4OHT). Activation of Akt signaling in embryonic chondrogenesis enhanced chondrocyte proliferation and inhibited hypertrophic differentiation, presumably due to the suppressed expression of Runx2, a transcription factor critical for chondrocyte terminal differentiation. Conversely, inhibition of PI3K by its inhibitor accelerated terminal hypertrophic differentiation, resulting in a shorter bone. Essentially the same results were obtained in a second line of experiments using human synovial stromal cells (hSSCs), which are mesenchymal progenitor cells isolated from adult joints. These findings demonstrate that PI3K/Akt signaling is a key regulator in terminal chondrocyte differentiation in both embryonic and adult chondrogenesis. | 18,782,222 |
Four million neonatal deaths: counting and attribution of cause of death. | Each year there are an estimated four million neonatal deaths and at least 3.2 million stillbirths. Three-quarters of the world's neonatal deaths are counted only through five-yearly retrospective household surveys. Without these surveys we would have no data, but limitations remain particularly in detecting deaths on the first day of life. Comparable reliable neonatal cause of death data through vital registration are available for less than 5% of the world's neonatal deaths, necessitating modelled estimates for the majority of the world. Improving the quantity, quality and frequency of data for numbers and causes of neonatal deaths is essential to effectively guide the increasing investments to reduce these deaths. Advancing the data requires general investment in information systems and specific improvements of tools and methods for both household surveys and verbal autopsy, particularly the use of consistent case definitions and hierarchical attribution of cause of death. An important paradigm shift is from historical categories for cause of death ('perinatal causes') to programmatic categories which are consistent with the International Classification of Diseases. If neonatal deaths remain uncounted, they cannot count in policy and in programmes. | 18,782,248 |
Effect of HLA genotype or CTLA-4 polymorphism on cytokine response in healthy children. | Type 1 diabetes (T1D) is considered to be a T-cell-mediated autoimmune disease in which genetic predisposition is affected by HLA class II alleles and polymorphisms in cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) gene. We tested the hypothesis whether these T1D-related gene polymorphisms modulate cytokine response and thus contribute to the development of autoimmunity. The study includes 67 non-diabetic children, typed for HLA class II alleles and CTLA-4 polymorphisms (+49A/G, CT60A/G, CTBC217_1C/T). We measured cytokine secretion of peripheral blood mononuclear cells after stimulation with tetanus toxoid (TT), polio virus, coxsackie virus B4, pertussis toxin (PT) and phytohemagglutinin (PHA). We saw higher IL-13 response to TT in individuals with DR3-DQ2 haplotype (P = 0.002). HLA class II protective haplotype, DR2-DQ6, showed association with increased production of IFN-gamma (P < 0.001) and IL-2 (P = 0.005) in response to polio virus. In children with the autoimmunity-related homozygous genotypes CTLA-4 +49G/G, CT60G/G and CTBC217_1T/T, we found enhanced PT- and PHA-induced IFN-gamma production (P < 0.05). The cytokine responses to studied antigens were weakly modified by HLA class II risk haplotypes, and children with T1D-associated HLA risk haplotypes are not specifically inclined to develop an immune response in general. Higher IFN-gamma and IL-2 response to enterovirus in children with HLA class II protective haplotype DR2-DQ6 could be of importance in the protection from T1D-associated enterovirus infections. All autoimmunity related CTLA-4 polymorphisms were associated with enhanced IFN-gamma. This suggests impaired downregulation of cellular immunity by these CTLA-4 polymorphisms. | 18,782,261 |
Autoantibody response to chromatographic fractions from oxidized LDL in unstable angina patients and healthy controls. | Levels of autoantibodies to oxidized low-density lipoprotein (oxLDL) have been correlated to atherosclerosis; however, contradictory results have been shown. To better understand the role of autoantibodies to oxLDL in atherogenesis, and their potential to predict risk of developing coronary artery disease we investigated the antibody response of unstable angina (UA) patients and healthy controls against chromatographic separated fractions of oxLDL. Five major peaks were detected after chromatographic separation of oxLDL and 10 fractions were collected. Surprisingly, when the response to high molecular weight fractions was analysed, we observed a significant increase in the levels of autoantibodies in controls compared to UA. In contrast, when the autoantibody response to intermediate and low molecular weight fractions was analysed, we observed that the UA group showed consistently higher levels compared with controls. Our data demonstrates that within oxLDL there are major fractions that can be recognized by autoantibodies from either UA patients or healthy individuals, and that the use of total oxLDL as an antigen pool may mask the presence of some antigenic molecules and their corresponding antibodies. Further studies are needed, but the analysis of antibody profiles may indeed open up a novel approach for evaluation and prevention against atherosclerosis. | 18,782,276 |
Distribution and maturity of dendritic cells in diseases of insufficient placentation. | The immunological equilibrium at the feto-maternal interphase contributes towards late gestational diseases like growth restriction (IUGR) pre-eclampsia (PE) and hemolysis, elevated liver enzymes, low platelets (HELLP)-syndrome. The state of activation of decidual dendritic cells (DC) has emerged as one of the central players influencing this immunological equilibrium. Paraffin-embedded tissue sections from 27 pregnancies were immunostained for DC markers DEC-205, DC-SIGN, DC-LAMP and costained for DC-SIGN/CD56 and DC-SIGN/ vascular endothelial growth factor receptor (VEGFR) -1 and -2. We investigated placental tissue of IUGR fetuses and of patients who developed PE or HELLP-syndrome as well as placental tissue derived from normal pregnancies. We found that expression of DEC-205 and DC-SIGN was significantly upregulated in HELLP placentas, whereas expression of DC-LAMP was abrogated almost entirely. Costaining showed an interaction between DC-SIGN(+) DC and natural killer cells as well as costaining of VEGFR-1 and -2 and DC-SIGN. Pre-eclamptic and IUGR placentas showed no significant change in any of the investigated markers compared to normal controls. Our data suggest a participation of DC-mediated immunological mechanisms in HELLP syndrome. | 18,782,285 |
Anti-HLA donor-specific antibodies detected in positive B-cell crossmatches by Luminex predict late graft loss. | The significance of B-cell crossmatching in kidney transplantation is controversial. Recipients (n = 471) transplanted in a single centre from 1987 to 2005 with complete T- and B-cell crossmatch records were studied. Sera from 83 patients transplanted across a positive B-cell crossmatch, with concomitant negative T-cell crossmatch (T-B+) on either current and/or peak sera were studied using Luminex to determine presence of donor-specific antibodies (DSA). Clinical outcomes of T-B+ patients were compared with 386 T-B- patients. T-B+ predicted vascular (p = 0.01), but not cellular (p = 0.82) or glomerular (p = 0.14) rejection. IgG HLA DSA were found in 33% (n = 27) of the T-B+ patients and were associated with higher risk of any (p = 0.047), vascular (p = 0.01) or glomerular (p < 0.001) rejection at 6 months. Of 27 patients with DSA, 18/21 (86%) were the complement-fixing IgG(1) and/or IgG(3) subclass antibodies. DSA imposed a statistically significant higher risk of graft loss 5 years posttransplant (1.8 [1.0-3.3], p = 0.045). This study showed that only one-third of positive B-cell crossmatch (BXM) was caused by DSA and was associated with late graft loss. Thus, using BXM to preclude kidney transplantation may potentially disadvantage >60% of patients in whom BXM is not indicative of the presence of DSA. | 18,782,289 |
Psoriasis and the risk of incident diabetes mellitus: a population-based study. | Cross-sectional studies, mostly in hospitalized patients, reported a possible positive association between psoriasis and diabetes mellitus (DM). However, information on the temporal relation is scarce, and incidence rates of new-onset DM in patients with psoriasis are lacking. To assess and compare incidence rates of new-onset DM between patients with psoriasis and a comparison group without psoriasis, and to explore the role of psoriasis severity and body mass index (BMI). We conducted a follow-up study with a nested case-control analysis within the U.K.-based General Practice Research Database. The study population consisted of patients with a first-time diagnosis of psoriasis between 1994 and 2005 and a matched group of psoriasis-free patients. We used psoriasis duration and treatment as proxy for disease severity, and we applied conditional logistic regression to obtain odds ratios (ORs) with 95% confidence intervals (CIs). Within the study population of 65 449 patients we identified 1061 incident cases of DM. Of these, 59% had a history of psoriasis, yielding a crude incidence rate ratio of 1.36 (95% CI 1.20-1.53). The adjusted OR for patients with >or=2 years disease duration and >2 prescriptions per year for oral psoriasis treatment was 2.56 (95% CI 1.11-5.92). In an analysis restricted to patients with normal BMI, the adjusted OR was 2.02 (95% CI 1.31-3.10). In this large observational study the risk of incident DM was increased for patients with psoriasis as compared with a psoriasis-free comparison group. The risk increased with psoriasis duration and severity and was not driven by high BMI alone. | 18,782,318 |
Evaluation of eosin-5-maleimide flow cytometric test in diagnosis of hereditary spherocytosis. | A flow cytometry-based test using eosin-5-maleimide (EMA) dye was used for diagnosis of hereditary spherocytosis (HS). The mean fluorescence intensiy (MFI) of EMA tagged erythrocytes is lower in HS than that in other hemolytic and nonhemolytic anemias. We enrolled 114 subjects comprising 20 confirmed HS, 20 suspected HS/hemolytic anemia (HA), 20 normal controls, 20 other hemolytic anemias [13 autoimmune hemolytic anemia, three congenital dyserythropoietic anemia (CDA), one pyruvate kinase deficiency, two microangiopathic hemolytic anemia], 18 microcytic anemia and 16 macrocytic anemia cases. All samples were subjected to flow cytometry as per standard protocol. The mean MFI of normal control subjects was 11 861.5 (SD 883.5) and of confirmed HS was 7949.3 (SD 1304.1). Using this test, of 20 patients suspected to be HS/HA but with no confirmatory diagnosis, eight patients were diagnosed as HS. Using logistic regression analysis, the optimum cut-off MFI value between HS and normal controls was 10126. The area under the ROC curve was 0.99. The statistical significance of MFI values was obtained by t-test or Wilcoxon rank sum test as applicable. Compared with normal controls, the MFI values in HS were lower and in megaloblastic anemia were higher which was statistically highly significant (P<0.01), and the MFI values in CDA were lower which was statistically significant (P<0.05). False-positive values were obtained in three cases of AIHA and two cases of CDA. The sensitivity and specificity was 96.4% and 94.2% respectively. The EMA-based flow cytometry test is a highly sensitive and specific method for the diagnosis of HS. | 18,782,334 |
Parallel lines: nothing has changed? | The exponential increase in mortality rate with age is a universal feature of aging and is described mathematically by the Gompertz equation. When this equation is transformed semilogarithmically, it conforms to a straight line, the slope of which is generally used to reflect the rate of senescence. Historical and contemporary data of human and nonhuman populations show that adverse environmental conditions do not always change the slope of the log mortality rate over age. From these latter observations it is sometimes mistakenly inferred that the rate of senescence is unaffected by environmental conditions. Current biological inference emphasizes that gene action is dependent on the environment in which it is expressed. Here, we propose using the tangent line of the Gompertz equation to assess whether the rate of senescence has altered. Such an approach unmasks different rates of senescence when parameter G has remained constant, an observation that is in line with the notion that a plastic life history trait such as the rate of senescence results from the interplay of both genes and environment. | 18,782,347 |
Multiple MyD88-dependent responses contribute to pulmonary clearance of Legionella pneumophila. | MyD88-dependent signalling is important for secretion of early inflammatory cytokines and host protection in response to Legionella pneumophila infection. Although toll-like receptor (TLR)2 contributes to MyD88-dependent clearance of L. pneumophila, TLR-independent functions of MyD88 could also be important. To determine why MyD88 is critical for host protection to L. pneumophila, the contribution of multiple TLRs and IL-18 receptor (IL-18R)-dependent interferon-gamma (IFN-gamma) production in a mouse was examined. Mice deficient for TLR5 or TLR9, or deficient for TLR2 along with either TLR5 or TLR9, were competent for controlling bacterial replication and had no apparent defects in cytokine production compared with control mice. MyD88-dependent production of IFN-gamma in the lung was mediated primarily by natural killer cells and required IL-18R signalling. Reducing IFN-gamma levels did not greatly affect the kinetics of L. pneumophila replication or clearance in infected mice. Additionally, IFN-gamma-deficient mice did not have a susceptibility phenotype as severe as the MyD88-deficient mice and were able to control a pulmonary infection by L. pneumophila. Thus, MyD88-dependent innate immune responses induced by L. pneumophila involve both TLR-dependent responses and IL-18R-dependent production of IFN-gamma by natural killer cells, and these MyD88-dependent pathways can function independently to provide host protection against an intracellular pathogen. | 18,782,351 |
Calcium phosphate-based remineralization systems: scientific evidence? | Dental caries remains a major public health problem in most communities even though the prevalence of disease has decreased since the introduction of fluorides. The focus in caries research has recently shifted to the development of methodologies for the detection of the early stages of caries lesions and the non-invasive treatment of these lesions. Topical fluoride ions, in the presence of calcium and phosphate ions, promote the formation of fluorapatite in tooth enamel by a process referred to as remineralization. The non-invasive treatment of early caries lesions by remineralization has the potential to be a major advance in the clinical management of the disease. However, for net remineralization to occur adequate levels of calcium and phosphate ions must be available and this process is normally calcium phosphate limited. In recent times three calcium phosphate-based remineralization systems have been developed and are now commercially available: a casein phosphopeptide stabilized amorphous calcium phosphate (Recaldent (CPP-ACP), CASRN691364-49-5), an unstabilized amorphous calcium phosphate (ACP or Enamelon) and a bioactive glass containing calcium sodium phosphosilicate (NovaMin). The purpose of this review was to determine the scientific evidence to support a role for these remineralization systems in the non-invasive treatment of early caries lesions. The review has revealed that there is evidence for an anticariogenic efficacy of the Enamelon technology for root caries and for the Recaldent technology in significantly slowing the progression of coronal caries and promoting the regression of lesions in randomized, controlled clinical trials. Hence the calcium phosphate-based remineralization technologies show promise as adjunctive treatments to fluoride therapy in the non-invasive management of early caries lesions. | 18,782,374 |
Attachment to parents, parental tobacco smoking and smoking among Year 10 students in the 2005 New Zealand national survey. | To assess whether low attachment to parents is a consistent risk factor for adolescent smoking or is modified by ethnicity and parental smoking. A national, cross-sectional multi-ethnic 2005 survey of 28,395 Year 10 students aged 14 and 15 years (18,934 Europeans, 4,769 Maori, 2,795 Asians, 1,897 Pacific Islanders). Students answered an anonymous questionnaire including measures of attachment to parents from the Inventory of Parent and Peer Attachment. The prevalence of adolescent smoking > or = monthly, going from the lowest to the highest quartile of parent attachment score, was 28%, 16%, 12% and 10%. The relative risk of smoking > or = monthly for students in parent attachment quartile 1, compared to quartile 4, was increased in all ethnic groups, being 4.37 (95% confidence interval 3.00, 6.38) in Asian, 3.12 (2.77, 3.51) in European, 1.97 (1.45, 2.67) in Pacific Island, and 1.36 (1.23, 1.51) in Maori students, adjusting for sex and school socioeconomic decile. The ethnic variation in relative risk was explained mostly by a variable smoking prevalence in the reference category (quartile 4) which ranged from 3% in Asian students to 29% in Maori. A similar pattern was seen when students were categorised by parental smoking, with students in the lowest parent attachment quartile having a significantly (p<0.05) raised relative risk of smoking > or = monthly compared to the highest quartile, regardless of whether their parents smoked or not. Low parent attachment score is associated with an increased risk of adolescent smoking regardless of ethnicity and parental smoking. | 18,782,398 |
Hip fracture fixation in a patient with below-knee amputation presents a surgical dilemma: a case report. | Hip fracture fixation surgery in patients with below-knee amputations poses a challenging problem to the surgeon in terms of obtaining traction for reduction of the fracture. The absence of the foot and part of the leg in these patients makes positioning on the fracture table difficult. We highlight this difficult problem and suggest techniques to overcome it. A 73-year-old man with bilateral below-knee amputations presented with a history of fall. Radiographs revealed an inter-trochanteric fracture of the femur. A dynamic hip screw fixation was planned for the fracture but the dilemma was on how to position the patient on the fracture table for the surgery. Special attention was needed in positioning the patient and in surgical fixation of the fracture. Hip fracture fixation in patients with below-knee amputations poses a special problem in positioning for fracture reduction and fixation. In this case report, we share our experience and suggest techniques to use when encountering this difficult problem. | 18,782,438 |
Long-term (48-week) safety of ezetimibe 10 mg/day coadministered with simvastatin compared to simvastatin alone in patients with primary hypercholesterolemia. | This study evaluated the long-term safety and tolerability of ezetimibe/simvastatin coadministration therapy compared to simvastatin monotherapy in patients with primary hypercholesterolemia. After completing a 12-week randomized, double-blind, placebo-controlled, factorial, 10-armed study comparing ezetimibe 10 mg/simvastatin 10, 20, 40, or 80 mg; simvastatin 10, 20, 40, or 80 mg; ezetimibe 10 mg; or placebo, 768 patients entered a 48-week extension, with randomized, blinded, reassignment of the simvastatin 10 mg, ezetimibe, and placebo groups to one of the ezetimibe/simvastatin groups. Patients previously receiving ezetimibe/simvastatin combination therapy, or simvastatin 20, 40, and 80 mg monotherapy continued the same therapies in this 7-arm extension study. During the extension study, investigators assessed adverse events (AEs). Ezetimibe/simvastatin (n = 539) and simvastatin monotherapy (n = 229) groups generally had a similar incidence of all clinical AEs (73 vs. 69%), treatment-related AEs (14 vs. 11%), clinical serious AEs (SAE) (5.2 vs. 2.6%), treatment-related SAEs (0.2 vs. 0%), discontinuations due to all clinical AEs (4.5 vs. 2.6%) and discontinuations due to treatment-related AEs (2.8 vs. 2.2%), respectively. The incidence of total laboratory-related AEs for the ezetimibe/simvastatin and simvastatin monotherapy groups was also similar (12.2 vs. 11.9%), as was treatment-related laboratory AEs (6.2 vs. 5.3%), laboratory SAEs (0 vs. 0%), treatment-related laboratory SAEs (0 vs. 0%), discontinuations due to laboratory AEs (3.0 vs. 0.9%) and discontinuations due to treatment-related laboratory AEs (3.0 vs. 0.4%), respectively. There were no cases of myopathy, rhabdomyolysis, or serious hepatotoxicity observed in any group during this extension study. During this 48-week extension study, the coadministration of ezetimibe/simvastatin was generally as well tolerated as simvastatin monotherapy. The direct application of study observations to clinical practice is limited by patient selection criteria and dosage regime, which randomly applied relatively high doses rather than titration which often occurs in clinical practice. | 18,782,465 |
Is the maturation of monosynaptic stretch reflex in rats affected by neonatal malnutrition? | We compared the maturation of the monosynaptic stretch reflex in control rats and in rats submitted to neonatal malnutrition. Electrical stimulations of the sciatic nerve were applied in wakeful rats of different ages (21-90 days) to record, by surface electrodes, the maximal direct motor response (M(max)) or the maximal Hoffmann reflex (H(max)). Percussion on the Achilles tendon induced the T-reflex. Animals submitted to neonatal malnutrition showed significant reductions in H-reflex latency and in velocity index of nervous conduction. The H- or T-reflex amplitudes were lower for malnourished rats of 21 days but the difference was significant only for the T(max)/M(max) ratios. The reflexes evoked at older ages did not present differences between control and malnourished rats. In conclusion, rats submitted to neonatal malnutrition present long-term alteration in reflex latency and nervous conduction velocity. Neonatal malnutrition also alters the reflex excitability at weaning but, since the rat were submitted to a normal diet after weaning, a normal reflex excitability was rapidly recovered which indicates a remarkable plasticity of the reflex pathway. | 18,782,480 |
Effect of calorie-protein supplementation on the cognitive recovery of patients with subacute stroke. | The objective of this study was to investigate whether protein-calorie supplementation may enhance the cognitive retrieval of patients with stroke. A randomized, double-blind, controlled pilot clinical trial was performed comparing diet and diet plus protein-calorie supplementation regimens. The subjects were 48 patients with subacute stroke (>or14 days from index event). Anthropometric and nutritional (3-day diary) variables, cognitive function (Mini-Mental State Examination; MMSE) were determined before and 21 days after randomization in control and daily supplemented group (formula providing 250 kcal + 20 g protein). At day 21 after starting the protocol, only the supplemented group significantly improved their performance to MMSE (log(10)MMSE +0.6+/-0.4 score; P=0.01 from baseline). Protein-calorie supplementation may enhance the recovery of cognitive function in subacute stroke patients. | 18,782,484 |
Lack of association between MTHFR C677T and MTHFR A1298C genetic polymorphisms and mental retardation. | Findings suggest that there is no association between MTHFR C677T and MTHFR A1298C and mental retardation in the studied Italian population and that these polymorphisms are not contributing to the aetiology of mental retardation. | 18,782,485 |
School-based health education for the control of soil-transmitted helminthiases in Kanchanaburi province, Thailand. | Soil-transmitted helminthiases are major parasitic diseases that cause health problems world-wide. School-based health education is one of several basic interventions currently recommended by the World Health Organization for the control of these infections. A 3-year programme of health education for the control of soil-transmitted helminths (STH) has recently been completed in four primary schools in the Hauykayeng subdistrict of Thong Pha Phum district, in the Kanchanaburi province of Thailand. Overall, the percentage of the schoolchildren found infected with STH increased between the start of year 1 of the intervention (16.6%) and the end of year 2 (23.8%) but showed signs of falling by the end of year 3 (19.4%). Although none of these year-on-year changes in overall prevalence was statistically significant, some significant trends were detected when the six school grades (i.e. age-groups) were considered separately. The grade showing the highest prevalence of STH infection changed, from grade 6 (representing the oldest children investigated) at the start of year 1 (when grade-1 children were excluded from the survey) to grade 1 (representing the youngest children) at the ends of year 2 and year 3. By the end of year 3, the children in grades 5 and 6 had significantly lower prevalences of infection than the grade-1 subjects. The prevalence of STH infection in the grade-1 children was significantly higher than that in any of the older grades at the end of year 2 and significantly higher than that in grades 3-6 at the end of year 3. These results indicate that the health education had a greater impact on the children in the higher grades (who, presumably had better levels of understanding and practised better, personal, infection prevention) than on the younger children. Although school-based interventions can serve as a useful entry point for parasite control, more effort, including anthelminthic treatment, may be required among the youngest children. The activities need to be sustainable and supported by appropriate school-health policies. | 18,782,491 |
Nonpharmacologic treatment of insomnia. | Insomnia is a widespread and debilitating disorder. Regardless of the initial cause, it may assume a chronic course perpetuated by psychological and behavioral factors. Although sedative-hypnotic medications are the most common treatment for insomnia, they pose certain risks such as adverse effects and dependence. Furthermore, medications target symptoms and fail to address the underlying perpetuating mechanisms. There are many nonpharmacologic treatment options for insomnia, including cognitive/behavioral methods, relaxation strategies, and complementary and alternative medicine (CAM) approaches. Most CAM therapies lack sufficient scientific evidence to recommend their use. Over the past 30 years, cognitive-behavioral therapies have emerged as the treatment of choice for chronic insomnia. These therapies target behavioral, cognitive, and conditioning factors underlying insomnia, thereby restoring normal sleep-wake functioning. The effectiveness of these therapies is well established. They compare favorably to pharmacologic approaches, with the added benefits of few or no adverse effects and no risk of abuse or dependence. Perhaps most importantly, behavioral insomnia therapies offer a potential cure for the insomnia, instead of the symptom-focused approach provided by medications. Despite the proven success of cognitive-behavioral therapies, they are not widely available to patients with insomnia because of a paucity of behavioral sleep specialists. Efforts are now being made to disseminate these treatments to meet the demand. Emerging therapies hold promise for further refinement and development of successful treatments. | 18,782,507 |
[SP-TAT-Apoptin induces G1 arrest in HepG2 cells]. | To investigate the effect of SP-TAT-Apoptin in inducing HepG2 cells apoptosis and the possible application on hepatocellular carcinoma gene therapy. Recombinant gene SP-TAT-Apoptin was amplified by PCR and cloned into the eukaryotic vector plenti6-V5-D-TOPO. After the recombinant plasmid was identified by restriction enzyme digestion analysis and DNA sequencing, CHO cells were stably transfected with SP-TAT-Apoptin gene and the culture supernatant was collected. Then the expression of the fusion protein was detected by RT-PCR and Western blot. HepG2 cells were co-cultured with the supernatant. At various times post co-culture, HepG2 cells were detected by FCM. The secretory Tat-Apoptin has an additive bystander effect as an anti-cancer therapy in vitro. The recombinant Apoptin was able to be secreted from transfected cells and re-enter adjacent un-transfected HepG2 cells, it can induce HepG2 cells apoptosis and induce G0/G1 arrest. SP-TAT-Apoptin can induce HepG2 cell apoptosis and cell cycle G1 arrest. | 18,782,517 |
[Prokaryotic expression, purification and identification of VEGFR2 D3.4/GST fusion protein in E.coli]. | To construct a prokaryotic expression vector for the expression of VEGFR2 D3.4/GST fusion protein, Express and purify the fusion protein. The coding sequence of the third and fourth extracellular domain of human VEGFR2 gene fragment was synthesized and subcloned into pGEX4T-1 vector downstream of the GST fragment, an E.coli expression vector, to construct a recombinant plasmid pGEX4T-VEGFR D3.4. Then the plasmid was transformed into E.coli BL21 (DE3) pLysS and induced to express fusion protein VEGFR2 D3.4/GST with IPTG. The expressed protein was purified by washing in urea and detected by SDS-PAGE and Western blot. SDS-PAGE analysis showed that a novel protein with the expected molecular mass (M(r);) about 46 000 was expressed with the inducement of IPTG. And it existed mostly in the form of inclusion body. Grayscale scanning showed that the expressed VEGFR2 D3.4/GST fusion protein accounted for 38.6% of the total bacterium protein. After the purified product was washed by urea, its purity reached 87.1%. Western blot confirmed the recombinant protein was VEGFR2 D3.4/GST fusion protein. High purification VEGFR2 D3.4/GST fusion protein is obtained through the E.coli expression system. | 18,782,519 |
Parallel kinetic analysis and affinity determination of hundreds of monoclonal antibodies using the ProteOn XPR36. | The production of antibodies for diagnostic and therapeutic applications is a major focus for biotechnology and pharmaceutical companies, and it requires the development of fast, high-throughput methodologies for screening and selecting appropriate candidate antibodies for development. These candidates must have very high affinity for the target as well as high specificity and low cross-reactivity. This study demonstrates the use of the ProteOn XPR 36 protein interaction array system for the rapid screening and selection of high-affinity antibodies--"one-shot" kinetics. This approach allows multiple quantitative protein binding analyses in parallel, providing association, dissociation, and affinity constants for several antibodies simultaneously in one experiment. We have used this new methodology to screen hundreds of monoclonal supernatants containing antibodies against two proteins of potential clinical interest: human interleukin 12 (IL-12) and a human hemoglobin (Hb) variant. In fact, approximately 250 supernatants raised against each antigen were screened in approximately 17 h, providing several high-affinity candidate monoclonal antibodies for each of these antigens. | 18,782,554 |
Activation of negative regulators of the hypoxia-inducible factor (HIF) pathway in human end-stage heart failure. | The hypoxia-inducible transcription factor HIF is induced early in acute myocardial ischemia in humans, but it is unknown whether this activation of HIF persists during chronic heart failure. The HIF system was characterized in left ventricular myocardia from 18 explanted failing hearts and 11 non-failing donor hearts by quantitative RT-PCR and Western analysis. HIF-1alpha mRNA levels were significantly decreased while its natural antisense transcript aHIF was nearly twofold higher (p<0.01) in failing myocardia than in control hearts. Moreover, compared to donor hearts a significantly increased expression of HIF-3alpha, which may act as a competitive inhibitor of HIF-1/2alpha activity, and PHD3, which upon hydroxylation of prolyl residues directs HIF-alpha subunits towards proteasomal degradation, was observed in the failing myocardium. Although negative regulators of HIF were induced, the HIF pathway obviously remains activated in chronic human heart failure, because prototype HIF target genes, such as ABCG2, VEGF, and BNIP3, were significantly induced. | 18,782,560 |
Direct and nondestructive verification of PNA immobilization using click chemistry. | The fluorogenic 1,3-Huisgen dipolar cycloaddition reaction was used as part of a novel immobilization strategy of PNA capture probes on a microarray. By using this click chemistry, azidocoumarin-anchored PNA probes were immobilized on phenyl acetylene-modified glass slides with the simultaneous generation of the fluorescent triazolylcoumarin moiety. Since the emitting moieties are generated in the immobilization reaction itself, fluorescent signals can be used to directly monitor the integrity of immobilization in a nondestructive manner. By using this strategy, PNA microarrays were prepared and successfully employed to perform microarray-based diagnosis of selected mutations in the breast cancer susceptibility gene BRCA1. | 18,782,561 |
Striatal 19S Rpt6 deficit is related to alpha-synuclein accumulation in MPTP-treated mice. | Striatal mitochondrial proteins were investigated using proteomics in the 1-methyl 4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease. Four proteins, 19S proteasome ATPase Rpt6 (19S Rpt6), Lectin-related nature killer cell receptor LY 49S, Zinc finger A20 domain containing 1, and the sodium channel-associated protein 1 isoform 2, were significantly decreased while alpha-synuclein was increased in MPTP-treated mice. The altered levels of 19S Rpt6 and alpha-synuclein were further verified by Western blot. Experiments using small interfering RNA (siRNA) showed that alpha-synuclein was increased by 50% in cultured striatal neurons when 19S Rpt6 was knocked down. Taken together, our results imply that a deficiency in 19S Rpt6 may be partially related to the MPTP-induced increase in alpha-synuclein in the striatum. | 18,782,562 |
Association between serum retinol-binding protein 4 and small dense low-density lipoprotein cholesterol levels in young adult women. | Serum retinol-binding protein 4 (RBP4) and small dense low-density lipoprotein (sdLDL) have been suggested to be associated with insulin resistance, but no information is available on the relationship between RBP4 and sdLDL. We determined serum RBP4, sdLDL-cholesterol, and other metabolic variables on 38 young women, aged 19-29 years. The homeostatic model assessment of insulin resistance (HOMA-IR) was used for the estimation of insulin resistance. In simple regression analyses, RBP4 levels had significant correlations with total cholesterol (r=0.354, P=0.029), LDL-cholesterol (r=0.396, P=0.014), and sdLDL-cholesterol (r=0.510, P=0.001) levels. The sdLDL-cholesterol levels also correlated significantly with total cholesterol (r=0.402, P=0.012), LDL-cholesterol (r=0.627, P<0.001) and triglycerides (r=0.449, P=0.005). Stepwise multiple regression analyses showed only sdLDL-cholesterol (beta coefficient (ss)=0.510, P=0.001) level was a significant independent predictor of RBP4 levels (adjusted R(2)=0.240), whereas RBP4 (ss=0.289, P=0.026) level was one of major factors affecting sdLDL-cholesterol levels (adjusted R(2)=0.519). There was no significant association of HOMA-IR with RBP4 or sdLDL levels. We showed an independent linkage between serum RBP4 and sdLDL-cholesterol levels in young adult women. These findings may contribute to understanding of lipoprotein metabolisms involved in diabetes and cardiovascular disease. | 18,782,570 |
Protein markers of algal toxin contamination in shellfish. | Filter-feeding bivalve molluscs are often contaminated by algal toxins. We have probed whether proteomic analysis of extracts from the digestive gland (DG) of mussels could be employed to identify biomarkers of contamination due to okadaic acid-group toxins. The protein extracts were obtained from 18 separate mussel samples and were analyzed by two-dimensional gel electrophoresis. When samples were divided into four different classes based on the content of OA-group toxins in the starting material, we found that two proteins varied as a function of OA contamination. By BLAST analysis, the two proteins were identified as a component of photosystem II and a subunit of NADH dehydrogenase. The analysis of peptide homologies showed that the peptide of photosystem II we detected in extracts from the DG of mussels contaminated by OA-group toxins is identical to its counterpart in Dinophysis algae, which are the producers of this group of toxins. We concluded that proteomic analysis can be used for the detection and identification of biomarkers of biotoxin contamination in shellfish, including both proteins expressed by the toxin producers and components that participate to the tissue response to the exogenous bioactive contaminant. | 18,782,583 |
Effect of visual experience on the maturation of ON-OFF direction selective ganglion cells in the rabbit retina. | Activity-dependent neural plasticity is well known in the development of the visual cortical circuitry. However, the role of neural plasticity in the developing retina is less well understood. In the light of recent findings that light deprivation alters the development of synaptic pathway in the mouse and turtle retinas, we studied whether visual experience is required for the maturation of the ON-OFF direction selective ganglion cells (DSGCs) in the rabbit retina. The DSGCs of rabbits raised under a normal light-dark cycle and in the constant darkness were recorded extracellularly at various postnatal stages. Receptive field properties, such as direction selectivity, velocity tuning, classical center-surround interaction and motion-induced surround inhibition were examined. Recorded cells were subsequently injected with Neurobiotin in order to characterize their morphological features and tracer coupling patterns. Our results revealed that visual experience is not critical for the maturation of the classical receptive field properties of the DSGCs, such as direction selectivity and velocity tuning. However, the dark-reared rabbits showed altered surround inhibition, which is mediated by the amacrine cells of the inner retina. In addition, the DSGCs of both normal- and dark-reared rabbits showed similar dendritic features and tracer coupling patterns. Taken together, this study indicates that visual experience plays a less significant role on the DS circuitry maturation in the retina than in the cortex. | 18,782,584 |
Low Ca2+ buffering in hypoglossal motoneurons of mutant SOD1 (G93A) mice. | Mutations in the Cu/Zn superoxide dismutase (SOD1) gene are associated with amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disorder characterized by a selective degeneration of brainstem and spinal motoneurons. The pathomechanism of degeneration is still incompletely understood, but includes a disruption in cellular Ca2+ homeostasis. Here we report a quantitative microfluorometric analysis of the Ca2+ homeostasis in vulnerable hypoglossal motoneurons of neonatal mutant (G93A) SOD1 transgenic mice, a mouse model of human ALS. Ca2+ transient decay times (tau = 0.3 s), extrusion rates (gamma = 92 s(-1)) and exceptionally low intrinsic Ca2+ binding ratios (kappaS = 30) were found to be in the same range as compared to non-transgenic animals. Together with the previous observation of high Ca2+ binding ratios in ALS-resistant neurons (e.g. oculomotor), this supports the assumption that low Ca2+ buffering in vulnerable motoneurons represents a significant risk factor for degeneration. On the other hand, alterations in buffering properties by expression of mutant SOD1 are unlikely to be involved in disease initiation. | 18,782,598 |
RAGE expression is up-regulated in human cerebral ischemia and pMCAO rats. | To determine whether the receptor for advanced glycation endproducts (RAGE) contributes to cerebral ischemia, we evaluated RAGE expression in human cerebral ischemia and a model of permanent middle cerebral artery occlusion (pMCAO) in rats. Biopsy specimens were obtained from 12 patients with unilateral cerebral infarction. For the pMCAO model, the middle cerebral artery (MCA) of Sprague-Dawley (SD) rats was permanently occluded. Immunohistochemistry and Western blotting were used to measure RAGE expression in the ischemic hemisphere relative to the normal hemisphere. PC12 cells subjected to oxygen and glucose deprivation (OGD) were used to evaluate the role of RAGE in cell injury. As expected, cerebral ischemia patients expressed elevated levels of RAGE in the ischemic hemisphere. In 1 and 2 days pMCAO rats, levels of RAGE were higher in the ischemic hemisphere relative to the non-ischemic hemisphere, and expression was primarily located in the penumbra of the ischemic hemisphere. In PC12 cells, levels of RAGE increased after 7h of OGD culture. Notably, blockade of RAGE with a selective RAGE antibody in vitro reduced the cytotoxicity caused by OGD. The present data suggest that RAGE is up-regulated in human cerebral ischemia and pMCAO rats, suggesting a role for RAGE in brain ischemia. | 18,782,604 |
Physicochemical aspects of doxorubicin-loaded pH-sensitive polymeric micelle formulations from a mixture of poly(L-histidine)-b-poly(ethylene glycol)/poly(L-lactide)-b-poly(ethylene glycol) [corrected]. | In this study, doxorubicin (DOX) was physically incorporated into pH-sensitive micelles made from a mixture of poly(L-histidine)-b-poly(ethylene glycol)/poly(L-lactide)-b-poly(ethylene glycol) (75/25, wt.%). The DOX-loaded mixed micelles were formulated using dialysis methods and optimal DOX incorporation was achieved at a drug/polymer feed ratio of 0.2 (wt./wt.) when a proper amount of aqueous phase (0.2, v./v.) was added into the common solvent (DMSO) solution, followed by dialysis at 4 degrees C. Based on the results obtained from dynamic light scattering, UV-Vis absorption, and fluorescence experiments, it was demonstrated that the encapsulated drugs were mainly located inside the hydrophobic micelle cores, well protected and inaccessible to the exterior molecules. Under in vitro conditions, although the microstructure of the micelles was altered below pH 8.0 by the encapsulated drugs, the drug-loaded micelles still exhibited a desirable ability to control the drug release in response to tumor extracellular pH. | 18,782,616 |
Release of cytokines/chemokines and cell death in UVB-irradiated human keratinocytes, HaCaT. | Ultraviolet (UV) B can lead to inflammatory responses such as sunburn, which involves the production of various inflammatory cytokines and chemokines, and the induction of cell death. Keratinocytes in the skin has one of the highest risks of exposure to UV. However, the detailed mechanisms underlying UVB irradiation-induced inflammation and cell death are not well known. Thus, we investigated the effect of UVB irradiation on the production of various cytokines/chemokines and the induction of cell death in UVB-irradiated human keratinocytes (HaCaT cells). We evaluated 11 cytokines/chemokines in cell culture supernatants from HaCaT cells exposed to 0-400 mJ/cm(2) UVB irradiation. UVB at a dose 400 mJ/cm(2) induced the release of various cytokines; interleukin (IL)-1beta, IL-6, IL-8, interferon (IFN)-gamma, granulocyte-colony stimulating factor (G-CSF), macrophage inflammatory protein (MIP)-1beta, and tumor necrosis factor (TNF)-alpha. These results suggest that UVB irradiation-induced the release of several cytokines/chemokines and led to cell death in human keratinocytes. UV exposure may be associated with multiple physiological events in the human skin. | 18,782,623 |
Rapid and sensitive detection of African horse sickness virus by real-time PCR. | A highly sensitive and specific TaqMan-MGB real-time RT-PCR assay has been developed and standardised for the detection of African horse sickness virus (AHSV). Primers and MGB probe specific for AHSV were selected within a highly conserved region of genome segment 7. The robustness and general application of the diagnostic method were verified by the detection of 12 AHSV isolates from all of the nine serotypes. The analytical sensitivity ranged from 0.001 to 0.15 TCID(50) per reaction, depending on the viral serotype. Real-time PCR performance was preliminarily assessed by analysing a panel of field equine samples. The same primer pair was used to standardise a conventional RT-PCR as an affordable, useful and simple alternative method in laboratories without access to real-time PCR instruments. The two techniques present novel tools to improve the molecular diagnosis of African horse sickness (AHS). | 18,782,637 |
Potential emissions from two mechanically-biologically pretreated (MBT) wastes. | The interaction of parameters determining the potential emissions of two different mechanically-biologically pretreated municipal solid wastes (MBT wastes) is elucidated in this work. The origins of the wastes are Germany and Sweden. By means of lab-scale experiments, increased stabilisation through composting is preferably determined by a decrease in respiration activity. Concurrently, the stabilisation is verified for the leachates by a decrease in COD, DOC, and BOD(5). Total organic carbon content reflects stabilisation less accurately. FT-IR and thermal analytical methods add valuable information about the state of degradation, especially when several distinct thermal parameters are taken into account. Mobility of Cr, Ni, Pb, and Zn produced by a batch leaching test with deionized water is reduced by the pretreatment of both materials. Mobility of copper unambiguously increased. A principle component analysis (PCA) of membrane fractionated leachates indicates an affinity of Cu to mobile humic acids or dissolved organic carbon. High Cr, Zn, and Ni contents in the solid co-occur with high contents of solid humic acids. To a lesser extent, this is also true for solid Cd, Cu, and Pb contents. Due to differences in required landfilling conditions, actual emissions and after-care phase length will depend on whether each waste is landfilled in Germany or Sweden. | 18,782,660 |
Intermittent preventive antimalarial treatment to children (IPTc): firebreak or fire trap? | Intermittent preventive treatment is the prescheduled administration of antimalarial drugs to at-risk patients in endemic areas. This approach, which is recommended for pregnant women, is being evaluated in children. Sulfadoxine-pyrimethamine plus amodiaquine recently proved to be more protective than artemisinin-containing regimens. Therefore, the use of artemisinin derivatives could potentially be restricted to symptomatic patients. Determinants of three pending issues: safety, efficacy throughout childhood, and effectiveness--the latter depending on the implementation of sustainable delivery mechanisms--are analyzed in this comment. | 18,782,680 |
Recommendations for permanent prostate brachytherapy with (131)Cs: a consensus report from the Cesium Advisory Group. | Published clinical information on the safety and efficacy of (131)Cs implants is limited. We provide consensus recommendations for (131)Cs prostate brachytherapy based on experience to date. The Cesium Advisory Group (CAG) consists of experienced (131)Cs users. Recommendations are based on three clinical trials, one of which has completed accrual and has been published in the peer reviewed literature, and combined CAG experience of more than 1200 (131)Cs implants. We recommend using 1.059cGyh(-1)U(-1) as the dose rate constant for the IsoRay source. The prescription for monotherapy implants is 115Gy and when combined with 45-50Gy external beam it is 85Gy. Suggested individual source strength ranges from 1.6 to 2.2U. The release criterion for (131)Cs implants is 6mRh(-1) at 1m. (131)Cs brachytherapy should be performed differently from (125)I and (103)Pd brachytherapy: source placement is further from the urethra and rectum; the prostate V(150) should be < or =45%; sufficient margins may be obtained while limiting source placement to the capsule or close to the capsule. The increased dose rate may cause degradation of postimplant quantifiers due to edema. However, large variability in the magnitude and rate of resolution of edema make determination of the most representative postoperative imaging time impossible. The CAG recommends postimplant imaging on the day of the implant. Recommended postimplant evaluation goals include prostate D(90) greater than the prescription dose; maintaining D(u)(,30)<140% of the prescription dose and keeping V(r)(,100)<0.5cm(3). It was the consensus of the CAG that optimal (131)Cs implants should be performed differently from those performed with (125)I or (103)Pd. Guidelines have been established to allow for safe and effective delivery of (131)Cs prostate brachytherapy. | 18,782,682 |
Poor presurgical performance on both verbal and visual memory measures is associated with low risk for memory decline following left temporal lobectomy for intractable epilepsy. | Studies have shown a lower risk for verbal memory decline following dominant anterior temporal lobectomy (ATL) among patients with poor, presurgical verbal memory scores. It is unclear however, if the risk of decline is increased in patients who also have reduced visual memory. Objective and subjective memory outcome following left ATL was examined in twelve patients with reduced presurgical visual and verbal memory scores. Only one patient demonstrated a meaningful decline in memory scores, with a decline in visual memory following surgery. Presurgically, this patient demonstrated poor memory bilaterally on Wada testing and small discrepancy in hippocampal volumes. She was also one of two patients who continued to have seizures post-surgery. This preliminary study suggests that patients with unilateral, left TLE and poor verbal and visual memory are unlikely to show meaningful memory declines following left ATL, particularly if they demonstrate expected patterns on Wada testing, hippocampal volume discrepancy (left < right), and postsurgical seizure-freedom. | 18,782,688 |
The impact of prescription depth, dose rate, plaque size, and source loading on the central axis using 103Pd, 125I, and 131Cs. | Modern dosimetry data are not available for Collaborative Ocular Melanoma Study-based eye plaques. This report aims to provide these data for eye plaques ranging from 10 to 22 mm, and for three different low-energy, photon-emitting radionuclides. Recent publications on brachytherapy dosimetry parameters for 103Pd, 125I, and 131Cs were evaluated for use as eye plaque reference data. These data were entered into the Pinnacle treatment planning system for 3D calculations of brachytherapy dose distributions along the central axis for depths ranging from -1 to 10 mm based on the origin positioned at the inner sclera. In accordance with the original Collaborative Ocular Melanoma Study protocol and in the absence of radionuclide-specific heterogeneity factors, inhomogeneity corrections were not applied. As expected due to the mean photon energies, 103Pd, 125I, and 131Cs provided increasingly penetrating dose distributions. Dose distribution tables were prepared for fully loaded plaques and for plaques with the central source(s) removed. Over the entire range of central axis depths, and for all plaque sizes and loadings, 131Cs produced minimal outer scleral doses. Similarly, 103Pd generally produced more favorable dose distributions than 125I for depths less than 4mm. A modern analysis of eye plaque dosimetry evaluated dose as a function of lesion height and applicator size, and showed dependence on radionuclide selection and implant duration. For a fixed dose at the prescription point, we observed higher scleral dose corresponded with lower photon energy for a variety of plaque sizes and lesion heights. | 18,782,684 |
Cough syncope misinterpreted as epileptic seizure. | Cough syncopes are rare but may be one of the cause of sudden loss of consciousness. We recorded under video-EEG monitoring a typical syncope triggered by voluntary coughing (video) and Valsava maneuvre in a patient referred for the diagnosis of generalized tonic-clonic seizures. There were no signs of active epilepsy. The attacks were associated with overweight, obstructive sleep apnea and heavy consumption of cigarettes. [Published with video sequences]. | 18,782,692 |
Clinical impact of a high-frequency seizure onset zone in a case of bitemporal epilepsy. | High-frequency activity has been described as having a role in the initiation of epileptic seizures. The case of a patient with refractory bitemporal epilepsy is presented. Extraoperative monitoring with depth and subdural electrodes revealed an ictal pattern with a build-up of high-frequency (> 80 Hz) activity originating in the cortex, with spread to both hippocampi. This observation was only revealed with the use of high-pass filtering, and represented crucial information that significantly influenced the decision about the side, localization and extent of resection. Removal of the cortex generating high-frequency activity, led to cessation of seizures in this patient. Current knowledge about the role of high-frequency activity and the case presented here support the importance of recording with equipment capable of detecting fast activity during the presurgical invasive monitoring. An active search for a high-frequency seizure onset zone in patients with structurally-unaffected hippocampi may improve the outcome beyond that possible with conventional bandwidth, invasive EEG recordings. | 18,782,695 |
Use of high-thoracic epidural analgesia in pulmonary endarterectomy: a randomized feasibility study. | The suitability of combined high-thoracic epidural anesthesia for pulmonary endarterectomy was studied. A prospective randomized clinical study was conducted in a university medical center from November 2005 to December 2006. The primary endpoint of this study was to evaluate perioperative hemodynamic data; secondary endpoints were to evaluate the duration of artificial ventilation, length of stay in the intensive care unit, and the impact on postoperative morbidity and mortality. The 16 patients in the study group received high-thoracic epidural anesthesia plus general anesthesia; the 16 control patients received total intravenous anesthesia alone. Hemodynamic parameters and drug use, as well as the time to extubation, rate of complications, postoperative pain, the length of intensive care unit stay, and mortality, were recorded. The 2 groups were comparable with respect to hemodynamic stability during induction of anesthesia. The study group patients had significantly lower sufentanil consumption (mean +/- SD, 2.1 +/- 0.7 microg/kg versus 9.1 +/- 3.1 microg/kg; P <.001), a shorter period of artificial ventilation (34 +/- 35 hours versus 52 +/- 49 hours; P = .0318), and lower postoperative pain scores at 3 hours (0.10 +/- 0.26 versus 0.93 +/- 1.38; P = .015), 12 hours (0.14 +/- 0.53 versus 0.93 +/- 0.79; P = .002), and 24 hours (0.35 +/- 0.49 versus 1.33 +/- 1.04; P = .007). This study has shown that combined epidural and general anesthesia is a suitable anesthetic option in patients who are selected for pulmonary endarterectomy. It provides hemodynamic stability and reduces the duration of tracheal intubation postoperatively and improves postoperative pain relief, although this option has not been shown to decrease either the length of the intensive care unit stay or mortality. | 18,782,697 |
Restrictive mitral valve annuloplasty for chronic ischemic mitral regurgitation: a 5-year clinical experience with the physio ring. | This study investigated the results of restrictive mitral annuloplasty with the semirigid Carpentier-Edwards Physio ring in patients with moderately severe to severe chronic ischemic mitral regurgitation (IMR) and advanced ischemic cardiomyopathy (ICM). From 2003 to 2007, 100 consecutive patients (mean age +/- SD, 69 +/- 10 years) with chronic IMR of grades 3 to 4 (3.6 +/- 0.5) and a left ventricular ejection fraction (LVEF) of 31% +/- 9% (range, 12%-45%) underwent standardized restrictive prosthetic ring annuloplasty (ie, downsizing of 2.7 +/- 1.0 [range, 2-4] ring sizes) and concomitant coronary artery bypass grafting. All surviving patients were restudied 8 +/- 1 days, 3 +/- 1 months, and 2.5 +/- 1.0 years after surgery to assess survival, residual MR, New York Heart Association (NYHA) class, and LV function (end-systolic and end-diastolic dimension/volume indices and LVEF). Data were analyzed exploratatively. Survival rates at the postoperative reexamination times were 98%, 97%, and 94%, respectively (1 noncardiac and 5 cardiac deaths). NYHA class improved from 3.5 +/- 0.5 to 1.4 +/- 0.5 (P < .0005). The residual MR grades at discharge, early follow-up, and late follow-up were 0.4 +/- 0.5, 0.5 +/- 0.5, and 0.4 +/- 0.6, respectively (P < .0005). Post-operative recurrence of significant IMR (>grade 2) was absent in all patients. The leaflet coaptation height was 8 +/- 1 mm and did not decrease significantly over time. All LV dimension and volume indices and the LVEF (41% +/- 9% at 2.5 years) improved significantly after surgery (P < .0005), even in patients with initially severely reduced myocardial function and a preoperative LVEF of <30% (n = 42; LVEF, 22% +/- 5% versus 33% +/- 6% at late follow-up; P < .0005). Restrictive mitral valve annuloplasty using the semirigid Physio ring corrected chronic IMR in ICM patients with very low mortality and improved contractility. Surgery also prevented recurrence of significant IMR in parallel with the phenomenon of postoperative continuous reverse myocardial remodeling. | 18,782,701 |
Acute mitral regurgitation requiring urgent surgery because of chordae ruptures after extreme physical exercise: case report. | Chordae rupture is the most common cause of severe acute mitral insufficiency. Many different mechanisms can cause an acute chordal rupture: degenerative mitral valve disease, infective endocarditis, myocardial infarction, or a posttraumatic event. We present 2 cases of acute mitral regurgitation requiring urgent surgery due to a posterior leaflet chorda rupture after extreme physical exercise. | 18,782,707 |
Evolution of New Zealand's terrestrial fauna: a review of molecular evidence. | New Zealand biogeography has been dominated by the knowledge that its geophysical history is continental in nature. The continental crust (Zealandia) from which New Zealand is formed broke from Gondwanaland ca 80 Ma, and there has existed a pervading view that the native biota is primarily a product of this long isolation. However, molecular studies of terrestrial animals and plants in New Zealand indicate that many taxa arrived since isolation of the land, and that diversification in most groups is relatively recent. This is consistent with evidence for species turnover from the fossil record, taxonomic affinity, tectonic evidence and observations of biological composition and interactions. Extinction, colonization and speciation have yielded a biota in New Zealand which is, in most respects, more like that of an oceanic archipelago than a continent. | 18,782,728 |
Using the Australian Therapy Outcome Measures for Occupational Therapy (AusTOMs-OT) to measure outcomes for clients following stroke. | To examine a range of measures used to document client outcomes following stroke, describe the Australian Therapy Outcome Measure for Occupational Therapy (AusTOMs-OT) as a tool suitable to measure multiple outcomes, and provide an overview of three outcomes research programs using this measure. The AusTOMs-OT was developed to measure global therapy outcomes and offers therapists a choice of 12 function-focused scales (including self-care, domestic life, community life, upper limb function). Therapists evaluate the client's status globally in relation to four domains: the underlying impairment, activity limitation, participation restriction, and distress/well-being. The first study presents a comparison of outcomes for clients at two Australian acute care facilities on the self-care scale (n = 82). Similarly, the second study presented is a comparison of stroke rehabilitation outcomes using the self-care scale for clients in Sweden and Australia (n = 70). The final study is an Australian benchmarking study using the upper limb scale (n = 40). All three studies demonstrated that clients improved during therapy as measured on the four domains of AusTOMs-OT. Study 3 examined client outcomes at one facility against an agreed benchmark using the AusTOMs-OT upper limb scale and found that clients attained benchmark outcomes. A variety of outcome measures are available for clinicians to document the progress clients make during stroke rehabilitation. However, the AusTOMs-OT can measure global outcomes across multiple domains in just a few moments. Three studies reporting outcomes for clients with stroke using the AusTOMs-OT demonstrate its utility in documenting client change during therapy and for comparing or benchmarking services. | 18,782,738 |
The impact of increased duration of exercise therapy on functional recovery following stroke--what is the evidence? | This article focuses on the impact of increased duration of exercise therapy on functional recovery after stroke. A comprehensive literature search using multiple databases was used to identify all relevant randomized controlled trials. Their quality was reviewed by two independent assessors, and a narrative systematic review and meta-analysis was completed. Methodological quality of all the 20 randomized controlled trials (RCTs) identified had a median of 6 points (range 5-8) on the 10-point PEDro scale. A meta-analysis was completed for studies that had a common outcome measure. For each outcome measure, the estimated effect size (ES) and the summary effect size (SES) were expressed as standardized mean differences (SMD). The results of the meta-analysis demonstrated that increased duration of exercise therapy time has a small but positive effect on activities of daily living as measured by the Barthel Index (SES 0.13; CI 0.01-0.25; Z = 2.15; p = .03) and that these improvements are maintained over a 6-month period (SES 0.15; CI 0.05-0.26; Z = 2.8; p = .00). Pooling reported differences in the various upper and lower extremity outcome measures demonstrated no significant SESs. However, the meta-analysis is supportive of the hypothesis that additional, focused exercise on the lower extremity has a favourable effect on lower extremity impairment and walking speed. The narrative review raises a number of issues that need to be considered in the development of future RCTs. | 18,782,739 |
Trophic and individual efficiencies of size-structured communities. | Individual and trophic efficiencies of size-structured communities are derived from mechanistically based principles at the individual level. The derivations are relevant for communities with a size-based trophic structure, i.e. where trophic level is strongly correlated with individual size as in many aquatic systems. The derivations are used to link Lindeman's trophic theory and trophic theory based on average individuals with explicit individual-level size spectrum theory. The trophic efficiency based on the transfer of mass between trophic levels through predator-prey interactions is demonstrated to be valid only when somatic growth can be ignored. Taking somatic growth into account yields an average individual growth efficiency that is smaller than the trophic efficiency. | 18,782,750 |
Experimental evidence for paternal effects on offspring growth rate in Arctic charr (Salvelinus alpinus). | Sexual selection theory predicts that females should choose males that signal viability and quality. However, few studies have found fitness benefits among females mating with highly ornamented males. Here, we use Arctic charr (Salvelinus alpinus), a teleost fish with no parental care, to investigate whether females could gain fitness benefits by mating with highly ornamented and large-sized males. Carotenoid-based coloration signalled by males during spawning is believed to be an indicator of good genes for this species. Paternal effects on offspring size (body length and dry body mass) were examined experimentally by crossing eggs and sperm in vitro from 12 females and 24 males in a split-brood design and raising larvae to 30 days past hatching. We clearly demonstrated that there was a relationship between offspring size and paternal coloration. However, a negative interaction between paternal length and coloration was evident for offspring length, indicating that positive effects of paternal coloration were only present for smaller males. Thus, the red spawning coloration of the male Arctic charr seems to be an indicator of good genes, but the effect of paternal coloration on offspring length, an indicator of 'offspring quality', is size dependent. | 18,782,751 |
Structural insight into bioremediation of triphenylmethane dyes by Citrobacter sp. triphenylmethane reductase. | Triphenylmethane dyes are aromatic xenobiotic compounds that are widely considered to be one of the main culprits of environmental pollution. Triphenylmethane reductase (TMR) from Citrobacter sp. strain KCTC 18061P was initially isolated and biochemically characterized as an enzyme that catalyzes the reduction of triphenylmethane dyes. Information from the primary amino acid sequence suggests that TMR is a dinucleotide-binding motif-containing enzyme; however, no other functional clues can be derived from sequence analysis. We present the crystal structure of TMR in complex with NADP+ at 2.0-angstroms resolution. Despite limited sequence similarity, the enzyme shows remarkable structural similarity to short-chain dehydrogenase/reductase (SDR) family proteins. Functional assignments revealed that TMR has features of both classic and extended SDR family members and does not contain a conserved active site. Thus, it constitutes a novel class of SDR family proteins. On the basis of simulated molecular docking using the substrate malachite green and the TMR/NADP+ crystal structure, together with site-directed mutagenesis, we have elucidated a potential molecular mechanism for triphenylmethane dye reduction. | 18,782,772 |
Osteoclast inhibitory lectin, an immune cell product that is required for normal bone physiology in vivo. | Osteoclast inhibitory lectin (OCIL or clrb) is a member of the natural killer cell C-type lectins that have a described role mostly in autoimmune cell function. OCIL was originally identified as an osteoblast-derived inhibitor of osteoclast formation in vitro. To determine the physiological function(s) of OCIL, we generated ocil(-/-) mice. These mice appeared healthy and were fertile, with no apparent immune function defect, and phenotypic abnormalities were limited to bone. Histomorphometric analysis revealed a significantly lower tibial trabecular bone volume and trabecular number in the 10- and 16-week-old male ocil(-/-) mice compared with wild type mice. Furthermore, ocil(-/-) mice showed reduced bone formation rate in the 10-week-old females and 16-week-old males while Static markers of bone formation showed no significant changes in male or female ocil(-/-) mice. Examination of bone resorption markers in the long bones of ocil(-/-) mice indicated a transient increase in osteoclast number per unit bone perimeter. Enhanced osteoclast formation was also observed when either bone marrow or splenic cultures were generated in vitro from ocil(-/-) mice relative to wild type control cultures. Loss of ocil therefore resulted in osteopenia in adult mice primarily as a result of increased osteoclast formation and/or decreased bone formation. The enhanced osteoclastic activity led to elevated serum calcium levels, which resulted in the suppression of circulating parathyroid hormone in 10-week-old ocil(-/-) mice compared with wild type control mice. Collectively, our data suggest that OCIL is a physiological negative regulator of bone. | 18,782,774 |
Daptomycin versus vancomycin plus gentamicin for treatment of bacteraemia and endocarditis due to Staphylococcus aureus: subset analysis of patients infected with methicillin-resistant isolates. | In a prospective, randomized trial, daptomycin was non-inferior to standard therapy for Staphylococcus aureus bacteraemia and right-sided endocarditis. Since rates of infection due to methicillin-resistant S. aureus (MRSA) infection are increasing and treatment outcomes for bacteraemia caused by MRSA are generally worse than those observed with methicillin-susceptible S. aureus bacteraemia, clinical characteristics and treatment results in the trial's pre-specified subset of patients with MRSA were analysed. Clinical characteristics and outcomes of patients receiving daptomycin were compared with those receiving vancomycin plus low-dose gentamicin. Success was defined as clinical improvement with clearance of bacteraemia among patients who completed adequate therapy, received no potentially effective non-study antibiotics and had negative blood cultures 6 weeks after end of therapy. Twenty of the 45 (44.4%) daptomycin patients and 14 of the 43 (32.6%) vancomycin/gentamicin patients were successfully treated (difference 11.9%; confidence interval -8.3 to 32.1). Success rates for daptomycin versus vancomycin/gentamicin were 45% versus 27% in complicated bacteraemia, 60% versus 45% in uncomplicated bacteraemia and 50% versus 50% in right-sided MRSA endocarditis. Cure rates in patients with septic emboli and in patients who received pre-enrolment vancomycin were similar between treatment groups. However, in both treatment groups, success rates were lower in the elderly (>/=75 years). Persisting or relapsing bacteraemia occurred in 27% of daptomycin and 21% of vancomycin/gentamicin patients; among these patients, MICs of >/=2 mg/L occurred in five daptomycin and four vancomycin/gentamicin patients. The clinical course of several patients may have been influenced by lack of surgical intervention. Daptomycin was an effective alternative to vancomycin/gentamicin for MRSA bacteraemia or right-sided endocarditis. | 18,782,781 |
Cytologically malignant margin without continuous pulmonary tumor lesion: cases of wedge resection, segmentectomy and lobectomy. | The surgical margin is usually investigated during the operation using a pathological method, though cytological methods are also used to identify remaining malignant cells. We reviewed cases of pulmonary resection for a malignant tumor. At our institution, an on-site surgical margin examination using a cytological method is mandated for cases of wedge resection and segmentectomy, and an option in lobectomy cases. We examined 21 wedge resection (3 primary lung cancer, 18 metastasis), 17 segmentectomy (13 primary lung cancer, 4 metastasis), and 4 lobectomy (all primarily lung cancer) cases. Six cases showed malignant cells in the surgical margin, of which one had a microscopic skip lesion pattern and five an 'occult' pattern (positive cytology, negative pathology). Cytological malignancy occurred even in cases of wedge resection of a tiny (4 mm in diameter) lesion metastasized from colon cancer, as well as segmentectomy with a sufficient gross margin containing microscopic skip lesions and right middle lobectomy with an additional right upper lobectomy due to two previous cytological malignancies in a residual lobe. Surgical margin cytology revealed remaining malignancy in the residual lobe, which provided important information for deciding additional procedures during surgery. | 18,782,788 |
Animal models of chronic lung infection with Pseudomonas aeruginosa: useful tools for cystic fibrosis studies. | Cystic fibrosis (CF) is caused by a defect in the transmembrane conductance regulator (CFTR) protein that functions as a chloride channel. Dysfunction of the CFTR protein results in salty sweat, pancreatic insufficiency, intestinal obstruction, male infertility and severe pulmonary disease. In most patients with CF life expectancy is limited due to a progressive loss of functional lung tissue. Early in life a persistent neutrophylic inflammation can be demonstrated in the airways. The cause of this inflammation, the role of CFTR and the cause of lung morbidity by different CF-specific bacteria, mostly Pseudomonas aeruginosa, are not well understood. The lack of an appropriate animal model with multi-organ pathology having the characteristics of the human form of CF has hampered our understanding of the pathobiology and chronic lung infections of the disease for many years. This review summarizes the main characteristics of CF and focuses on several available animal models that have been frequently used in CF research. A better understanding of the chronic lung infection caused particularly by P. aeruginosa, the pathophysiology of lung inflammation and the pathogenesis of lung disease necessitates animal models to understand CF, and to develop and improve treatment. | 18,782,827 |
The putative RNase P motif in the DEAD box helicase Hera is dispensable for efficient interaction with RNA and helicase activity. | DEAD box helicases use the energy of ATP hydrolysis to remodel RNA structures or RNA/protein complexes. They share a common helicase core with conserved signature motifs, and additional domains may confer substrate specificity. Identification of a specific substrate is crucial towards understanding the physiological role of a helicase. RNA binding and ATPase stimulation are necessary, but not sufficient criteria for a bona fide helicase substrate. Here, we report single molecule FRET experiments that identify fragments of the 23S rRNA comprising hairpin 92 and RNase P RNA as substrates for the Thermus thermophilus DEAD box helicase Hera. Both substrates induce a switch to the closed conformation of the helicase core and stimulate the intrinsic ATPase activity of Hera. Binding of these RNAs is mediated by the Hera C-terminal domain, but does not require a previously proposed putative RNase P motif within this domain. ATP-dependent unwinding of a short helix adjacent to hairpin 92 in the ribosomal RNA suggests a specific role for Hera in ribosome assembly, analogously to the Escherichia coli and Bacillus subtilis helicases DbpA and YxiN. In addition, the specificity of Hera for RNase P RNA may be required for RNase P RNA folding or RNase P assembly. | 18,782,831 |
Comparative Toxicogenomics Database: a knowledgebase and discovery tool for chemical-gene-disease networks. | The Comparative Toxicogenomics Database (CTD) is a curated database that promotes understanding about the effects of environmental chemicals on human health. Biocurators at CTD manually curate chemical-gene interactions, chemical-disease relationships and gene-disease relationships from the literature. This strategy allows data to be integrated to construct chemical-gene-disease networks. CTD is unique in numerous respects: curation focuses on environmental chemicals; interactions are manually curated; interactions are constructed using controlled vocabularies and hierarchies; additional gene attributes (such as Gene Ontology, taxonomy and KEGG pathways) are integrated; data can be viewed from the perspective of a chemical, gene or disease; results and batch queries can be downloaded and saved; and most importantly, CTD acts as both a knowledgebase (by reporting data) and a discovery tool (by generating novel inferences). Over 116,000 interactions between 3900 chemicals and 13,300 genes have been curated from 270 species, and 5900 gene-disease and 2500 chemical-disease direct relationships have been captured. By integrating these data, 350,000 gene-disease relationships and 77,000 chemical-disease relationships can be inferred. This wealth of chemical-gene-disease information yields testable hypotheses for understanding the effects of environmental chemicals on human health. CTD is freely available at http://ctd.mdibl.org. | 18,782,832 |
Surveillance of physical activity in the UK is flawed: validation of the Health Survey for England Physical Activity Questionnaire. | Public health surveillance of physical activity in children in the UK depends on a parent-reported physical activity questionnaire which has not been validated. We aimed to validate this questionnaire against measurement of physical activity using accelerometry in 6-7-year-old children. In 130 children aged 6-7 years (64 boys, 66 girls) we estimated habitual moderate-vigorous intensity physical activity (MVPA) using the Health Survey for England parent-report questionnaire for physical activity. For the same time period and the same children, we measured MVPA objectively using 7-day accelerometry with the Actigraph accelerometer. The questionnaire over-estimated MVPA significantly (paired t test, p<0.01). Mean error (bias) when using the questionnaire was 122 min/day (95% CI 124 to 169). Mean time spent in MVPA was 146 min/day (95% CI 124 to 169) using the questionnaire and 24 min/day (95% CI 22 to 26) using the accelerometer. Rank order correlations between MVPA measured by accelerometer and estimated by the questionnaire were not statistically significant. Public health surveillance of physical activity should not rely on this questionnaire. Levels of habitual physical activity in children are likely to be substantially lower than those reported in UK health surveys. | 18,782,845 |
Efficacy of 99mTc-DTPA lung clearance test in the diagnosis of PCP in HIV-positive patients. | The study aims to evaluate the efficacy of technetium-99m diethylenetriaminepentaacetic acid ((99m)Tc-DTPA) lung clearance test in the diagnosis of pneumocystis carinii pneumonia (PCP) in HIV-positive paediatric patients. Twenty HIV-negative patients with no chest symptoms constituted Group A, 25 HIV antibody positive asymptomatic children formed Group B, while 45 HIV antibody positive children with respiratory infections comprised Group C. Group C was subdivided into C(1) (n = 20, documented PCP on microbiology), C(2) (n = 10, tuberculosis) and C(3) (n = 15, bacterial pneumonias). The mean age group of patients in Group A, Group B and Group C was 4.7 +/- 1.9, 4.2 +/- 1.5 and 4.8 +/- 1.7 years, respectively. All patients were subjected to complete blood count, blood culture, chest radiographs, microscopic staining of sputum (PCP stains, Ziehl-Nielsen staining, Gram staining), ABG and Mantoux test. All these patients underwent dynamic lung scans using (99m)Tc-DTPA aerosols and lung clearance was calculated in terms of half-time transfer value (T(1/2)) value. T(1/2) was compared between different groups and lung scan findings were correlated with radiological and microbiological results. Patients with PCP had T(1/2) in the range of 9.02 +/- 1.35, TB 28.2 +/- 3.03 min and other bacterial pneumonias in the range of 20.5 +/- 3.1 min (range for normal individuals was 49.8 +/- 6.13 min). T(1/2) in patients with PCP was found to be significantly lower when compared with T(1/2) in other groups. Patients with PCP had characteristic biphasic curves while the rest had monophasic curves. Some patients with PCP had low T(1/2) values even when chest radiographs and arterial blood gases were normal. (99m)Tc-DTPA lung clearance test is a sensitive, safe and non-invasive diagnostic tool for the early detection of PCP in HIV-positive paediatric patients. | 18,782,858 |
Analysis of WASp function during the wound inflammatory response--live-imaging studies in zebrafish larvae. | Wiskott-Aldrich syndrome protein (WASp) is haematopoietically restricted, and is the causative protein underlying a severe human disorder that can lead to death due to immunodeficiency and haemorrhaging. Much is known about the biochemistry of WASp and the migratory capacity of WASp-defective cells in vitro, but in vivo studies of immune-cell behaviour are more challenging. Using the translucency of zebrafish larvae, we live-imaged the effects of morpholino knockdown of WASp1 (also known as Was) on leukocyte migration in response to a wound. In embryos at 22 hours post-fertilisation, primitive macrophages were impaired in their migration towards laser wounds. Once a circulatory system had developed, at 3 days post-fertilisation, we observed significantly reduced recruitment of neutrophils and macrophages to ventral fin wounds. Cell-tracking studies indicated that fewer leukocytes leave the vessels adjacent to a wound and those that do exhibit impaired navigational capacity. Their cell morphology appears unaltered but their choice of leading-edge pseudopodia is more frequently incorrect, leading to impaired chemotaxis. We also identified two zebrafish mutants in WASp1 by TILLING, one of which was in the WIP-binding domain that is the hotspot for human lesions, and mutants exhibited the same deficiencies in wound inflammation and thrombus formation as WASp1 morphants. | 18,782,862 |
Influences of gender on the interaction between sympathetic nerve traffic and central adiposity. | Sympathetic activation promotes insulin resistance and arterial hypertension with increasing adiposity. A difference in the relationship between adiposity and sympathetic activity between women and men could contribute to the known gender difference in cardiovascular disease risk. We tested whether muscle sympathetic nerve activity (MSNA) is correlated differently with waist circumference, waist to hip ratio (WHR), and body mass index (BMI) in women and men. We pooled data from two microneurography centers (Berlin, Germany; Gdansk, Poland) for a cross-sectional study. We studied 111 normotensive, healthy Caucasian subjects (70 males and 41 females). Age ranged between 19 and 62 yr and BMI ranged between 18 and 40 kg/m(2). No intervention was applied during the study. Supine heart rate, blood pressure, and MSNA were recorded after at least 30 min rest. MSNA in bursts per minute was age dependent in both sexes [r (male) = 0.56, r (female) = 0.34, P < 0.01]. Controlling for waist and hip circumferences, age dependence remained highly significant in men (r = 0.43) and women (r = 0.43). Adjusting for age, in men, waist circumference (r = 0.29), WHR (r = 0.39), and BMI (r = 0.31) were predictive for MSNA and directly correlated (P < 0.01) but not in women. Adjusting for BMI, in men, only WHR (r = 0.40) remained predictive for MSNA. These data support the hypothesis of a gender difference in the regulation of the sympathetic nervous system, in which MSNA mainly relates to WHR in men but not women. The phenomenon may contribute to the sexual dimorphism in cardiovascular disease risk. | 18,782,878 |
Pediatric laparoscopy. | Significant developments in minimally invasive surgery (MIS) for the adult population have led to increased application of MIS techniques for pediatric patients. Laparoscopy is the most common MIS procedure used in pediatrics. Traditional surgical procedures that are now being performed laparoscopically include gastrostomy, pyloromyotomy, and repair of congenital diaphragmatic hernia and imperforate anus. All perioperative team members must be prepared to provide appropriately sized instruments and equipment to facilitate use of MIS techniques in the pediatric population and must ensure safe patient care to achieve optimal patient outcomes. | 18,782,939 |
Optimizing dialysis modality choices around the world: a review of literature concerning the role of enhanced early pre-ESRD education in choice of renal replacement therapy modality. | This article presents recent studies on factors affecting choice of self-care dialysis from around the world, denoting the relationship between early pre-end stage renal disease (ESRD) education and increased selection of self-care dialysis modalities. Style and content of various pre-ESRD education programs, barriers to early pre-ESRD education, and programs designed to decrease late referral are discussed. Economic factors favoring referral to incenter hemodialysis despite the lower cost of self-care dialysis are reviewed. | 18,783,001 |
[The US Government's effort in decreasing the cost of sleep-related problems and its outcome]. | Sleepiness and inattention caused by sleep and circadian rhythm disorders or inadequate sleep habits adversely affect workers in many industries as well as the general public, and these disorders are likely to lead to public health and safety problems and adversely affect civilian life. Evidence is accumulating that these sleep related problems are contributing factors not only in many errors of judgement and accidents, but also related to some highly prevalent diseases, such as diabetes, obesity and hypertension. For each of these societal concerns, sleep science must be translated to the general public and to those in policy positions for improving public policy and public health awareness. In the United State, the National Commission for Sleep Disorders Research (established by the US Congress in 1998) completed a comprehensive report of its findings in 1993 to address these problems. The commission estimated that sleep disorders and sleepiness cost the United States $50 billion and called for permanent and concentrated efforts in expanding basic and clinical research on sleep disorders as well as in improving public awareness of the dangers of inadequate sleep hygiene. As a result of these efforts, the number of sleep centers has increased steadily and the total of the NIH (National Institutes of Health) funding for sleep research has also grown. In response to this progress in the US (together with appeals by Japanese Sleep Specialists), the Science Council of Japan published "The Recommendation of Creation of Sleep Science and Progression of Research" in 2002. In this article, we introduce and detail to the Japanese readers the US Government's efforts focusing on the report of the National Commission for Sleep Disorders Research, and we believe that the US Government's effort is a good example for the Japanese society to follow. | 18,783,014 |
[The efficacy of a health education activity for multi-risk workers persists in the medium run]. | Recently, we reported the effectiveness of a health education activity for multi-risk workers. In this study, we investigated whether or not the efficacy of the 1-year health education program persists in the medium run. BMI, systolic blood pressure and triglyceride out of 5 items which improved significantly after a 1-year health education program, persisted after 3-5 years. Total cholesterol improved additionally while systolic blood pressure deteriorated. A gamma-GTP, which did not show betterment significantly, was enhanced after 3-5 years. The percentage of those who are following a good lifestyle regarding excise, alcohol and nutrition, increased after 3-5 years than before the education program. The efficacy of the health education activity for multi-risk workers continues in the medium run. | 18,783,015 |
Characterization of endothelin receptors in the peripheral lung tissues of horses unaffected and affected with recurrent airway obstruction. | The purpose of the study was to determine and compare the expression of endothelin (ET) receptors in the peripheral lungs of healthy horses and those affected with recurrent airway obstruction (RAO) using reverse transcriptase polymerase chain reaction (RT-PCR), real-time PCR, Western blot analysis, and immunohistochemical techniques. Two groups of horses (7 healthy and 7 RAO-affected) were selected from a pool of horses destined for euthanasia. The grouping of horses was based on the history, clinical scoring, and pulmonary function testing. After euthanasia, gross postmortem evaluation of the lungs was conducted, and lung samples were collected and either stored at -80 degrees C or fixed in zinc-formalin for 12 h. The RT-PCR was performed by using specific primers for ETA and ETB receptors, and beta-actin. To determine the relative gene expression real-time PCR was performed. To detect ET receptor protein expression, Western blotting and immunohistochemical studies were performed using polyclonal antibodies against ETA and ETB receptors and beta-actin. The ET receptor expression was determined by performing either densitometric analyses or scoring of immunostaining. Statistical analyses were performed to detect differences in receptor expression within and between the 2 groups. The results indicated that ET receptor expression, particularly ETB receptors, was significantly greater in the peripheral lungs of RAO-affected horses than in those of healthy horses. Clinical trials using ET receptor antagonists, particularly ETB antagonists might help in developing a therapeutic strategy to treat this career-ending disease. | 18,783,023 |
Effects of the opioid remifentanil on the arrhythmogenicity of epinephrine in halothane-anesthetized dogs. | Opioids may exert a protective effect against ventricular arrhythmias via a vagally mediated mechanism. This study evaluated the effects of the opioid remifentanil on arrhythmogenicity of epinephrine during halothane anesthesia. Eight dogs were assigned to 2 treatments in a randomized crossover design, with 1-week intervals between treatments. Anesthesia was maintained with 1.3% end-tidal halothane in oxygen and mechanical ventilation to maintain eucapnia. A constant rate infusion of remifentanil (0.72 microg/kg/min) was administered throughout the study in the experimental treatment, while control animals received physiologic saline as placebo. The arrhythmogenic dose of epinephrine (ADE), defined as 4 premature ventricular complexes (PVCs) within 15 s, was determined by administering progressively increasing infusion rates of epinephrine (2.5, 5.0, and 10 microg/kg/min), allowing 20 min intervals between each infusion rate. In both treatments, epinephrine infusions induced bradyarrhythmias and atrioventricular conduction disturbances, which were followed by escape beats and PVCs. In the remifentanil treatment, mean +/- s ADE values (11.3 +/- 4.9 microg/kg) did not differ from values observed in control animals (9.9 +/- 6.1 microg/kg). On the basis of the ADE model for assessing the arrhythmogenity of drugs during halothane anesthesia, the present study did not demonstrate a protective effect of remifentanil (0.72 microg/kg/min) against ventricular arrhythmias in dogs. | 18,783,026 |
A cluster study of gastroschisis: single center experience. | A cluster of 10 neonates admitted with a diagnosis of gastroschisis at birth to the Neonatal Intensive Care Unit (NICU) at the University of Kentucky Medical Center in the year 1996, prompted us to perform a retrospective analysis to determine environmental or genetic causes. A total of 36 neonates with gastroschisis were admitted during the period 1/1992 to 12/1996, and the maternal and patient demographics were evaluated by chart review. The mean maternal age was 21.5 years (14-35 years) of which 42% were teenagers, 66% were primiparous, 42% were smokers, 6% had a history of illicit drug use, and 72% had a history of taking prenatal vitamins. Mean birth weight was 2438g (990-3700g) with 54% being preterm with a mean gestational age of 36 wks (29-40 wks). Family history was negative and chromosomes were normal in patients in whom a karyotype was performed (25%). There was no recurring environmental or drug exposure in the study group. The mothers were from 24 different counties of Kentucky. The 36 cases were not uniformly distributed over the five-year period (chi square statistic = 46.8, degrees of freedom = 4, p < 0.0001). However, there was no evidence that the cases clustered in any 1 year (p = 0.99 for Ederer-Myers-Mantel test). This is one of the few cluster studies of babies born with gastroschisis. Many of the mothers were teenagers, primiparous, and had an increased frequency of smoking. There was no evidence of temporal or spatial clustering in the gastroschisis cases. We conclude that the cluster of gastroschisis cases in our study occurred as a matter of chance. | 18,783,039 |
[Exercise training parameters and pre- and post-test scores in the light of the most recent studies: review of the literature]. | Exercise test is the simplest, most thorough and cost-effective tool capable of providing diagnostic and prognostic evaluation of patients with known or suspected coronary heart disease. Imaging tests have been lately utilized with increasing frequency: while quite useful to define the presence and extent of ischemia, these tests do not have the prognostic insight offered by data derived from exercise parameters like effort duration, behavior of heart rate, blood pressure and occurrence of arrhythmias. The diagnostic and prognostic value of exercise test-derived data may be further enhanced by the utilization of scores. The authors have carried out a comprehensive review of the current literature on this topic. | 18,783,082 |
The susceptibility of bleached enamel to staining as measured by Quantitative Light-induced Fluorescence (QLF). | To report the use of Quantitative Light-induced Fluorescence (QLF) to determine if there was a tendency for bleached enamel to take up extrinsic stains more than unbleached enamel. Bovine teeth devoid of stains were selected, the roots removed and enamel gently pumiced. Each tooth was sectioned into two and each half randomly assigned to two groups (bleached or unbleached). Windows were created on each half using clear acid resistant varnish. 38% Hydrogen peroxide gel was applied to the exposed windows of the bleached group for 1 hour. The teeth were rinsed and dried. Bleached and unbleached halves of the same teeth were then mounted on glass rods attached to pot lids using green stick. QLF images were taken. The teeth were subjected to a cycle of artificial saliva, chlorhexidine and tea (2 minutes in each solution). This was repeated 5 times. QLF images were taken at the end of each cycle. The uptake and progression of stain was detected in all the sections by QLF. Using paired t- test (SPSS) there was no significant difference between the two groups for the change from baseline to the final stain cycle (p > 0.05), however there was variability in stain uptake within the groups as the cycles progressed. Bleaching of enamel in vitro does not appear to increase the susceptibility of enamel to extrinsic staining. | 18,783,113 |
The clinical effectiveness of a brief consultation and advisory approach compared to treatment as usual in child and adolescent mental health services. | A brief consultation and advice (BCA) approach to dealing with routine referrals was introduced into a child and adolescent mental health service (CAMHS) over an 18-month period. This is a time-limited, client-centred and solution-focused approach to dealing with common non-complex referrals. The model proposes that all families are seen for an initial 'consultation' appointment followed by a maximum of two further appointments. A randomized controlled study compared the clinical effectiveness of BCA treatment with treatment as usual (TAU) over a 6-month period. The parents of children referred to CAMHS were eligible to participate if their child was deemed 'non-complex'. Ethical approval was granted by the relevant ethics committee. Families who consented to participate in the study were randomly allocated to either the BCA or TAU group. Sixty children enrolled in the study. Both groups showed improvements on a number of variables at 3 months post treatment, but only those receiving BCA showed continued improvement at 6 months. Participants in both groups showed high levels of satisfaction with the treatment received. Participants in the TAU group expressed dissatisfaction with long waiting times and had a higher drop out rate than the BCA treatment group. During the time frame studied, the introduction of the BCA approach did not lead to a decrease in overall mean waiting time. These results and the usefulness of a BCA model are discussed. | 18,783,120 |
Influence of reduced feed ration on Lepeophtheirus salmonis infestation and inflammatory gene expression in juvenile pink salmon. | The effect of reduced feed ration on infestation levels with the sea louse Lepeophtheirus salmonis and gene expression in juvenile pink salmon Oncorhynchus gorbuscha was tested in three laboratory trials. Body weight was significantly lower among fish on the reduced ration for 27, 34, or 65 d than fish on the full ration. Neither the prevalence nor the abundance of L. salmonis differed between fish on full and reduced rations at any time in any trial. In trial 2, sea louse rejection was delayed among fish on reduced rations; however, the parasite was ultimately rejected from all fish in this trial regardless of ration. Proinflammatory gene expression in salmon exposed to L. salmonis was modulated by reduced rations. There was a reduction in the expression of interleukin-8 in pink salmon on reduced rations 7 d after exposure but not 14 d after exposure. In contrast, the 7-d expression of interleukin-1 beta (IL-1beta) was reduced in exposed pink salmon regardless of ration. By day 14, however, expression of IL-1beta was increased in association with reduced rations among exposed salmon. Similarly, the expression of tumor necrosis factor alpha (TNFalpha) was increased 14 d after exposure among salmon on a reduced ration. There was no evidence that short-duration exposure of otherwise healthy juvenile pink salmon to a reduced ration affected susceptibility to L. salmonis. The expression data do not suggest an obvious mechanism of louse rejection; rather, they indicate that a more comprehensive suite of inflammatory pathways should be surveyed to better understand the early pink salmon response to L. salmonis. | 18,783,131 |
[S-100 protein positivity in osteogenic tumours and tumour-like bone forming lesions]. | Various osteogenic tumours and bone producing tumour-like lesions of bone were examined for S-100 protein using the immunostaining methods. The positive reaction for S-100 protein of some bone cells was detected not only in osteoblastic osteosarcomas and osteoblastomas, but also in osteoplastic reactive lesions, fibrous dysplasia, Paget's disease and in the tissue of the bony callus. The positive reaction for osteocalcin in these cells showed, that they may be of osteoblastic and osteocytic lineage. The S-100 protein positive bone cells have to be differentiated from chondrocytes persisting in new-formed bone trabecullae. On the one hand S-100 protein positive osteocytes and osteoblasts may represent transient form of osteocytes histogenetically related to chondrocytes, but we were not able to prove such suggestion. Therefore, S-100 protein positivity can be caused by polyclonal character of the used antibody, that is a mixture of three antibodies, S-100 A1, A6 and anti B2. The specificity of these three components differs depending on the histogenesis of cells and their functional status. Such explanation is supported by the results of our study, because we also observed intense positivity of bone cells in the reaction with monoclonal antibody against S-100A6. In contrast, no staining of bone cells was detected with monoclonal antibodies against S-100 A1 and B2. | 18,783,135 |
[Expression of CD34 and CD117 in juxtaglomerular cell tumor of kidney]. | Juxtaglomerular cell tumor (JGCT) is an uncommon tumor of the kidney, typically found in young adults. Patients with this tumor suffer from hypertension, hyperaldosteronism and hypokalaemia. Expression of renin and intracytoplasmatic rhomboid crystals or granules in electron microscopic picture are diagnostic features of this tumor. CD34 and CD117 immunoreactivity have recently been reported as helpful markers of JGCT. | 18,783,141 |
[Nature and civilization: the decorative panels of the Teatro Amazonas foyer]. | The decorative panels in the foyer of the Teatro Amazonas, inaugurated in 1896, stand out from the rest of the building's ornamental iconography. The rubber trade brought great wealth to the capitals of Pará and Amazonas and as these cities gained national and international fame, their urban fabric and forms of sociability underwent significant changes. The article looks for parallels between the landscape representations of Amazonian nature adorning the building's foyer, the construction of the modern city, and social uses of the Teatro Amazonas, symbol of the era and emblem of the newly rich elite, who were then taking their place on the regional and national stages. The Teatro Amazonas formed the center of the era's social life and its foyer played host to veritable rituals of 'civilization', in which Brazilian and foreign guests enjoyed the fine setting of Amazon's nature as represented in the decorative wall panels. | 18,783,143 |
Development on time. | Temporal control is considered the fourth dimension in embryonic development and it sets the pace to attain the correct molecular patterning of the developing embryo. In this chapter we review one of the best-studied time dependent events in embryogenesis, which is the formation ofsomites. Somites are the basis of the future segmented framework of the vertebrate adult body and their reiterated appearance during the early stages of embryo development establishes the proper temporal and physical template from where other structures will develop and consequently shape the segmentation pattern of the embryo. Several models have been proposed over the last few decades to explain the mechanism(s) regulating somite periodicity, but no molecular evidence seemed to back up any of the postulated models. Remarkably, in 1997 the first evidence that the formation of the somites depended on an intrinsic molecular clock was at last provided through the description of oscillating gene expression in the tissue from which somites are generated. Since then, a huge amount of data has been and continues to be provided that is gradually revealing the ever more complex molecular mechanism underlying this segmentation clock. We are also beginning to learn about embryonic structures other than the somites which exhibit oscillations of gene expression suggesting they too are dependent upon a segmentation-like clock. This is in itself the clearest evidence that there is still a long way to go before we unveil the myriad of molecular mechanisms that lead to the time control of embryonic development. | 18,783,172 |
Reverse engineering models of cell cycle regulation. | From general considerations of the basic physiological properties of the cell division cycle, we deduce what the dynamical properties of the underlying molecular control system must be. Then, taking a few hints from the biochemistry of cyclin-dependent kinases (the master regulators of the eukaryotic cell cycle), we guess what molecular mechanisms must be operating to produce the desired dynamical properties of the control system. | 18,783,174 |
Molar volumes and heat capacities of electrolytes and ions in N,N-dimethylformamide. | Densities and heat capacities of various 1:1 and higher-charged electrolytes have been measured in N,N-dimethylformamide (DMF) at 25 degrees C using a series-connected flow densimeter and Picker calorimeter. Standard molar volumes V (o) and isobaric heat capacities C p (o) derived from these data were split into their ionic contributions using the tetraphenylphosphonium tetraphenylborate (TPTB) reference electrolyte assumption. The values so obtained have enabled a meaningful separation of the effects of cationic size and charge for the first time in a nonaqueous solvent. As in water, V (o)(M (n+) ) values in DMF are markedly more negative for higher-charged cations due to increasing electrostriction of the solvent. In contrast, ionic charge has a much smaller effect on C p (o)(M (n+) ) in DMF than in water. Ionic volumes in DMF show the expected dependence on size but those of small monatomic monovalent cations and anions imply a significant difference in accessibility of the electron donor and acceptor sites on the DMF molecule. Ionic heat capacities in DMF show a relatively weak dependence on ionic size that, when corrected for charge, is opposite to that in water. Both V (o)(R 4N (+)) and C p (o)(R 4N (+)) in DMF show the usual linear dependence on carbon number but differ from their values in aqueous solution due to the absence of hydrophobic interactions in DMF. | 18,783,193 |
Orientational motions of vibrational chromophores in molecules at the air/water interface with time-resolved sum frequency generation. | The first time-resolved experiments in which interfacial molecules are pumped to excited electronic states and probed by vibrational sum frequency generation (SFG) are reported. This method was used to measure the out-of-plane rotation dynamics, i.e. time dependent changes in the polar angle, of a vibrational chromophore of an interfacial molecule. The chromophore is the carbonyl group, the rotation observed is that of the -C=O bond axis, with respect to the interfacial normal, and the interfacial molecule is coumarin 314 (C314) at the air/water interface. The orientational relaxation time was found to be 220+/-20 ps, which is much faster than the orientational relaxation time of the permanent dipole moment axis of C314 at the same interface, as obtained from pump-second harmonic probe experiments. Possible effects on the rotation of the -C=O bond axis due to the carbonyl group hydrogen bonding with interfacial water are discussed. From the measured equilibrium orientation of the permanent dipole moment axis and the carbonyl axis, and knowledge of their relative orientation in the molecule, the absolute orientation of C314 at the air/water interface is obtained. | 18,783,198 |
Identification of BRAF inhibitors through in silico screening. | The BRAF protein kinase, a molecule in the RAS-RAF-MEK-ERK signaling pathway, is mutated to harbor elevated kinase activity in approximately 7% of human cancers, which makes it an important therapeutic target for inhibition. Several BRAF protein-kinase inhibitors have been developed through high-throughout screening in vitro; however, many of these compounds suffer from a lack of suitable kinase specificity and other chemotherapeutic properties. In silico screening has evolved as a powerful complimentary approach to protein-kinase inhibitor identification. Here we describe an in silico screen for BRAF inhibitors that leads to the identification of a series of purine-2,6-dione analogues with IC50 values in the single-digit micromolar range and with significant selectivity for BRAF over other representative protein kinases. The binding modes of these inhibitors to BRAF are analyzed through molecular docking to derive structure-activity relationships and to assist in the future development of more potent and more specific BRAF inhibitors. | 18,783,202 |
Development of catalytic asymmetric 1,4-addition and [3 + 2] cycloaddition reactions using chiral calcium complexes. | Catalytic asymmetric 1,4-addition and [3 + 2] cycloaddition reactions using chiral calcium species prepared from calcium isopropoxide and chiral bisoxazoline ligands have been developed. Glycine Schiff bases reacted with acrylic esters to afford 1,4-addition products, glutamic acid derivatives, in high yields with high enantioselectivities. During the investigation of the 1,4-addition reactions, we unexpectedly found that a [3 + 2] cycloaddition occurred in the reactions with crotonate derivatives, affording substituted pyrrolidine derivatives in high yields with high enantioselectivities. On the basis of this finding, we investigated asymmetric [3 + 2] cycloadditions, and it was revealed that several kinds of optically active substituted pyrrolidine derivatives containing contiguous stereogenic tertiary and quaternary carbon centers were obtained with high diastereo- and enantioselectivities. In addition, optically active pyrrolidine cores of hepatitis C virus RNA-dependent polymerase inhibitors and potential effective antiviral agents have been synthesized using this [3 + 2] cycloaddition reaction. NMR spectroscopic analysis and observation of nonamplification of enantioselectivity in nonlinear effect experiments suggested that a monomeric calcium species with an anionic ligand was formed as an active catalyst. A stepwise mechanism of the [3 + 2] cycloaddition, consisting of 1,4-addition and successive intramolecular Mannich-type reaction was suggested. Furthermore, modification of the Schiff base structure resulted in a modification of the reaction course from a [3 + 2] cycloaddition to a 1,4-addition, affording 3-substituted glutamic acid derivatives with high diasterero- and enantioselectivities. | 18,783,222 |
Stereoselective syntheses of the C(1)-C(9) fragment of amphidinolide C. | Stereoselective syntheses of the C(1)-C(9) fragments 18 and 28 of amphidinolide C have been developed. The first-generation sequence involves a diastereoselective chelate-controlled [3 + 2]-annulation reaction of 6 and 7, while the second-generation synthesis involves an intramolecular hetero-Michael cyclization of 8. | 18,783,230 |
Effects of starvation and water quality on the purging process of farmed Murray cod (Maccullochella peelii peelii). | The aim of this study was to determine the effects of starvation and water quality during the purging process on the biometric parameters, fatty acids, and flavor volatiles of Murray cod farmed in a recirculation system. Market size Murray cod, at the end of the grow-out stage, were divided into eight treatments. The treatments were either fed/starved (F or S) and kept in clean water (CW: CWF2, CWS2, CWF4, and CWS4) or fed/starved and kept in recycled water (RW: RWF2, RWS2, RWF4, and RWS4) for either 2 or 4 weeks. Fish were sampled at 0, 2, and 4 week intervals. Food deprivation was responsible for a significant (P < 0.05) weight loss compared to that of fed treatments. The same was observed for the condition factor (K), hepatosomatic index (HSI), and dress-out percentage (DP). No significant changes were, however, observed in the visceral fat index (VFI). Saturated fatty acids (SFA) were highest in RWF4 and lowest in CWS4 (P < 0.05), while monounsaturated fatty acids (MUFA) were lowest in CWF4 (P < 0.05). Starvation did not affect the flavor volatile compounds, which were mainly affected by changes in water quality. Specifically, total aldehyde (% w/w) content was significantly (P < 0.05) affected by water quality, but the time of purging was not responsible for any noteworthy differences. This study was able to separate the effects of starvation and water quality, in the purging process, on the final eating quality of farmed market size Murray cod. It is concluded that because of the inevitable weight loss during starvation, Murray cod should be fed during the purging stage but kept in clean water and deprived of food only for the time necessary to empty the gastro-intestinal tract. | 18,783,236 |
Highly efficient O-glycosylations with p-tolyl thioribosides and p-TolSOTf. | A wide variety of p-tolyl thioriboside donors are examined for O-ribosylations of primary and secondary alcohols. p-Tolylsulfenyl trifluoromethanesulfonate (p-TolSOTf) is very effective in promoting O-ribosylations with p-tolyl thioriboside; all reactions are completed within 1-15 min to provide the desired products in good yield with reliable alpha/beta selectivity. A wide range of functional groups are tolerated under these conditions. The described O-ribosylation conditions are very useful for the generation of ribosaminouridine library molecules in solution or on polymer support. | 18,783,274 |
A bifurcated pathway to thiazoles and imidazoles using a modular flow microreactor. | A scalable method for the preparation of 4,5-disubstituted thiazoles and imidazoles as distinct regioisomeric products using a modular flow microreactor has been devised. The process makes use of microfluidic reaction chips and packed immobilized-reagent columns to effect bifurcation of the reaction pathway. | 18,783,277 |
General framework for the prediction of oral drug interactions caused by CYP3A4 induction from in vivo information. | Induction of cytochrome P450 (CYP) 3A4 potentially reduces the blood concentrations of substrate drugs to less than one-tenth, which results in ineffective pharmacotherapy. Although the prediction of drug-drug interactions (DDIs) that are mediated by induction of CYP3A4 has been performed mainly on the basis of in vitro information, such methods have met with limited success in terms of their accuracy and applicability. Therefore, a realistic method for the prediction of CYP3A4-mediated inductive DDIs is of major clinical importance. The objective of the present study was to construct a robust and accurate method for the prediction of CYP3A4-mediated inductive DDIs. Such a method was developed on the basis of the principle applied for prediction of inhibitory DDIs in a previous report. A unique character of this principle is that the extent of alterations in the area under the plasma concentration-time curve (AUC) is predicted on the basis of in vivo information from minimal clinical studies without using in vitro data. The analysis is based on 42 DDI studies in humans reported in 37 published articles over the period 1983-2007. Kinetic analysis revealed that the reduction in the AUC of a substrate of CYP3A4 produced by consecutive administration of an inducer of CYP3A4 could be approximated by the equation 1/(1 + CRCYP3A4 * ICCYP3A4), where CRCYP3A4 is the ratio of the apparent contribution of CYP3A4 to the oral clearance of a substrate and ICCYP3A4 is the apparent increase in clearance of a substrate produced by induction of CYP3A4. Using this equation, the ICCYP3A4 was calculated for seven inducers (bosentan, carbamazepine, efavirenz, phenytoin, pioglitazone, rifampicin [rifampin], and St John's wort [hypericum]) on the basis of the reduction in the AUC of a coadministered standard substrate of CYP3A4, such as simvastatin, in ten DDI studies. The CRCYP3A4 was calculated for 22 substrates on the basis of the previously reported method from inhibitory DDI studies using a potent CYP3A4 inhibitor such as itraconazole or ketoconazole. The proposed method enabled the prediction of AUC reduction by CYP3A4 induction with any combination of these substrates and inducers (total 154 matches). To assess the accuracy of the prediction, the AUC reductions in 32 studies were analysed. We found that the magnitude of the deviation between the mean values of the observed and predicted AUCs of all substrate drugs was <20% of the AUCs of the respective substrate drugs before administration of the inducers. In addition, rifampicin was found to be the most potent inducer among the compounds analysed in the present study, with an ICCYP3A4 value of 7.7, followed by phenytoin and carbamazepine, with values of 4.7 and 3.0, respectively. The ICCYP3A4 values of the other CYP3A4 inducers analysed in the present study were approximately 1 or less, which suggests that the AUCs of coadministered drugs may not be reduced to less than approximately half, even if the drug is metabolized solely by CYP3A4. By using the method reported in the present study, the susceptibilities of a substrate drug of CYP3A4 to inductive DDIs can be predicted quantitatively. It was indicated that coadministration of rifampicin, phenytoin and carbamazepine may reduce plasma AUCs to less than half for a broad range of CYP3A4 substrate drugs, with CRCYP3A4 values greater than 0.13, 0.21 and 0.33, respectively. | 18,783,297 |
Capecitabine versus bolus fluorouracil plus leucovorin (folinic acid) as adjuvant chemotherapy for patients with Dukes' C colon cancer : economic evaluation in an Italian NHS setting. | In the recent X-ACT (Xeloda in Adjuvant Colon cancer Therapy) trial, oral capecitabine (Xeloda) demonstrated superior efficacy and an improved safety profile compared with infused fluorouracil + leucovorin (folinic acid) [FU+LV] in patients with Dukes' C colorectal cancer. We used the X-ACT results to determine the cost effectiveness of capecitabine compared with FU+LV from the perspective of the Italian National Health Service (NHS). Medical resource use data were collected throughout the treatment period. Unit costs for drug administration, hospitalization, emergency room visits and concomitant medications were obtained using Italian published sources. A health-state transition model was used to estimate the incremental cost-effectiveness ratio per quality-adjusted life-month (QALM) gains in the intent-to-treat population (1004 and 983 patients in the capecitabine and FU+LV arms, respectively). Costs and effectiveness were discounted at 3.5%. Costs were calculated in euros (2005 values). Administration of capecitabine required fewer clinic visits per patient than FU+LV (7.35 vs 28.0, respectively). Mean acquisition costs per patient for capecitabine were higher than for FU+LV (euro 2533 vs euro 231, respectively), but this difference was offset by the difference in mean chemotherapy administration costs per patient for FU+LV (euro 4338, compared with euro 152 for capecitabine). Mean total hospital days and medication costs for treatment-related adverse events were higher for FU+LV than for capecitabine (euro 352 vs euro 78, respectively). The cost of emergency room visits for the treatment of adverse events did not differ between the treatment groups. With respect to the lifetime horizon, compared with FU+LV, capecitabine is projected to increase QALMs by a mean 6.5 months, with overall cost savings of euro 2234 over the treatment period. These findings show that capecitabine is an economically dominant treatment in this setting. Adjuvant capecitabine for patients with Dukes' C colon cancer has the same activity in terms of outcome when compared with FU+LV but is a lower cost option from the economic perspective of the Italian NHS. | 18,783,303 |
Exemestane-induced subclinical hypothyroidism : a case report. | Several conditions and drugs induce subclinical hypothyroidism. We report the first case of subclinical hypothyroidism in a 65-year-old woman with breast cancer receiving therapy with the third-generation aromatase inhibitor exemestane 25 mg/day for 2 months. The patient presented with complaints of increasing fatigue and weakness since being commenced on exemestane and was taking no other drugs. There was no past history or family history of thyroid disease. Thyroid function tests prior to breast cancer surgery were normal. Detailed clinical examination and laboratory tests to determine the cause of the patient's increasing fatigue and weakness revealed only subclinical hypothyroidism, that is, an elevated level of thyroid-stimulating hormone (thyrotropin, TSH) only. Ultrasonography revealed a normal thyroid gland. Based on a diagnosis of symptomatic subclinical hypothyroidism, the patient was commenced on levothyroxine sodium 50 microg/day and exemestane was withdrawn. Thyroid dysfunction was restored 4 months after her admission with a significant improvement in symptoms. Levothyroxine sodium was withdrawn 6 months later and no recurrence of thyroid dysfunction occurred during a 1-year follow-up. We believe that the increasing fatigue and weakness in our patient might have been associated either with subclinical hypothyroidism or with administration of exemestane (a known adverse effect of the drug) or both. Further studies are required to investigate how exemestane influences thyroid function. | 18,783,305 |
Rapidly cleared episodes of herpes simplex virus reactivation in immunocompetent adults. | Herpes simplex virus (HSV) remains latent in nerve root ganglia of infected persons and is thought to reactivate several times yearly. Recent in situ data show the localization of HSV-specific CD8(+) T cells at the dermal epidermal junction next to peripheral sensory nerve endings, suggesting that viral reactivation may occur more frequently than previously appreciated. Twenty-five HSV-2-seropositive and 18 HSV-1-seropositive healthy adults collected anogenital and oral swabs, respectively, 4 times per day for 60 days. Swabs were assayed for HSV, using a quantitative polymerase chain reaction assay. Twenty-four percent of anogenital reactivations and 21% of oral reactivations lasted < or =6 h, and 49% of anogenital reactivations and 39% of oral reactivations lasted < or =12 h. Lesions were reported in only 3 (7%) of 44 anogenital reactivations and 1 (8%) of 13 oral reactivations lasting < or =12 h. The median HSV DNA levels at initial and last detection were 10(3.5) and 10(3.3) copies/mL, respectively, during anogenital reactivation and 10(3.7) and 10(3.0) copies/mL, respectively, during oral reactivation. This high frequency of short subclinical HSV reactivation in immunocompetent hosts strongly suggests that the peripheral mucosal immune system plays a critical role in clearing HSV reactivations. | 18,783,315 |
Phase II study of vicriviroc versus efavirenz (both with zidovudine/lamivudine) in treatment-naive subjects with HIV-1 infection. | Vicriviroc (VCV) is a CCR5 antagonist with nanomolar activity against human immunodeficiency virus (HIV) replication in vitro and in vivo. We report the results of a phase II dose-finding study of VCV plus dual nucleoside reverse-transcriptase inhibitors (NRTIs) in the treatment-naive HIV-1-infected subjects. This study was a randomized, double-blind, placebo-controlled trial that began with a 14-day comparison of 3 dosages of VCV with placebo in treatment-naive subjects infected with CCR5-using HIV-1. After 14 days of monotherapy, lamivudine/zidovudine was added to the VCV arms; subjects receiving placebo were treated with efavirenz and lamivudine/zidovudine; the planned treatment duration was 48 weeks. Ninety-two subjects enrolled. After 14 days of once-daily monotherapy, the mean viral loads decreased from baseline values by 0.07 log(10) copies/mL in the placebo arm, 0.93 log(10) copies/mL in the VCV 25 mg arm, 1.18 log(10) copies/mL in the VCV 50 mg arm, and 1.34 log(10) copies/mL in the VCV 75 mg arm (P < .001 for each VCV arm vs. the placebo arm). The combination-therapy portion of the study was stopped because of increased rates of virologic failure in the VCV 25 mg/day arm (relative hazard [RH], 21.6; 95% confidence interval [CI], 2.8-168.9) and the VCV 50 mg/day arm (RH, 11.7; 95% CI, 1.5-92.9), compared with that in the control arm. VCV administered with dual NRTIs in treatment-naive subjects with HIV-1 infection had increased rates of virologic failure, compared with efavirenz plus dual NRTIs. No treatment-limiting toxicity was observed. Study of higher doses of VCV as part of combination therapy is warranted. | 18,783,318 |
Barrett's Esophagus and esophageal adenocarcinoma. | The incidence of esophageal adenocarcinoma (EAC) has risen dramatically over the past three decades in western countries. The importance of Barrett's esophagus (BE) derives from its potential to transform to adenocarcinoma. BE is characterized by endoscopically recognized displacement of the squamocolumnar junction proximal to the gastroesophageal junction, with replacement of squamous mucosa with columnar lined mucosa. Adenocarcinomas of the esophagus appear to arise from Barrett's mucosa through progressive degrees of dysplasia, but the pathogenesis and natural history of this process are still unclear. Much of our knowledge regarding BE and the risk of EAC is based on observational and cross-sectional analyses, and recommendations regarding management have traditionally represented "expert opinion." The past few years have seen an explosion in new information and the initiation of longitudinal studies to define the risk of adenocarcinoma in BE, the identification of predictive and prognostic markers of cancer risk, sensitive and cost-effective methods of surveillance, and methods of management of dysplasia and early neoplasia including disease prevention. | 18,783,330 |
Regulation of kinin B(2) receptors by bradykinin in human lung cells. | Bradykinin is a potent mediator of inflammation that has been shown to participate in allergic airway inflammation. The biologic effects of bradykinin are mediated by binding and activation of its cognate receptor, the B(2) receptor (B(2)R). In the lung fibroblast cell line IMR-90, binding of bradykinin to B(2)R triggers down-regulation of receptor surface expression, suggesting that bradykinin-induced inflammation is transient and self-limited. Notably, subjects with chronic airway inflammation continue to respond to BK following a first challenge. B(2)Rs are expressed on many different lung cell types, including airway epithelial cells. We therefore compared IMR-90 cells with the human lung epithelial cell line BEAS2B and found that B(2)R expression in the two cell types is differently regulated by BK. Whereas BK induces down-regulation of B(2)R in IMR-90 cells, the same treatment leads to up-regulation of the receptor in BEAS2B cells. These results provide a possible explanation for the potency of bradykinin in inducing ongoing airway inflammation. | 18,783,336 |
Acid beta-glucosidase: insights from structural analysis and relevance to Gaucher disease therapy. | In mammalian cells, glucosylceramide (GlcCer), the simplest glycosphingolipid, is hydrolyzed by the lysosomal enzyme acid beta-glucosidase (GlcCerase). In the human metabolic disorder Gaucher disease, GlcCerase activity is significantly decreased owing to one of approximately 200 mutations in the GlcCerase gene. The most common therapy for Gaucher disease is enzyme replacement therapy (ERT), in which patients are given intravenous injections of recombinant human GlcCerase; the Genzyme product Cerezyme has been used clinically for more than 15 years and is administered to approximately 4000 patients worldwide. Here we review the crystal structure of Cerezyme and other recombinant forms of GlcCerase, as well as of their complexes with covalent and non-covalent inhibitors. We also discuss the stability of Cerezyme, which can be altered by modification of its N-glycan chains with possible implications for improved ERT in Gaucher disease. | 18,783,340 |
Preliminary validation of real-time PCR assays for the identification of Yersinia pestis. | Yersinia pestis (Y. pestis) is a zoonotic bacterium mainly circulating among rodents and their fleas. Transmission to humans can cause bubonic, pneumonic or septicemic plague with a high case-fatality rate. Therefore, rapid and reliable diagnostic tools are crucial. The objective of this study was to assess the inter-laboratory reproducibility of in-house developed real-time PCR assays for the identification of Y. pestis. A total of four samples of quantified Y. pestis DNA and two blank samples were sent blinded to 14 laboratories. To standardize the procedures, oligonucleotides were provided and the same instrument platform and a commercial mastermix were used. The participants were requested to report their results including cycle threshold and melting temperature values. All participating laboratories were able to perform the real-time PCR assays according to the protocols provided and identified the samples containing Y. pestis DNA correctly. Significant differences between the reference laboratory and participating laboratories were observed in cycle threshold values and melting temperatures. This, however, did not adversely affect the interpretation of results. Our real-time PCR system proved to be highly reproducible and has the potential of complementing the diagnostic tools for rapid identification of Y. pestis isolates. Further steps of validation are needed to determine diagnostic accuracy and predictive values with clinical samples. | 18,783,342 |
Examination of cyberbullying experiences among Turkish students from different school types. | The purpose of this study was to examine the nature of cyberbullying experiences among public and private school students in Turkey. One hundred eighty-three participants between the ages of 14 and 15 were recruited for the study. Participants were asked to respond to questionnaires measuring demographic information, usage frequency of Internet-mediated communication tools (IMCT), and cyberbullying experience (as a victim and as a bully). Participants who reported cyberbullying victimization were also asked how they felt and whether they sought help after such experiences. Results indicated that public school students were more likely than private school students to report being cyberbullies and cybervictims despite that private school students were more likely than public school students to report more frequent usage of IMCT. The findings of the logistic regression analyses indicated that usage frequency of IMCT was a significant predictor of cyberbullying/victimization for public school students but not for private school students. While victims from private school revealed that they did not mind the cyberbullying experience because they thought it was a joke, victims from public school reported that they felt angry when they experienced cyberbullying. Both public and private schools indicated that friends were their first choice for help. | 18,783,345 |
Repetitive transcranial magnetic stimulation over the primary motor cortex disrupts early boost but not delayed gains in performance in motor sequence learning. | In humans the consolidation of recently learned motor skills is a multi-step process. We previously showed that performance on the finger-tapping task (FTT; i.e. a sequential motor skill) temporarily improves early on, 5-30 min after practice has ended, but not 4 h later. In the absence of any further practice to the task, this early boost in performance was predictive of the performance levels eventually achieved 48 h later, suggesting its functional relevance for long-term memory consolidation [Hotermans, Peigneux, Maertens de Noordhout, Moonen, and Maquet (2006) Early boost and slow consolidation in motor skill learning. Learn. Mem., 13, 580-583]. Here, we focused on the role of the primary motor cortex (M1) in consolidation using repetitive transcranial magnetic stimulation (rTMS) applied immediately before testing at 30 min, 4 or 24 h after practice of the FTT. Immediately after learning, rTMS over M1 depressed the early boost in performance, but did not affect the delayed improvement observed 48 h later. Four and 24 h after practice, rTMS did not disrupt performance anymore. These results suggest that M1 supports performance during the early post-training phase of motor skill consolidation, but is no longer mandatory in the subsequent, delayed stages of consolidation. | 18,783,369 |
Electrical properties of interneurons found within the trigeminal motor nucleus. | The trigeminal motor nucleus contains the somata of motoneurons innervating the jaw muscles, but also those of interneurons that we have characterized morphologically and immunohistochemically previously. Here we compare their basic physiological characteristics and synaptic inputs from the peri-trigeminal area (PeriV) to those of motoneurons using whole-cell recordings made with pipettes containing biocytin in brainstem slices of rats that had a tracer injected into their masseters. Values for input resistance, spike duration and overall duration of afterhyperpolarization (AHP) were greater for interneurons than for motoneurons. Some interneurons (44%) and motoneurons (33%) had an outward rectification during depolarization. Hyperpolarization-induced inward rectification was seen predominantly in interneurons (85% vs. 31% for motoneurons). Few interneurons (15%) showed depolarization and time-dependent firing frequency accommodation, while half (52%) of the motoneurons did. Rebound excitation at the offset of hyperpolarization was more common in interneurons than in motoneurons (62% vs. 34%). Both populations received synaptic inputs from PeriV. These inputs were predominantly excitatory and were mediated by non-N-methyl-d-aspartate glutamatergic receptors. Response latencies and rise times of the evoked potentials were longer in interneurons than in motoneurons, suggesting that some of the inputs to interneurons could be polysynaptic and/or occurring at distal dendritic locations. Miniature synaptic events could be seen in about half of the neurons in both populations. These results suggest that interneurons can be clearly distinguished from motoneurons on the basis of some electrophysiological properties like the input resistance and spike and AHP durations, and the kinetics of their synaptic inputs from adjacent areas. | 18,783,374 |
Empathic neural reactivity to noxious stimuli delivered to body parts and non-corporeal objects. | Neuroimaging studies report that the experience of observing or imagining the pain of others is mapped on a set of neural structures that largely overlap those called into play during the personal experience of pain (the so-called pain matrix). Empathy for pain is a multifaceted process that may be triggered by higher-order variables (such as imagination of others' suffering) or by the direct vision of painful situations. Most functional magnetic resonance imaging studies indicate that the empathic mapping of others' pain may rely on the affective and not on the sensorimotor division of the pain matrix. However, as empathy for pain is a complex, multifarious process, it is possible that different brain regions, even beyond the classic pain matrix, may be called into action in different circumstances. By using functional magnetic resonance imaging we explored the neural activity induced by needles deeply penetrating a hand or a non-corporeal object. We found that observation of pain in others brought about activation in the middle cingulate, left premotor and left and right supramarginal regions. This pattern of neural activity indicates that the direct vision of strong painful stimuli delivered to others activates neural regions in the onlooker's brain specifically concerned with the resonant, interindividual sharing of basic sensorimotor reactivity to pain. We also found that bilateral posterior parietal and temporo-occipital regions were activated during observation of painful stimuli delivered to the body of others as well as to non-body stimuli. Therefore, our study expands current knowledge on the neural reactivity to potentially dangerous stimuli delivered in the peripersonal space. | 18,783,380 |
The clinical and economic burden of nonadherence with antihypertensive and lipid-lowering therapy in hypertensive patients. | We sought to determine lifetime costs, morbidity, and mortality associated with varying adherence to antihypertensive and 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statin) therapy in a hypertensive population. A model was constructed to compare costs and outcomes under three adherence scenarios: no treatment, ideal adherence, and real-world adherence. Simulated patients' characteristics matched those of participants in the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid-Lowering Arm and event probabilities were calculated with Framingham Heart Study risk equations. The real-world adherence scenario employed adherence data from an observational study of a US population; risk reductions at each level of adherence were based on linear extrapolations from clinical trials. Outputs included life expectancy, frequencies of primary and secondary coronary heart disease and stroke, and direct medical costs in 2006 US$. The incremental cost per life-year gained and incremental cost per event avoided were calculated comparing the three adherence scenarios. Mean life expectancy was 14.73 years (no-treatment scenario), 15.07 (real-world adherence), and 15.49 (ideal adherence). The average number of cardiovascular events per patients was 0.738 (no treatment), 0.610 (real-world adherence), and 0.441 (ideal adherence). The incremental cost of real-world adherence versus no treatment is $30,585 per life-year gained, and ideal adherence versus real-world adherence is $22,121 per life-year gained. Hypertensive patients taking antihypertensive and statin therapy at real-world adherence levels can be expected to receive approximately 50% of the potential benefit seen in clinical trials. Depending on its cost, the incremental benefits of an effective adherence intervention program could make it an attractive value. | 18,783,393 |
Virchow and his triad: a question of attribution. | Virchow's triad describes three factors that contribute to the development of venous thrombosis: hypercoagulability, stasis and endothelial injury. Yet, extensive review of the historical literature casts doubt on the existence of a triad described by Virchow in the form it is currently quoted throughout contemporary medical literature. Certainly his work involved extensive study of venous thrombosis and pulmonary embolism, with these two terms being coined by Virchow, but a triad of factors relating to the development of venous thrombosis is elusive. Interestingly, Virchow only began to be routinely credited with this triad one hundred years after publication of his work on venous thrombosis. This acknowledgement coincided with the accumulation of experimental evidence for the role these factors play in thrombogenesis. Controversial as the origins of Virchow's triad might be, it is apt given his substantial contribution to our knowledge of venous thromboembolism, and the fact that the triad continues to be clinically relevant today that a triad pertaining to Virchow should remain. | 18,783,400 |
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