title stringlengths 0 1.13k | abstract stringlengths 1 15.7k | PMID int64 22 36.5M |
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Arachidonic acid cytochrome P450 epoxygenase pathway. | Cytochrome P450 (CYP) epoxygenases convert arachidonic acid to four epoxyeicosatrienoic acid (EET) regioisomers, 5,6-, 8,9-, 11,12-, and 14,15-EET, that function as autacrine and paracrine mediators. EETs produce vascular relaxation by activating smooth muscle large-conductance Ca2+-activated K+ channels (BKCa). In addition, they have anti-inflammatory effects on blood vessels and in the kidney, promote angiogenesis, and protect ischemic myocardium and brain. CYP epoxygenases also convert eicosapentaenoic acid to vasoactive epoxy-derivatives, and endocannabinoids containing 11,12- and 14,15-EET are formed. Many EET actions appear to be initiated by EET binding to a membrane receptor that activates ion channels and intracellular signal transduction pathways. However, EETs also are taken up by cells, are incorporated into phospholipids, and bind to cytosolic proteins and nuclear receptors, suggesting that some functions may occur through direct interaction of the EET with intracellular effector systems. Soluble epoxide hydrolase (sEH) converts EETs to dihydroxyeicosatrienoic acids (DHETs). Because this attenuates many of the functional effects of EETs, sEH inhibition is being evaluated as a mechanism for increasing and prolonging the beneficial actions of EETs. | 18,952,572 |
Regression of subependymal giant cell astrocytoma with rapamycin in tuberous sclerosis complex. | The authors present a 21-year-old woman who has been receiving rapamycin for 5 months for bilateral subependymal giant cell astrocytomas. The patient was started at a dose of 0.2 mg/kg/day. Levels were maintained between 11 and 13 ng/mL. Magnetic resonance imaging of the brain 2(1/2) months after initiating rapamycin demonstrated a decrease in size of both astrocytomas (11 to 7.5 mm on the right and 8 to 5 mm on the left). Further studies are needed with prolonged observation to confirm these findings, determine the length of necessary treatment, and evaluate recurrence risk after discontinuation of rapamycin. | 18,952,591 |
S6K directly phosphorylates IRS-1 on Ser-270 to promote insulin resistance in response to TNF-(alpha) signaling through IKK2. | S6K1 (p70S6K) is a serine kinase downstream from Akt in the insulin signaling pathway that is involved in negative feedback regulation of insulin action. S6K1 is also activated by TNF-alpha, a pro-inflammatory cytokine. However, its role remains to be characterized. In the current study, we elucidated a mechanism for S6K1 to mediate TNF-alpha-induced insulin resistance in adipocytes and hepatocytes. S6K1 was phosphorylated at Thr-389 in response to TNF-alpha. This led to phosphorylation of IRS-1 by S6K1 at multiple serine residues including Ser-270, Ser-307, Ser-636, and Ser-1101 in human IRS-1 (Ser-265, Ser-302, Ser-632, and Ser-1097, in rodent IRS-1). Direct phosphorylation of these sites by S6K1 was observed in an in vitro kinase assay using purified IRS-1 and S6K1. Phosphorylation of all these serines was increased in the adipose tissue of obese mice. RNAi knockdown demonstrated an important role for S6K1 in mediating TNF-alpha-induced IRS-1 inhibition that led to impaired insulin-stimulated glucose uptake in adipocytes. A point mutant of IRS-1 (S270A) impaired association of IRS-1 with S6K1 resulting in diminished phosphorylation of IRS-1 at three other S6K1 phosphorylation sites (Ser-307, Ser-636, and Ser-1101). Expression of a dominant negative S6K1 mutant prevented TNF-induced Ser-270 phosphorylation and IRS-1 protein degradation. Moreover, in IKK2 (but not IKK1)-null cells, TNF-alpha treatment did not result in Thr-389 phosphorylation of S6K1. We present a new mechanism for TNF-alpha to induce insulin resistance that involves activation of S6K by an IKK2-dependent pathway. S6K directly phosphorylates IRS-1 on multiple serine residues to inhibit insulin signaling. | 18,952,604 |
Smad7 is required for the development and function of the heart. | Transforming growth factor-beta (TGF-beta) family members, including TGF-betas, activins, and bone morphogenetic proteins, exert diverse biological activities in cell proliferation, differentiation, apoptosis, embryonic development, and many other processes. These effects are largely mediated by Smad proteins. Smad7 is a negative regulator for the signaling of TGF-beta family members. Dysregulation of Smad7 is associated with pathogenesis of a variety of human diseases. However, the in vivo physiological roles of Smad7 have not been elucidated due to the lack of a mouse model with significant loss of Smad7 function. Here we report generation and initial characterization of Smad7 mutant mice with targeted deletion of the indispensable MH2 domain. The majority of Smad7 mutant mice died in utero due to multiple defects in cardiovascular development, including ventricular septal defect and non-compaction, as well as outflow tract malformation. The surviving adult Smad7 mutant mice had impaired cardiac functions and severe arrhythmia. Further analyses suggest that Smad2/3 phosphorylation was elevated in atrioventricular cushion in the heart of Smad7 mutant mice, accompanied by increased apoptosis in this region. Taken together, these observations pinpoint an important role of Smad7 in the development and function of the mouse heart in vivo. | 18,952,608 |
Biliary penetration and pharmacodynamic exposure of linezolid in liver transplant patients. | The aim of the study was to assess the biliary penetration of linezolid and the probabilities of attaining optimal pharmacodynamic exposure against vancomycin-resistant enterococci (VRE) in the bile of liver transplant (LTx) patients who received linezolid for the treatment of multidrug-resistant Gram-positive hospital infections. After at least 2 days of standard 600 mg twice-daily therapy, simultaneous bile and blood samples for linezolid assay were collected from six LTx patients just prior to drug administration to determine trough concentrations (Cmin) at steady-state in both sites. Linezolid concentrations in plasma and in bile were analysed by means of HPLC. Biliary penetration of linezolid was calculated as the ratio between Cmin in bile and in plasma. Optimal theoretical pharmacodynamic exposure of linezolid against VRE in bile was defined as biliary Cmin>MIC90. C(min) of linezolid in bile achieved very high values at steady-state, which were significantly higher than in plasma (median of 21.77 versus 8.08 mg/L, P=0.021). The very high biliary penetration of linezolid (median value of 1.93; range 1.31-4.83) enabled achievement of optimal theoretical pharmacodynamic exposure against VRE in bile (Cmin>2 mg/L) on all of the occasions. These preliminary data suggest a potential role for linezolid in the treatment of cholangitis due to VRE in LTx patients. Obviously, further confirmatory data assessing also the AUC/MIC ratio of linezolid in bile are needed. | 18,952,619 |
Adipocytokines and risk of stroke in older people: a nested case-control study. | Inflammation may play an important role in atherothrombosis and in promoting cerebral damage after stroke. We hypothesized that plasma adipocytokine concentrations would be associated with risk of stroke in older people. Nested case-control study from the Prospective Study of Pravastatin in the Elderly (PROSPER). Subjects were aged 70-82 years and followed up for a mean of 3.2 years: 266 incident stroke cases (179 confirmed as ischaemic) were compared with 532 controls matched for age, gender and treatment allocation (pravastatin or placebo). Adipocytokines [adiponectin, interleukin- (IL-)18 and tumour necrosis factor (TNF)alpha] were measured on stored baseline plasma samples. Elevated plasma adiponectin was associated with lower risk of ischaemic stroke on univariate analysis: odds ratio (OR) 0.78 per 1 SD increase (95% CI 0.62-0.97). There were no associations of IL-18 or TNFalpha with risk for ischaemic or total strokes. In multivariate models the independent predictors of ischaemic stroke were prior cerebrovascular accident (OR 2.68, 95% CI 1.60-4.50), any alcohol use (1.98, 1.33-2.94), triglycerides (1.40, 1.11-1.77), Barthel score (0.75, 0.58-0.96) and known diabetes (1.72, 1.04-2.83); adiponectin, IL-18 and TNFalpha did not contribute. A similar pattern of risk was seen for total stroke. Reduced adiponectin may have a modest role in the aetiology of ischaemic stroke in older people, however IL-18 and TNFalpha are unlikely to play any important part. These adipocytokines do not have clinical predictive utility; history of prior cerebrovascular accident, known diabetes mellitus, prior disability and higher alcohol intake explain much of the stroke risk. | 18,952,622 |
Coagulase-negative staphylococcal prosthetic valve endocarditis--a contemporary update based on the International Collaboration on Endocarditis: prospective cohort study. | To describe the contemporary features of coagulase-negative staphylococcal (CoNS) prosthetic valve endocarditis (PVE). Observational study of prospectively collected data from a multinational cohort of patients with infective endocarditis. Patients with CoNS PVE were compared to patients with Staphylococcus aureus and viridans streptococcal (VGS) PVE. The International Collaboration on Endocarditis-Prospective Cohort Study (ICE-PCS) is a contemporary cohort of patients with infective endocarditis from 61 centres in 28 countries. Adult patients in the ICE-PCS with definite PVE and no history of injecting drug use from June 2000 to August 2005 were included. None. Heart failure, intracardiac abscess, death. CoNS caused 16% (n = 86) of 537 cases of definite non-injecting drug use-associated PVE. Nearly one-half (n = 33/69, 48%) of patients with CoNS PVE presented between 60 days and 365 days of valve implantation. The rate of intracardiac abscess was significantly higher in patients with CoNS PVE (38%) than in patients with either S aureus (23%, p = 0.03) or VGS (20%, p = 0.05) PVE. The rate of abscess was particularly high in early (50%) and intermediate (52%) CoNS PVE. In-hospital mortality was 24% for CoNS PVE, 36% for S aureus PVE (p = 0.09) and 9.1% for VGS PVE (p = 0.08). Meticillin resistance was present in 68% of CoNS strains. Nearly one-half of CoNS PVE cases occur between 60 days and 365 days of prosthetic valve implantation. CoNS PVE is associated with a high rate of meticillin resistance and significant valvular complications. | 18,952,633 |
Allele *2 of the HS1,2A enhancer of the Ig regulatory region associates with rheumatoid arthritis. | To investigate the role of the HS1,2 enhancer polymorphisms as a new candidate marker for rheumatoid arthritis (RA) and to define the possible association with autoantibody positivity and clinical outcome. Genomic DNA was obtained from two cohorts of patients with RA (100 with early RA (ERA) and 114 with longstanding RA (LSRA)) and from 248 gender-matched controls from the same geographical area. Clinical and immunological characteristics were recorded for all the patients. The percentage of the 2/2 genotype was higher in patients with ERA (27.0%), and in patients with LSRA (34.2%), than in controls (14.9%) (ERA: OR = 2.11 (95% CI 1.20 to 3.70) vs controls; LSRA: OR = 2.96 (95% CI 1.76 to 5.00) vs controls). A lower representation of allele *3 was present in patients with ERA (2.0%) than in controls (6.0%; OR = 0.32 (95% CI 0.11 to 0.91)). No significant associations were found between polymorphisms and autoantibodies positivity. The HS1,2A allele *2 associates with early and longstanding RA. | 18,952,640 |
The influence of socioeconomic status on the reporting of regional and widespread musculoskeletal pain: results from the 1958 British Birth Cohort Study. | This study aims to determine to what extent the reporting of pain in adulthood varies by adult socioeconomic status, whether there are additional long-term effects of socioeconomic status in childhood and whether any such relationships are mediated through adult psychological ill health. A prospective cohort study (the 1958 British Birth Cohort Study) was conducted. Participants were recruited, at birth, in 1958 and were followed-up throughout childhood and adulthood, most recently at 45 years when information was collected on regional and widespread pain, and various potential mediating factors. The prevalence of shoulder, forearm, low back, knee and chronic widespread pain at 45 years generally increased with lower adult social class. Persons in the lowest social class (compared to the highest) experienced nearly a threefold increase in the risk of chronic widespread pain: relative risk: 2.9 (95% CI 1.8 to 4.6). The strength of association varied between 1.5 and 2.0 for regional pains. Childhood social class also demonstrated a relationship with most regional pains and chronic widespread pain. With the exception of forearm pain, the magnitude of effect of childhood social status on reporting of pain in adulthood was less than that of adult social status. On multivariable analysis these relationships were partly explained by poor adult mental health, psychological distress, adverse life events and lifestyle factors. These results emphasise the importance and potential impact of measures to reduce social adversity, which will have the effect of improving musculoskeletal health in adult life and other major causes of morbidity. | 18,952,642 |
Vascular endothelial growth factor expression by hyalocytes and its regulation by glucocorticoid. | Tumour necrosis factor-alpha (TNF-alpha) is one of the major inflammatory cytokines involved in the pathogenesis of various vitreoretinal diseases. The authors investigated the effect of hypoxia, TNF-alpha and dexamethasone on vascular endothelial growth factor (VEGF) expression by cultured hyalocytes. Hyalocytes were isolated from bovine vitreous. Hypoxic and TNF-alpha-dependent effects on cultured hyalocytes were investigated using several assays to determine VEGF protein expression, hypoxia-inducible factor (HIF)-1alpha protein levels, HIF-1alpha-DNA-binding ability and VEGF mRNA stability. The effects of dexamethasone on VEGF expression and its intracellular signalling under hypoxic or TNF-alpha stimulated conditions were also examined. Hypoxic conditions and TNF-alpha stimulation induce VEGF expression in hyalocytes. These stimuli also stabilise HIF-1alpha protein and increase its DNA-binding ability. Dexamethasone significantly inhibits both HIF-1alpha protein levels and HIF-1alpha-DNA-binding activity, and also decreases the hypoxic- and TNF-alpha -dependent induction of VEGF expression in hyalocyte. However, dexamethasone has no significant effect on the stability of VEGF mRNA. Hyalocytes may be involved in various vitreoretinal diseases by increasing HIF-1alpha protein stability and HIF-1alpha-DNA binding, and thus increasing VEGF production under pathological conditions. Dexamethasone seems to be capable of inhibiting hypoxic and TNF-alpha dependent VEGF production, presumably via its inhibitory effects on HIF-1alpha protein levels and its DNA-binding activity. | 18,952,656 |
Harvesting keratolimbal allografts from corneoscleral buttons: a novel application of cyanoacrylate adhesive. | To describe an alternative and novel technique using cyanoacrylate glue to achieve successful limbal tissue dissection, from an organ culture media stored corneoscleral button, without an artificial anterior chamber. A donor corneoscleral button (leftover from penetrating keratoplasty) was divided into two equal semicircular halves. A thick layer of tissue adhesive (N-butyl-2-cyanoacrylate) was spread on a sterile rubber block (the under surface of the donor punch). One half of the donor corneoscleral rim was placed epithelial side up on the adhesive and allowed to attach firmly to the block. This composite provided stability to the donor rim allowing lamellar dissection of the limbal tissue to be performed without damaging the limbal epithelium. Regular, partial-thickness limbal tissue was obtained. There was no histological evidence of glue or cellular toxicity of the harvested limbal stem cells. This harvested tissue had been grafted successfully in patients with limbal stem cell deficiency also undergoing keratoplasty. Tissue adhesive can be a simple, effective and useful tool in the dissection and harvesting of corneal limbal stem cell allografts from corneoscleral buttons stored in organ culture media. | 18,952,657 |
Combined 5-HT1A and 5-HT1B receptor agonists for the treatment of L-DOPA-induced dyskinesia. | Appearance of dyskinesia is a common problem of long-term l-DOPA treatment in Parkinson's disease patients and represents a major limitation for the pharmacological management of the motor symptoms in advanced disease stages. We have recently demonstrated that dopamine released from serotonin neurons is responsible for l-DOPA-induced dyskinesia in 6-hydroxydopamine (6-OHDA)-lesioned rats, raising the possibility that blockade of serotonin neuron activity by combination of 5-HT(1A) and 5-HT(1B) agonists could reduce l-DOPA-induced dyskinesia. In the present study, we have investigated the efficacy of 5-HT(1A) and 5-HT(1B) agonists to counteract l-DOPA-induced dyskinesia in 1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine (MPTP)-treated macaques, the gold standard model of Parkinson's disease. In addition, we have studied the ability of this treatment to prevent development of l-DOPA-induced dyskinesia in 6-OHDA-lesioned rats. The results demonstrate the existence of a potent synergistic effect between 5-HT(1A) and 5-HT(1B) agonists in their ability to dampen l-DOPA-induced dyskinesia in the MPTP-treated macaques. Sub-threshold doses of the drugs, which individually produced no effect, were able to reduce the abnormal involuntary movements by up to 80% when administered in combination, without affecting the anti-parkinsonian properties of l-DOPA. Furthermore, chronic administration of low doses of the 5-HT(1) agonists in combination was able to prevent development of dyskinesia, and reduce the up-regulation of FosB after daily treatment with l-DOPA in the rat 6-OHDA model. Our results support the importance of a clinical investigation of the effect of 5-HT(1A) and 5-HT(1B) agonists, particularly in combination, in dyskinetic l-DOPA-treated Parkinson's disease patients. | 18,952,677 |
Impact of reporting rules of biopsy Gleason score for prostate cancer. | To investigate how the biopsy Gleason score (GS) and the clinical risk classification have been changed by the reporting rules. 565 prostate biopsy specimens were reassessed. Each Gleason pattern, 1 to 5, was interpreted according to the modified Gleason grading system proposed by the International Society of Urological Pathology. The GS for each case was assigned by the previous reporting rules in the institute (OLD rules), applying the overall-scoring, and ignoring a pattern occupying less than 5% and the tertiary pattern. The GS was also assigned according to the NEW rules, applying the highest-core scoring and reflecting a pattern occupying less than 5% and the tertiary pattern. GS upgrading by the NEW rules was observed in 195 (35%) patients. Of these, 179 (92%) patients were upgraded only by applying the highest-core scoring. Of 198 patients with GS 6 by the OLD rules, 22 (11%) were upgraded to GS 3+4. Of 172 patients with GS 3+4 by the OLD rules, 59 (34%) and 28 (16%), respectively, were upgraded to GS 4+3 and > or =8. Of 108 patients with GS 4+3 by the OLD rules, 63 (58%) were upgraded to GS > or =8. As a result, the distribution of D'Amico's clinical risk classification (low, intermediate and high risk) was changed from 26%, 43% and 31% to 23%, 35% and 41%, respectively. Clinicians should be aware that the reporting rules, especially the highest-core scoring, contribute to a significant upward shift of the biopsy GS and risk classification. | 18,952,690 |
Perivascular adipose tissue-derived visfatin is a vascular smooth muscle cell growth factor: role of nicotinamide mononucleotide. | Perivascular adipose tissue (PVAT) inhibits vascular smooth muscle cell (VSMC) contraction and stimulates VSMC proliferation by releasing protein factors. The present study was to determine whether visfatin is involved in these paracrine actions of PVAT, and if so, to explore the underlying mechanisms. Visfatin was preferentially expressed in Sprague-Dawley rat and monkey aortic PVAT, compared with subcutaneous and visceral adipose tissues. The PVAT-derived visfatin was found to be a VSMC growth factor rather than a VSMC relaxing factor, which was proved by visfatin-specific antibody/inhibitor and direct observation of recombinant visfatin. Exogenous visfatin stimulated VSMC proliferation in a dose- and time-dependent manner via extracellular signal-regulated kinase (ERK 1/2) and p38 signalling pathways. This proliferative effect was further confirmed by enhancement of DNA synthesis and upregulation of proliferative marker Ki-67. Visfatin had no anti-apoptotic effect on normal cultured VSMCs, and it exerted an anti-apoptotic effect only during cell apoptosis induced by H2O2, excluding a role of anti-apoptosis in the visfatin-induced VSMC proliferation. Insulin receptor knockdown did not show any action on the visfatin effect. However, visfatin acted as a nicotinamide phosphoribosyltransferase to biosynthesize nicotinamide mononucleotide (NMN), which mediated proliferative signalling pathways and cell proliferation similar to the visfatin effect. Visfatin stimulates VSMC proliferation via NMN-mediated ERK1/2 and p38 signalling. The present study provides a molecular link of visfatin to the paracrine action of PVAT, demonstrates a novel function of visfatin in promoting VSMC proliferation, and reveals NMN as a novel signalling molecule that triggers the proliferative process. | 18,952,695 |
Serum complexes of insulin-like growth factor-1 modulate skeletal integrity and carbohydrate metabolism. | Serum insulin-like growth factor (IGF) -1 is secreted mainly by the liver and circulates bound to IGF-binding proteins (IGFBPs), either as binary complexes or ternary complexes with IGFBP-3 or IGFBP-5 and an acid-labile subunit (ALS). The purpose of this study was to genetically dissect the role of IGF-1 circulatory complexes in somatic growth, skeletal integrity, and metabolism. Phenotypic comparisons of controls and four mouse lines with genetic IGF-1 deficits-liver-specific IGF-1 deficiency (LID), ALS knockout (ALSKO), IGFBP-3 (BP3) knockout, and a triply deficient LID/ALSKO/BP3 line-produced several novel findings. 1) All deficient strains had decreased serum IGF-1 levels, but this neither predicted growth potential or skeletal integrity nor defined growth hormone secretion or metabolic abnormalities. 2) IGF-1 deficiency affected development of both cortical and trabecular bone differently, effects apparently dependent on the presence of different circulating IGF-1 complexes. 3) IGFBP-3 deficiency resulted in increased linear growth. In summary, each IGF-1 complex constituent appears to play a distinct role in determining skeletal phenotype, with different effects on cortical and trabecular bone compartments. | 18,952,711 |
Irditoxin, a novel covalently linked heterodimeric three-finger toxin with high taxon-specific neurotoxicity. | A novel heterodimeric three-finger neurotoxin, irditoxin, was isolated from venom of the brown treesnake Boiga irregularis (Colubridae). Irditoxin subunit amino acid sequences were determined by Edman degradation and cDNA sequencing. The crystal structure revealed two subunits with a three-finger protein fold, typical for "nonconventional" toxins such as denmotoxin, bucandin, and candoxin. This is the first colubrid three-finger toxin dimer, covalently connected via an interchain disulfide bond. Irditoxin showed taxon-specific lethality toward birds and lizards and was nontoxic toward mice. It produced a potent neuromuscular blockade at the avian neuromuscular junction (IC(50)=10 nM), comparable to alpha-bungarotoxin, but was three orders of magnitude less effective at the mammalian neuromuscular junction. Covalently linked heterodimeric three-finger toxins found in colubrid venoms constitute a new class of venom peptides, which may be a useful source of new neurobiology probes and therapeutic leads. | 18,952,712 |
Cow/calf preweaning efficiency of Nellore and Bos taurus x Bos indicus crosses. | The objectives of this study were to determine if percentage Bos taurus (0 or 50%) of the cow had an effect on ME requirements and milk production, and to compare cow/calf efficiency among 3 mating systems. Metabolizable energy requirements were estimated during a feeding trial that encompassed a gestation and lactation feeding trial for each of 2 groups of cows. Cows were 0 or 50% Bos taurus (100 or 50% Nellore) breed type: Nellore cows (NL; n = 10) mated to Nellore bulls, NL cows (n = 9) mated to Angus bulls, Angus x Nellore (ANL; n = 10) and Simmental x Nellore (SNL; n = 10) cows mated to Canchim (5/8 Charolais 3/8 Zebu) bulls. Cows were individually fed a total mixed diet that contained 11.3% CP and 2.23 Mcal of ME/kg of DM. At 14-d intervals, cows and calves were weighed and the amount of DM was adjusted to keep shrunk BW and BCS of cows constant. Beginning at 38 d of age, corn silage was available to calves ad libitum. Milk production at 42, 98, 126, and 180 d postpartum was measured using the weigh-suckle-weigh technique. At 190 d of age, calves were slaughtered and body composition estimated using 9-10-11th-rib section to obtain energy deposition. Regression of BW change on daily ME intake (MEI) was used to estimate MEI at zero BW change. Increase in percentage Bos taurus had a significant effect on daily ME requirements (Mcal/d) during pregnancy (P < 0.01) and lactation (P < 0.01). Percentage Bos taurus had a positive linear effect on maintenance requirements of pregnant (P = 0.07) and lactating (P < 0.01) cows; during pregnancy, the ME requirements were 91 and 86% of those in lactation (131 +/- 3.5 vs. 145 +/- 3.4 Mcal x kg(-0.75) x d(-1)) for the 0 and 50% B. taurus groups, respectively. The 50% B. taurus cows, ANL and SNL, suckling crossbred calves had greater total MEI (4,319 +/- 61 Mcal; P < 0.01) than 0% B. taurus cows suckling NL (3,484 +/- 86 Mcal) or ANL calves (3,600 +/- 91 Mcal). The 0% B. taurus cows suckling ANL calves were more efficient (45.3 +/- 1.6 g/Mcal; P = 0.03) than straightbred NL (35.1 +/- 1.5 g/Mcal) and ANL or SNL pairs (41.0 +/- 1.0 g/Mcal). Under the conditions of this study, crossbreeding improved cow/ calf efficiency and showed an advantage for cows that have lower energy requirements. | 18,952,743 |
Pain in patients living in Norwegian nursing homes. | The aims of this study were to describe the pain and use of pain medication in nursing home patients and examine which variables that were associated with pain. Inpatients (n = 307) older than 64 years from nursing homes were included. Pain was measured with a 4-point verbal rating scale in the self-reported group (SRG) and Doloplus-2 in the proxy-rated group (PRG). The mean age was 86 years (SD, 7), and more than two-thirds were female. A total of 128 (60%) patients were able to self-report their pain. Approximately 50% of the SRG reported 'pain now', and of these, nearly 50% reported moderate or severe pain intensity. Better cognitive function was associated with higher pain and receiving more potent pain medication in the SRG. The pain prevalence in the PRG was higher than in the SRG (67.5% vs 51%), but no variable was associated with proxy-rated pain. Nearly 30% in the SRG and 40% in the PRG did not receive pain medication in spite of pain. Pain is still a huge problem in the nursing homes, and more research is needed on pain management in nursing home residents. | 18,952,745 |
Reflecting the scope and work of palliative care teams today: an action research project to modernise a national minimum data set. | The Minimum Data Set (MDS) for UK specialist palliative care services was developed in 1995 to provide annual data on palliative care services. Data collected is used for local and national purposes including service management, monitoring and audit, the commissioning of services and the development of national policy. The emergence of Payment by Results and HealthCare Resource Groups, which will have an impact on the funding processes, together with identified limitations of the current MDS resulted in a project to revise the MDS. An action research approach was used for the project and had distinctive phases including modifying the MDS, a pilot phase and an expert panel consultation. Modifications to all the sections of the MDS and changes to terminology were made. The action research approach enabled revisions made based upon a national consensus and met the changing provision of specialist palliative care services for the UK. | 18,952,752 |
Airway epithelial-derived factor relaxes pulmonary vascular smooth muscle. | The factors controlling the pulmonary vascular resistance under physiological conditions are poorly understood. We have previously reported on an apparent cross talk between the airway and adjacent pulmonary arterial bed where a factor likely derived from the bronchial epithelial cells reduced the magnitude of agonist-stimulated force in the vascular smooth muscle. The main purpose of this investigation was to evaluate whether bronchial epithelial cells release a pulmonary arterial smooth muscle relaxant factor. Conditioned media from SPOC-1 or BEAS-2B, a rat- and a human-derived bronchial epithelial cell line, respectively, were utilized. This media significantly relaxed precontracted adult but not fetal pulmonary arterial muscle in an oxygen tension-dependent manner. This response was mediated via soluble guanylate cyclase, involving AKT/PI3-kinase and neuronal nitric oxide synthase. Airway epithelial cell-conditioned media increased AKT phosphorylation in pulmonary smooth muscle cells (SMC) and reduced intracellular calcium change following ATP stimulation to a significantly greater extent than observed for bronchial SMC. The present data strongly support the evidence for bronchial epithelial cells releasing a stable and soluble factor capable of inducing pulmonary arterial SMC relaxation. We speculate that under physiological conditions, the maintenance of a low pulmonary vascular resistance, postnatally, is in part modulated by the airway epithelium. | 18,952,757 |
The pathway of oligomeric DNA melting investigated by molecular dynamics simulations. | Details of the reaction coordinate for DNA melting are fundamental to much of biology and biotechnology. Recently, it has been shown experimentally that there are at least three states involved. To clarify the reaction mechanism of the melting transition of DNA, we perform 100-ns molecular dynamics simulations of a homo-oligomeric, 12-basepair DNA duplex, d(A(12)).d(T(12)), with explicit salt water at 400 K. Analysis of the trajectory reveals the various biochemically important processes that occur on different timescales. Peeling (including fraying from the ends), searching for Watson-Crick complements, and dissociation are recognizable processes. However, we find that basepair searching for Watson-Crick complements along a strand is not mechanistically tied to or directly accessible from the dissociation steps of strand melting. A three-step melting mechanism is proposed where the untwisting of the duplex is determined to be the major component of the reaction coordinate at the barrier. Though the observations are limited to the characteristics of the system being studied, they provide important insight into the mechanism of melting of other more biologically relevant forms of DNA, which will certainly differ in details from those here. | 18,952,784 |
A quantitative model of cortical spreading depression due to purinergic and gap-junction transmission in astrocyte networks. | Spreading depression (SD), a propagating wave of electrical silence in the cortex and archicortex, involves depolarization of neurons and astrocytes for approximately 1 min, due principally to a large increase in extracellular K+. SD is accompanied by large increases in extracellular ATP and is blocked by glutamate N-methyl-D-aspartate receptor antagonists. As a principal means of transmission between astrocytes is through their release of ATP, we have investigated if a model in which SD is driven by the effects of astrocyte waves of ATP interacting with waves of glutamate release from neurons and astrocytes can give a quantitative account of experimental observations on SD. We show that the characteristics of SD and the accompanying extracellular ionic changes can be accommodated by such a model-whether astrocyte transmission is principally through the release of ATP, as in archicortex (hippocampus) and spinal cord, or via gap junctions, as in the neocortex. Furthermore, these models give quantitative accounts of the effects on the characteristics of SD of agents toxic for astrocytes and of gap-junction blockers. Finally, an additional series of critical tests of the model is suggested. | 18,952,785 |
The small RNA GcvB regulates sstT mRNA expression in Escherichia coli. | In Escherichia coli, the gcvB gene encodes a nontranslated RNA (referred to as GcvB) that regulates OppA and DppA, two periplasmic binding proteins for the oligopeptide and dipeptide transport systems. An additional regulatory target of GcvB, sstT, was found by microarray analysis of RNA isolated from a wild-type strain and a gcvB deletion strain grown to mid-log phase in Luria-Bertani broth. The SstT protein functions to transport L-serine and L-threonine by sodium transport into the cell. Reverse transcription-PCR and translational fusions confirmed that GcvB negatively regulates sstT mRNA levels in cells grown in Luria-Bertani broth. A series of transcriptional fusions identified a region of sstT mRNA upstream of the ribosome binding site needed for negative regulation by GcvB. Analysis of the GcvB RNA identified a sequence complementary to this region of the sstT mRNA. The region of GcvB complementary to sstT mRNA is the same region of GcvB identified to regulate the dppA and oppA mRNAs. Mutations predicted to disrupt base pairing between sstT mRNA and GcvB were made in gcvB, which resulted in the identification of a small region of GcvB necessary for negative regulation of sstT-lacZ. Additionally, the RNA chaperone protein Hfq was found to be necessary for GcvB to negatively regulate sstT-lacZ in Luria-Bertani broth and glucose minimal medium supplemented with glycine. The sstT mRNA is the first target found to be regulated by GcvB in glucose minimal medium supplemented with glycine. | 18,952,787 |
Geobacter sulfurreducens contains separate C- and A-adding tRNA nucleotidyltransferases and a poly(A) polymerase. | The genome of Geobacter sulfurreducens contains three genes whose sequences are quite similar to sequences encoding known members of an RNA nucleotidyltransferase superfamily that includes tRNA nucleotidyltransferases and poly(A) polymerases. Reverse transcription-PCR using G. sulfurreducens total RNA demonstrated that the genes encoding these three proteins are transcribed. These genes, encoding proteins designated NTSFI, NTSFII, and NTSFIII, were cloned and overexpressed in Escherichia coli. The corresponding enzymes were purified and assayed biochemically, resulting in identification of NTSFI as a poly(A) polymerase, NTSFII as a C-adding tRNA nucleotidyltransferase, and NTSFIII as an A-adding tRNA nucleotidyltransferase. Analysis of G. sulfurreducens rRNAs and mRNAs revealed the presence of heteropolymeric RNA 3' tails. This is the first characterization of a bacterial system that expresses separate C- and A-adding tRNA nucleotidyltransferases and a poly(A) polymerase. | 18,952,795 |
The beta-catenin/TCF4 pathway modifies alternative splicing through modulation of SRp20 expression. | Gene expression programs can become activated in response to extracellular signals. One evolutionarily conserved example is binding of Wnt glycoproteins to their receptor, which triggers a signal transduction cascade that stabilizes cytoplasmic beta-catenin protein, allowing it to translocate into the nucleus. There, beta-catenin binds to TCF/Lef family transcription factors and promotes the expression of target genes. Mutations in either the beta-catenin gene itself or its partner protein APC are responsible for the oncogenic activation of this pathway in colorectal tumors. Here we report the splicing factor SRp20 as a novel target gene of beta-catenin/TCF4 signaling. Transfection of activated beta-catenin mutants into colorectal cells increased expression of endogenous SRp20 transcript and protein and also stimulated a luciferase reporter construct containing the SRp20 gene promoter. In contrast, inhibition of endogenous beta-catenin signaling by a dominant-negative TCF4 construct down-regulated both luciferase reporter and SRp20 expression. We further demonstrate that the beta-catenin/TCF4-mediated increase in SRp20 protein levels is sufficient to modulate alternative splicing decisions in the cells. In particular, we observed a change in the alternative splicing pattern in a control minigene reporter as well as in the endogenous SRp20-regulated CD44 cell adhesion protein. These results demonstrate that the beta-catenin/TCF4 pathway not only stimulates gene transcription, but also promotes the generation of transcript variants through alternative splicing. Our data support the recent notion that transcription and alternative splicing represent two different layers of gene expression and that signaling pathways act upon a coordinated network of transcripts in each layer. | 18,952,824 |
The N-linked oligosaccharide at Fc gamma RIIIa Asn-45: an inhibitory element for high Fc gamma RIIIa binding affinity to IgG glycoforms lacking core fucosylation. | Human leukocyte receptor IIIa (Fc gamma RIIIa) plays an important role in mediating therapeutic antibodies' antibody-dependent cellular cytotoxicity (ADCC), which is closely related to the clinical efficacy of anticancer processes in humans in vivo. The removal of the core fucose from oligosaccharides attached to the Fc region of antibodies improves Fc gamma RIIIa binding, allowing the antibodies to enhance dramatically the antibody effector functions of ADCC. In this study, the contribution of Fc gamma RIIIa oligosaccharides to the strength of the Fc gamma RIIIa/antibody complex was analyzed using a serial set of soluble human recombinant Fc gamma RIIIa lacking the oligosaccharides. A nonfucosylated antibody IgG1 appeared to have a significantly higher affinity to the wild-type Fc gamma RIIIa fully glycosylated at its five N-linked oligosaccharide sites than did the fucosylated IgG1, and this increased binding was almost abolished once all of the Fc gamma RIIIa glycosylation was removed. Our gain-of-function analysis in the Fc gamma RIIIa oligosaccharide at Asn-162 (N-162) confirmed that N-162 is the element required for the high binding affinity to nonfucosylated antibodies, as previously revealed by loss-of-function analyses. Interestingly, beyond our expectation, the Fc gamma RIIIa modified by N-162 alone showed a significantly higher binding affinity to nonfucosylated IgG1 than did the wild-type Fc gamma RIIIa. Attachment of the other four oligosaccharides, especially the Fc gamma RIIIa oligosaccharide at Asn-45 (N-45), hindered the high binding affinity of Fc gamma RIIIa to nonfucosylated IgG1. Our data clearly demonstrated that N-45 is an inhibitory element for the high Fc gamma RIIIa binding affinity mediated by N-162 to nonfucosylated antibodies. This information can be exploited for the structural-based functional study of Fc gamma RIIIa. | 18,952,826 |
Beta-arrestin 2 is required for lysophosphatidic acid-induced NF-kappaB activation. | Lysophosphatidic acid (LPA) is a bioactive phospholipid and binds to its receptors, a family of G protein-coupled receptors (GPCR), which initiates multiple signaling cascades and leads to activation of several transcription factors, including NF-kappaB. Although LPA-induced signaling pathways have been intensively investigated, the molecular mechanism by which LPA activates NF-kappaB is not fully defined. In this work, we found that beta-arrestin 2, but not beta-arrestin 1, is required for LPA-induced NF-kappaB activation and interlukin-6 expression. Mechanistically, we found that beta-arrestin 2 associated with CARMA3, a scaffold protein that plays an essential role in GPCR-induced NF-kappaB activation, suggesting that beta-arrestin 2 may recruit CARMA3 to LPA receptors. Although beta-arrestin 2 deficiency did not affect LPA-induced IKKalpha/beta phosphorylation, it impaired LPA-induced IKK kinase activity, which is consistent with our previous findings that CARMA3 is required for IKKalpha/beta activation but not for the inducible phosphorylation of IKKalpha/beta. Together, our results provide the genetic evidence that beta-arrestin 2 serves as a positive regulator in NF-kappaB signaling pathway by connecting CARMA3 to GPCRs. | 18,952,848 |
Sensitivity analysis using elicited expert information for inference with coarsened data: illustration of censored discrete event times in the AIDS Link to Intravenous Experience (ALIVE) Study. | In this paper, the authors use the rubric of "coarsened data," of which missing and censored data are special cases, to motivate the elicitation and use of expert information for performing sensitivity analyses of censored event-time data. Elicited information is important because observed data are insufficient to estimate how study participants with coarsened data compare with participants with uncoarsened data, and misspecifying this comparison may produce biased analysis results. In the presence of coarsening, performing a sensitivity analysis over a range of plausible assumptions is the best one can do. Here the authors illustrate an approach for eliciting expert information for use in sensitivity analyses to compare cumulative incidence functions of censored nonmortality outcomes. An example of such data is the AIDS Link to Intravenous Experience (ALIVE) Study, where the authors aim to estimate and compare cumulative incidence functions for human immunodeficiency virus between risk factor categories. The interval and right-censoring and censoring due to death found in the ALIVE data (1988-1998) are thought to be informative; thus, a sensitivity analysis is performed using information elicited from 2 ALIVE scientists and an expert in acquired immunodeficiency syndrome epidemiology about the relation between seroconversion and censoring. | 18,952,850 |
In vivo Himar1 transposon mutagenesis of Burkholderia pseudomallei. | Burkholderia psedudomallei is the etiologic agent of melioidosis, and the bacterium is listed as a potential agent of bioterrorism because of its low infectious dose, multiple infectious routes, and intrinsic antibiotic resistance. To further accelerate research with this understudied bacterium, we developed a Himar1-based random mutagenesis system for B. pseudomallei (HimarBP). The transposons contain a Flp recombinase-excisable, approved kanamycin resistance selection marker and an R6K origin of replication for transposon rescue. In vivo mutagenesis of virulent B. pseudomallei strain 1026b was highly efficient, with up to 44% of cells transformed with the delivery plasmid harboring chromosomal HimarBP insertions. Southern analyses revealed single insertions with no evidence of delivery plasmid maintenance. Sequence analysis of rescued HimarBP insertions revealed random insertions on both chromosomes within open reading frames and intergenic regions and that the orientation of insertions was largely unbiased. Auxotrophic mutants were obtained at a frequency of 0.72%, and nutritional supplementation experiments supported the functional assignment of genes within the respective biosynthetic pathways. HimarBP insertions were stable in the absence of selection and could be readily transferred between naturally transformable strains. Experiments with B. thailandensis suggest that the newly developed HimarBP transposons can also be used for random mutagenesis of other Burkholderia spp., especially the closely related species B. mallei. Our results demonstrate that comprehensive transposon libraries of B. pseudomallei can be generated, providing additional tools for the study of the biology, pathogenesis, and antibiotic resistance of this pathogen. | 18,952,878 |
R93W mutation in Orai1 causes impaired calcium influx in platelets. | The intracellular Ca(2+) concentration of many nonexcitable cells is regulated by calcium store release and store-operated calcium entry (SOCE). In platelets, STIM1 was recently identified as the main calcium sensor expressed in the endoplasmic reticulum. To evaluate the role of the SOC channel moiety, Orai1, in platelet SOCE, we generated mice expressing a mutated, inactive form of Orai1 in blood cells only (Orai1(R93W)). Platelets expressing Orai1(R93W) were characterized by markedly reduced SOCE and impaired agonist-induced increases in [Ca(2+)](i). Orai1(R93W) platelets showed reduced integrin activation and impaired degranulation when stimulated with low agonist concentrations under static conditions. This defect, however, did not significantly affect the ability of Orai1(R93W) platelets to aggregate or to adhere to collagen under arterial flow conditions ex vivo. In contrast, these adherent Orai1(R93W) platelets were defective in surface phosphatidylserine exposure, suggesting that Orai1 is crucial for the platelets' procoagulant response rather than for other Ca(2+)-dependent cellular responses. | 18,952,890 |
Evaluating relevance ranking strategies for MEDLINE retrieval. | This paper evaluates the retrieval effectiveness of relevance ranking strategies on a collection of 55 queries and about 160,000 MEDLINE((R)) citations used in the 2006 and 2007 Text Retrieval Conference (TREC) Genomics Tracks. The authors study two relevance ranking strategies: term frequency-inverse document frequency (TF-IDF) weighting and sentence-level co-occurrence, and examine their ability to rank retrieved MEDLINE documents given user queries. Furthermore, the authors use the reverse chronological order-PubMed's default display option-as a baseline for comparison. Retrieval effectiveness is assessed using both mean average precision and mean rank precision. Experimental results show that retrievals based on the two strategies had improved performance over the baseline performance, and that TF-IDF weighting is more effective in retrieving relevant documents based on the comparison between the two strategies. | 18,952,932 |
Structured product labeling improves detection of drug-intolerance issues. | This study sought to assess the value of the Health Level 7/U.S. Food and Drug Administration Structured Product Labeling (SPL) drug knowledge representation standard and its associated terminology sources for drug-intolerance (allergy) decision support in computerized provider order entry (CPOE) systems. The Regenstrief Institute CPOE drug-intolerance issue detection system and its knowledge base was compared with a method based on existing SPL label content enriched with knowledge sources used with SPL (NDF-RT/MeSH). Both methods were applied to a large set of drug-intolerance (allergy) records, drug orders, and medication dispensing records covering >50,000 patients over 30 years. The number of drug-intolerance issues detected by both methods was counted, as well as the number of patients with issues, number of distinct drugs, and number of distinct intolerances. The difference between drug-intolerance issues detected or missed by either method was qualitatively analyzed. Although <70% of terms were mapped to SPL, the new approach detected four times as many drug-intolerance issues on twice as many patients. The SPL-based approach is more sensitive and suggests that mapping local dictionaries to SPL, and enhancing the depth and breadth of coverage of SPL content are worth accelerating. The study also highlights specificity problems known to trouble drug-intolerance decision support and suggests how terminology and methods of recording drug intolerances could be improved. | 18,952,933 |
Glutathione S-transferase M1 and T1 polymorphisms may predict adverse effects after therapy in children with medulloblastoma. | Glutathione S-transferases (GSTs) are polymorphic enzymes that catalyze the glutathione conjugation of alkylating agents, platinum compounds, and free radicals formed by radiation used to treat medulloblastoma. We hypothesized that GST polymorphisms may be responsible, in part, for individual differences in toxicity and responses in pediatric medulloblastoma. We investigated the relationship between GSTM1 and GSTT1 polymorphisms and survival and toxicity in 42 children with medulloblastoma diagnosed and treated at the Texas Children's Cancer Center. We conducted Kaplan-Meier analyses to determine if the GST polymorphisms were related to progression-free survival (PFS) and performed logistic regression to explore associations between GST polymorphisms and occurrence of grade 3 or greater (> or =Gr 3) myelosuppression, ototoxicity, nephrotoxicity, neurotoxicity, and intellectual impairment. Patients with at least one null genotype had a 4.3 (95% confidence interval, 1.1-16.8), 3.7 (1-13.6), and 6.4 (1.2-34) times increased risk for any > or =Gr 3 toxicity, any > or =Gr 3 toxicity excluding peripheral neuropathy, and any > or =Gr 3 toxicity requiring omission or cessation of chemotherapy, respectively. Compared with all others, patients with at least one null genotype had, on average, 27.2 (p x= 0.0002), 29 (p = 0.0004), and 21.7 (p = 0.002) lower full-scale, performance, and verbal intelligence quotient (IQ) scores, respectively. GSTM1 and GSTT1 polymorphisms may predict adverse events, including cognitive impairment after therapy, in patients with medulloblastoma. A larger study to validate these findings is under way. | 18,952,980 |
Sir Michael Foster MD FRS (1836-1907): the rise of the British school of physiology. | In 1867 William Sharpey (1802-80), Professor of General Anatomy and Physiology at University College, London, appointed Michael Foster to the unique post of Teacher of Practical Physiology; in Britain the study of experimental physiology was dormant. In 1870 Foster accepted a Praelectorship in Physiology at Trinity College, Cambridge, and soon established a school of physiology. He was the first Cambridge Professor of Physiology (1883-1903). Foster, a great teacher, had a remarkable ability to attract talented students and to inspire them to undertake research. He himself took inspiration from the scientific philosophy of Thomas Henry Huxley (1825-95) and of Claude Bernard (1813-78). Foster was active in the foundation of the Physiological Society (1876), and founded and edited the Journal of Physiology (1878). He was interested in the scientific training of medical students and wrote a highly lauded Text Book of Physiology (1877). Physiology became a profession in its own right and British physiologists were in the vanguard of research. | 18,952,994 |
Jean Langlais (1907-91): an historical case of a blind organist with stroke-induced aphasia and Braille alexia but without amusia. | The subject of a prior report of a blind organist with aphasia and Braille alexia without amusia, published in French, has been identified as Jean Langlais. His artistic and medical history is presented, the latter via translation of the original 1987 paper. | 18,952,998 |
Pimelic diphenylamide 106 is a slow, tight-binding inhibitor of class I histone deacetylases. | Histone deacetylase (HDAC) inhibitors, including various benzamides and hydroxamates, are currently in clinical development for a broad range of human diseases, including cancer and neurodegenerative diseases. We recently reported the identification of a family of benzamide-type HDAC inhibitors that are relatively non-toxic compared with the hydroxamates. Members of this class of compounds have shown efficacy in cell-based and mouse models for the neurodegenerative diseases Friedreich ataxia and Huntington disease. Considerable differences in IC(50) values for the various HDAC enzymes have been reported for many of the HDAC inhibitors, leading to confusion as to the HDAC isotype specificities of these compounds. Here we show that a benzamide HDAC inhibitor, a pimelic diphenylamide (106), is a class I HDAC inhibitor, demonstrating no activity against class II HDACs. 106 is a slow, tight-binding inhibitor of HDACs 1, 2, and 3, although inhibition for these enzymes occurs through different mechanisms. Inhibitor 106 also has preference toward HDAC3 with K(i) of approximately 14 nm, 15 times lower than the K(i) for HDAC1. In comparison, the hydroxamate suberoylanilide hydroxamic acid does not discriminate between these enzymes and exhibits a fast-on/fast-off inhibitory mechanism. These observations may explain a paradox involving the relative activities of pimelic diphenylamides versus hydroxamates as gene activators. | 18,953,021 |
Bacteriophage Mu integration in yeast and mammalian genomes. | Genomic parasites have evolved distinctive lifestyles to optimize replication in the context of the genomes they inhabit. Here, we introduced new DNA into eukaryotic cells using bacteriophage Mu DNA transposition complexes, termed 'transpososomes'. Following electroporation of transpososomes and selection for marker gene expression, efficient integration was verified in yeast, mouse and human genomes. Although Mu has evolved in prokaryotes, strong biases were seen in the target site distributions in eukaryotic genomes, and these biases differed between yeast and mammals. In Saccharomyces cerevisiae transposons accumulated outside of genes, consistent with selection against gene disruption. In mouse and human cells, transposons accumulated within genes, which previous work suggests is a favorable location for efficient expression of selectable markers. Naturally occurring transposons and viruses in yeast and mammals show related, but more extreme, targeting biases, suggesting that they are responding to the same pressures. These data help clarify the constraints exerted by genome structure on genomic parasites, and illustrate the wide utility of the Mu transpososome technology for gene transfer in eukaryotic cells. | 18,953,026 |
Mechanisms and consequences of macrophage apoptosis in atherosclerosis. | Macrophage apoptosis is an important feature of atherosclerotic plaque development. Research directed at understanding the functional consequences of macrophage death in atherosclerosis has revealed opposing roles for apoptosis in atherosclerotic plaque progression. In early lesions, macrophage apoptosis limits lesion cellularity and suppresses plaque progression. In advanced lesions, macrophages apoptosis promotes the development of the necrotic core, a key factor in rendering plaques vulnerable to disruption and in acute lumenal thrombosis. The first section of this review will examine the role of phagocytic clearance of apoptotic macrophages, a process known as efferocytosis, in the dichotomous roles of macrophage apoptosis in early vs. advanced lesions. The second section will focus on the molecular and cellular mechanisms that are thought to govern macrophage death during atherosclerosis. Of particular interest is the complex and coordinated role that the endoplasmic reticulum (ER) stress pathway and pattern recognition receptors (PRRs) may play in triggering macrophage apoptosis. | 18,953,058 |
Interaction between antihypertensives and NSAIDs in primary care: a controlled trial. | Non-steroidal anti-inflammatory drugs (NSAIDs) may increase blood pressure (BP) and blunt the effects of many antihypertensives. It seems that NSAIDs and the antihypertensive drugs differ in their propensity to such an interaction. To determine the extent of the interaction between two antihypertensives and three NSAIDs. A prospective clinical trial in a family practice included 88 treated hypertensives aged over 55 years; 39 controls and 49, also taking NSAIDs for osteoarthritis. During this 3-month study, two antihypertensives, lisinopril/hydrochlorothiazide and amlodipine, were compared with three NSAIDs: ibuprofen, acetaminophen, and piroxicam. BP was measured with standard mercury sphygmomanometer and with an automatic device, in standing, sitting, and supine position. The average starting blood pressure in the study group was 149.3A+/-9.8/88.6A+/-6.8 mm Hg. In the lisinopril/hydrochlorothiazide subgroup, both ibuprofen and piroxicam elevated systolic BP by 7.7-9.9% (p<0.001), which, during the acetaminophen period, decreased by 6.9-9.4% to 0.3-0.9% above baseline (p<0.001), increasing again by 7.0-7.7% (p<0.001) during the second exposition to these drugs. In the amlodipine subgroup, ibuprofen or piroxicam increased BP by 1.1-1.6% (p>0.290) only, and there were no significant shifts in the follow-up periods. Analogous deviations were observed with both measurement devices, in all the examinee's positions. In the control group, BP did not change appreciably. Piroxicam and ibuprofen markedly blunt the effects of antihypertensive drugs while acetaminophen is almost inert. Lisinopril/hydrochlorothiazide combination is much more affected by this interaction than amlodipine (ClinicalTrials.gov #NCT00631514). | 18,953,082 |
Antidepressant therapy during pregnancy: an insight on its potential healthcare costs. | Information on healthcare costs associated with poorly treated psychiatric disorders during and after pregnancy is limited. To compare the direct healthcare costs, during and after pregnancy, between women who continue their antidepressant therapy during the whole gestational period and those who discontinue their treatment during the first trimester. Data from a 'Medications and Pregnancy' registry were used. Eligible women were 1) aged 15 - 45, 2) insured by the Quebec drug plan for > or =12 months prior to, during, and > or =3 months after pregnancy, 3) had > or =1 diagnoses of psychiatric disorders before pregnancy, 4) used antidepressants for . or =30 days in the year before pregnancy, and 5) had delivered. Women who continued their antidepressant therapy throughout pregnancy (Group 1) were compared to those who discontinued during the first trimester (Group 2). Healthcare costs, expressed as mean total costs and cost ratios, were determined during and after pregnancy. In total, 2822 women met inclusion criteria. Of these, 501 (17.8%) were in Group 1, and 676 (23.4%) in Group 2. The median number of days of antidepressant use before pregnancy was higher in Group 1 (260 days vs. 144 days, p<.01); the proportion of women visiting a psychiatrist was also higher in Group 1 (33.7% vs. 26.8%, p<.01). The mean total cost during pregnancy in Groups 1 and 2 were $2981.5 vs. $1842.9 (p<.01), respectively, and after pregnancy were $1761.2 vs. $1024.9 (p<.01), respectively. When prescription costs were excluded, these differences in costs were no longer significant. Women who use antidepressants during pregnancy are likely to have disorders of greater severity compared to those who discontinue during the first trimester. They incur significantly greater healthcare costs. However, this increased cost is attributable to higher prescription costs. | 18,953,084 |
Excitatory neurosteroids attenuate apoptotic and excitotoxic cell death in primary cortical neurons. | Some neurosteroids show neuroprotective action in in vitro and in vivo studies, but their interaction with apoptotic/necrotic processes has been only partially unraveled. The aim of the present study was to examine the effect of dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS), pregnenolone (PGL) and allopregnanolone (Allo) on staurosporine-, glutamate-, and NMDA-induced damage in primary cortical neuronal culture. DHEA, DHEAS and PGL (0.1 and 1 microM) inhibited the staurosporine-evoked LDH release and decreased the number of apoptotic cells as shown by Hoechst;s staining, whereas Allo was without effect. The neurosteroids affected neither the staurosporine-evoked changes in caspase-3 activity nor the decrease in mitochondrial membrane potential. It was also shown that protective effects of DHEA, DHEAS and PGL against staurosporine-induced LDH release were attenuated by extracellular signal-regulated kinase (ERK)--mitogen-activated protein kinase (MAPK) inhibitor--PD 98059 (5 microM) but not by phosphatidylinositol-3-kinase (PI3-K) inhibitors such as LY 294002 (1 microM) or wortmannin (10 nM). The involvement of ERK2-MAPK in protective effects of neurosteroids was confirmed by Western blot study. Further study demonstrated that glutamate-induced cell damage was attenuated by DHEA, DHEAS, and PGL, but not by Allo. None of the steroids influenced NMDA-induced LDH release. The results of the present in vitro studies suggest that excitatory neurosteroids DHEA, DHEAS and PGL at physiological concentrations participate in the inhibition of cortical neuronal degeneration elicited by staurosporine and glutamate, whereas the most potent positive modulator of GABA(A) receptor--Allo--has no effect. Moreover, neurosteroids appear to attenuate the staurosporine-induced cell damage in a caspase-3 independent way and their neuroprotective mechanism of action involves the increase in ERK-MAPK phosphorylation. | 18,953,090 |
A low halogenated biphenyl (PCB3) increases CYP1A1 expression and activity via the estrogen receptor beta in the porcine ovary. | Polychlorinated biphenyls (PCBs) have been detected at high levels, up to hundreds of pg/ml, in human ovarian follicle fluid. The effect of PCBs on the ovary and the consequences of exposure are largely unknown. We have previously shown that PCB3 (4-chlorobiphenyl) increases the secretion of estradiol and the activity of cytochrome P450s (CYPs) in ovarian follicle cells. Our goal here is to elucidate the mechanism of CYP induction by this congener. Exposure of porcine follicle cells, a co-culture of theca and granulosa cells, to 6 ng/ml of PCB3 caused an increase in CYP1A1 protein and enzymatic activity, in the same manner as exposure to exogenous 17beta-estradiol. No changes were seen in the protein level of the aryl hydrocarbon receptor (AhR), which mediates the first step in the signaling pathway of CYP1A1 induction. However, a strong reduction was seen in the protein level of estrogen receptor beta (ERbeta), while no effect was seen on ERalpha protein levels. These result suggest that: 1) PCB3 acts as an agonist of ERbeta but not the Ah receptor in the ovarian follicles, 2) PCB3 is not only an efficacious inducer of CYP1A1 expression and activity, but also a substrate for this enzyme. Changes in the expression level of CYP1A1 not only alter the intensity of the activity of PCB3, but also the activity of estrogen in the ovary. | 18,953,099 |
Immunotherapy targeting pathological tau protein in Alzheimer's disease and related tauopathies. | Immunotherapies that target the amyloid-beta (Abeta) peptide in Alzheimer's disease (AD) have shown promise in animal and human studies. Although the first clinical trial was halted because of adverse reactions, this approach has been refined and additional trials are underway. Another important target in AD is the neurofibrillary tangles, composed primarily of hyperphosphorylated tau proteins, which correlate well with the degree of dementia. As Abeta and tau pathologies are likely synergistic, targeting both should be more effective and may be essential as early diagnosis prior to cognitive decline is currently not available. Also, Abeta immunotherapy only results in a very limited indirect clearance of tau aggregates in dystrophic neurites, showing the importance of developing a separate therapy that directly targets pathological tau. Our findings in two tangle mouse models indicate that immunization with a phospho-tau derivative reduces aggregated tau in the brain and slows progression of the tangle-related behavioral phenotype. These antibodies enter the brain and bind to pathological tau within neurons. We are currently clarifying further the mechanism of action of this promising therapeutic approach and determining its epitope specificity. | 18,953,105 |
Alzheimer disease therapeutics: perspectives from the developing world. | Although a majority of dementia patients live in middle-income and low-income countries, dementia represents an under-recognized public health burden in the developing world. Culturally and socially, it tends to be trivialized as an inevitable consequence of aging. Economic constraints are paramount, precluding the availability of institutionalized elder care and a state-sponsored health care system. Evidence-based practice for the management of dementia is also hampered by lack of a clear-cut expert consensus on the efficacy of anti-dementia drugs. Public health education, substantial health infrastructure development, and therapeutic advances are necessary for the developing world's looming dementia crisis to be adequately tackled. | 18,953,114 |
Lessons learned from failed and discontinued clinical trials for the treatment of Alzheimer's disease: future directions. | While advances have been made in understanding the neurobiological processes underlying Alzheimer's disease (AD), few treatment options currently exist. Numerous potential therapeutic and/or preventive agents have been tested in clinical trials, yet most have failed to show a clear therapeutic benefit. The lack of effective medical therapies coupled with the incipient projected dramatic increase in the number of persons with AD in the coming decades has put medical research in a crisis to urgently find effective treatment and prevention strategies. Researchers and funding agencies have been rethinking investigative approaches in order to accelerate scientific discovery in AD therapeutics, including methodological issues in the design and implementation of clinical trials. This review discusses lessons learned from discontinued and failed clinical trials for the treatment and prevention of AD with an emphasis on future directions of AD clinical trials. In particular, attention is given to choice of study outcome measures, participant selection and retention, and clinical trial design. While there are few treatments available for AD currently, the potential for discovery over the next decade is promising. | 18,953,117 |
Eliminating the paper medical archive by bulk document scanning of historic folders and implementing revised workflows for scanning new documents. | We made the decision in our hospital to radically eliminate the paper archive by bulk scanning over a million medical records. This reorganization goes together with installation of new workflows for injecting information that is still captured on paper as automatically as feasible into the electronic medical record. In this article we describe our organizational and technical approach and we highlight principles which our experience suggests to be useful. | 18,953,132 |
Predictors of Plasmodium vivax malaria-induced nephropathy in young Korean men. | Plasmodium vivax malaria accounts for more than half of all malaria cases in Asia and Latin America. Despite the high prevalence of disease caused by this parasite, research into its effects (especially its renal effect) has lagged disproportionately. To investigate predictors of vivax malaria-induced nephropathy, we analyzed the cases of vivax malaria-induced nephropathy in young Korean men. This was a retrospective analysis of P. vivax patients with acute nephropathy (all males, n = 75), defined by an absolute increase in serum creatinine of 0.3 mg/dl or more (equal to an estimated glomerular filtration rate (eGFR) <80 ml/min) (group 1, n = 31) or proteinuria (group 2, n = 44), between January 2004 and December 2007. The eGFR was calculated using a simplified Modification of Renal Disease (MDRD) equation. None of the patients had a history of traveling abroad, drug abuse or blood transfusion. The clinical manifestations, laboratory abnormalities and predictors of nephropathy were reviewed. Out of 398 cases of vivax malaria, 75 patients (all males) suffered from to vivax malaria-induced acute nephropathy. The mean age of the patients who were divided into two groups was 22.8 +/- 3.7 and 21.6 +/- 1.8 years, respectively (p = 0.089). In group 1, the total serum bilirubin significantly correlated with serum creatinine and eGFR (p = 0.004 and 0.035, correlation coefficient = 0.508 and -0.387, respectively). In group 2, 24-hour proteinuria significantly correlated with hemoglobin (p = 0.004, correlation coefficient = -0.424). Total serum bilirubin (group 1, an absolute increase in serum creatinine of 0.3 mg/dl or more (equal to an eGFR <80 ml/min)) and hemoglobin (group 2, proteinuria) are useful to predict vivax-induced nephropathy. | 18,953,180 |
The identification and treatment of toxic megacolon secondary to pseudomembranous colitis. | Toxic megacolon is an infrequently occurring, potentially life-threatening complication of pseudomembranous colitis. Although toxic megacolon may be considered rare, incidence is expected to increase because of the rapidly increased prevalence of pseudomembranous colitis. This article discusses the pathophysiology, clinical manifestation, diagnosis, treatment, and prognosis for toxic megacolon secondary to pseudomembranous colitis. Critical care nurses should be aware of the disease to intervene early and increase the chance of the patient's survival. | 18,953,191 |
Medication adherence self-report instruments: implications for practice and research. | After an acute cardiac event, adhering to recommendations for pharmacologic therapy is important in achieving optimal health outcomes. Considering the impressive evidence base for cardiovascular pharmacotherapy, strategies for promoting adherence are less well developed. Furthermore, accessing reliable, valid, and cost-effective mechanisms of monitoring adherence in the research and clinical settings is challenging. The aim of this article was to review published self-report measures assessing and monitoring medication adherence in cardiovascular disease and provide recommendations for research into medication adherence. The electronic databases CINAHL, Medline, and Science Direct were searched using the key search terms medication adherence and/or compliance, cardiovascular, self-report measures, and questionnaires. The World Wide Web was searched using the Google and Google Scholar search engines, and reference lists of retrieved documents were reviewed. The search strategy was verified by a health librarian. Instruments were included if they specifically addressed medication adherence as a discrete construct rather than a disease-specific or a generic health status measurement. Despite of the problems with medication adherence identified in the literature, only 7 instruments met the search criteria. There was limited use of instruments across studies and settings to enable comparison across populations and extensive psychometric evaluation. Medication adherence is a complex, multifaceted construct dependent on a range of physical, social, economic, and psychological considerations. In spite of the importance of adherence in ensuring optimal cardiovascular outcomes, conceptual underpinnings and methods of assessing medication adherence require further discussion and debate. | 18,953,213 |
Clinical and radiological outcome of patients suffering from chronic pancreatitis associated with gene mutations. | Cystic fibrosis transmembrane conductance regulator (CFTR), cationic trypsinogen gene (PRSS1), and serine protease inhibitor kazal type 1 (SPINK1) gene mutations have been associated with chronic pancreatitis (CP). The aim of this study was to compare clinical and radiological findings in sporadic CP with (CPgm) and without (CPwt) gene mutations. Data from patients observed between 2001 and 2006 were collected. All patients were tested for 25 CFTR gene mutations, for R122H and N29I on the PRSS1 gene, and for N34S mutation on the SPINK1 gene. We found 34 (17.2%) of 198 patients with CPgm, 23 (11.6%) of them on the CFTR gene, 11 (5.6%) on the SPINK1, and none on the PRSS1 gene. The age at clinical onset was younger in CPgm (36.2 +/- 17.2 years) than in CPwt (44 +/- 12.6 years; P = 0.005). There were more heavy drinkers among CPwt (33%) than among CPgm (9%; P = 0.003), and the same applied to smokers (69% vs 33%, respectively; P < 0.0001). In CPgm group, the onset of pancreatic calcifications was observed more frequently in drinkers and/or smokers. Exocrine and endocrine insufficiency occurred less frequently and later in CPgm than in CPwt patients. Clinical and radiological outcome differ in CPgm compared with CPwt. Alcohol, even in small quantities, and cigarette smoking influence the onset of pancreatic calcifications. | 18,953,248 |
Assessment of the prognostic value of certain acute-phase proteins and procalcitonin in the prognosis of acute pancreatitis. | Of patients with acute pancreatitis (AP), 20% develop severe attacks that need early and intensive therapy. Yet, to administer such treatment, it is important to classify early on the patients with mild and severe pancreatitis. The aim of this study was to evaluate the role of serum amyloid A, C-reactive protein, procalcitonin, and routinely measured parameters in the early prediction of the course of AP. A total of 40 consecutive patients with AP confirmed by computed tomography were prospectively enrolled in the study-29 were graded as mild and 11 were graded as severe. Blood samples were obtained on admission and 24 hours thereafter. Procalcitonin concentration in both measurements was significantly higher in patients with severe pancreatitis, and the cutoff level was estimated at 0.5 ng/mL. Although serum amyloid A and C-reactive protein levels rose significantly during the period of observation, these were not differentiated between both groups. Among the routinely measured parameters, a prognostic value was found for total calcium concentration, lactic dehydrogenase activity, and glucose concentration. The best efficiency in the early prediction of severe AP would be achieved with the measurement of procalcitonin, total calcium level, and lactic acid dehydrogenase activity immediately after admission to the ward. | 18,953,261 |
Inflammatory aneurysm of the thoracoabdominal aorta with associated dissection. | The inflammatory variant of aortic aneurysms has 3 unique features: marked thickening of the aneurysm wall, fibrosis of the adjacent retroperitoneum, and rigid adherence of the adjacent structures to the anterior aneurysm wall. Abdominal tenderness with or without a pulsatile abdominal mass is the most common finding, although it is present in only about 33% of patients. Systemic symptoms, such as fever, malaise, and weight loss, are reported in about 20% to 50% of patients. A contrast-enhanced computed tomography scan, magnetic resonance imaging, and a transesophageal echocardiogram are among the best modalities to evaluate for inflammatory thoracoabdominal aneurysm, but a transthoracic echocardiogram can frequently be very suggestive. Medical treatment options include corticosteroids or other anti-inflammatory and immunosuppressive therapies. Surgical intervention usually consists of a transperitoneal approach with infrarenal aortic clamping. This case review describes a 64-year-old woman with a history of hypertension and dyslipidemia who presented with anemia, lower back pain, and a recent 30-pound weight loss. | 18,953,281 |
Promoting epidural analgesia for labor: 2005-2007 diffusion in Lombardia, Italy. | Since January 2005 the Regional Government of Lombardia, a large Italian region with over 1/5 of all Italian births, allocated public funds for 3 consecutive years to help provide epidural analgesia (EA) for women in labor. The aim of the present study was to evaluate the trend of diffusion of EA in the triennium 2005-2007. Data obtained from regional Obstetric Departments, recognized by the National Health Care System, were elaborated by the Epidemiological Service of Regione Lombardia. The software looked for specific codes for vaginal deliveries, with or without EA, and Cesarean sections included in the administrative patient records. A substantial increase in epidurals administered in comparison to total vaginal deliveries was recorded after assignment of regional financing: from 8.2% in 2005, to 10.4% in 2006 and 12.9% in 2007 (P<0.0001). More than 60% of epidurals were performed in 8 hospitals with >2 000 births per year. The rate of EAs in these hospitals was 18% in 2005, 22% in 2006 and 24.9% in 2007. In the 69 hospitals with <2000 births per year, the rate of EAs was markedly lower: 4% in 2005, 5.5% in 2006 and 7.8% in 2007. In both cases, the increase was statistically significant (P<0.0001). At the three-year time-point, the rate of Cesarean sections did not change. The continuous increase of EA for labor after regional financings suggests that the low rate of pain relief procedures in Lombardia was mainly due to economic and organizational issues, rather than to cultural and psychological factors. | 18,953,285 |
Mutations of LRTOMT, a fusion gene with alternative reading frames, cause nonsyndromic deafness in humans. | Many proteins necessary for sound transduction have been identified through positional cloning of genes that cause deafness. We report here that mutations of LRTOMT are associated with profound nonsyndromic hearing loss at the DFNB63 locus on human chromosome 11q13.3-q13.4. LRTOMT has two alternative reading frames and encodes two different proteins, LRTOMT1 and LRTOMT2, detected by protein blot analyses. LRTOMT2 is a putative methyltransferase. During evolution, new transcripts can arise through partial or complete coalescence of genes. We provide evidence that in the primate lineage LRTOMT evolved from the fusion of two neighboring ancestral genes, which exist as separate genes (Lrrc51 and Tomt) in rodents. | 18,953,341 |
[Obesity, inflammation and insulin resistance: role of gp 130 receptor ligands]. | Obesity can be considered as a low grade inflammatory disease, characterized by increased plasma levels of proinflammatory cytokines such as tumoral necrosis factor-a (TNF-a), and acute phase reactant proteins like C-reactive protein. In this context, some cytokines of the interleukin-6 (IL-6) family have been involved in the inflammatory processes associated to obesity. In addition to IL-6, the IL-6 cytokine family includes IL-11, ciliary neurotrophic factor (cntf), cardiotrophin-1 (CT-1), cardiotrophin-like cytokine (CLC), leukemia inhibitory factor (LIF) y Oncostatin M (OsM). These proteins are also known as gp130 cytokines because all of them exert their action via the glycoprotein 130 (gp130) as a common transducer protein within their functional receptor complexes. However, their role in obesity and related disorders is controversial; thus, whereas some studies have described the involvement of gp130 cytokines in the development of obesity and its related cluster of pathophysiologic conditions like insulin-resistance, fatty liver and cardiovascular diseases, other trials have proposed the gp130 receptor ligands as therapeutic targets in the treatment of obesity and its related disorders. In fact, CNTF treatment has demonstrated to be effective in the reduction of body weight, by promoting the inhibition of food intake and the activation of the energy expenditure, together with an improvement of insulin sensitivity. This review analyzes the potential therapeutic role of some of the gp130 ligands in obesity and related diseases. | 18,953,360 |
[Effectiveness of primary health care in the diagnosis and treatment of arterial hypertension]. | Arterial hypertension (AHT) is a significant public health problem due to its high cardiovascular morbidity and mortality and its economic and social costs. Background. To identify the prevalence of AHT detected in primary care and its degree of control; to determine the types of treatment used and factors associated with its control. Patients and methods. Transversal comparative study of two years in the Villava Health Centre. The computerised clinical history data for the years 2003 and 2006 was analysed. The following variables were studied: age, gender, systolic and diastolic arterial pressure, total cholesterol, HDL, LDL, triglycerides, tobacco use, body mass index in both years. Hypotensor treatment in the year 2006. The variables for the year 2006 associated with good control were identified through logistic regression. Results. AHT prevalence detected in (3)18 year olds: 2003: 11.6% (CI:10.9-12.3); 2006: 16.6% (CI:15.8-17.4) (p<0.001). Control of hypertense persons with a register of arterial tension (AP:<140/90) in 2003: 45.1% (CI: 41.0-48.0) and in 2006: 40.4% (CI: 37.7-43.2) (p<0.05). Variables associated with good control: being male [OR 1.60 (IC: 1.26-2.03)] treatment with ARA II [OR 2.16 (CI: 1.50-3.09)] and being diabetic [OR 1.50 (CI: 1.10-2.03]. Associated with poor control: presenting cerebral vascular disease, peripheral vasculopathy and treatment with ACE inhibitors. Conclusions. A low prevalence of AHT was detected. The level of control was higher for the DAP than for the SAP. Treatment with AIIRA, being male and being diabetic were associated with a better control. Peripheral vasculopathy, ichaemic cardiopathy, cerebral vascular disease, ACE inhibitors use and age were associated with a poorer control. | 18,953,361 |
[Rare diseases: medicine's challenge in the XXI Century]. | Rare diseases (RD) are receiving increasing attention within both the scientific community and society in general. Many RDs are diagnosed during paediatric age and affect the patient throughout his life, but they can also be diagnosed during adult age. Advances in the biochemical, molecular and genetic diagnosis of these diseases are proving essential in improving clinical understanding and therapeutic possibilities. However, their low prevalence makes it difficult to develop suitable medicines for treatment and it is necessary to implement specific social and health protection programs for these medicines, which are called orphan medicines (OM). In general these serious, chronic diseases involving a high degree of disability are difficult to diagnose. For better diagnosis and monitoring it is necessary to develop reference units at the state level that will improve our knowledge of these pathologies. RDs have a direct repercussion on both the family, which in many cases becomes the carer, and on society, which must develop specific social, health and educational programs to support these patients. In short, RDs form a significant challenge of coordination for the scientific community and for society given their significant specific weight in the development of health care in our setting. | 18,953,368 |
Reprogramming primordial germ cells into pluripotent stem cells. | Specification of primordial germ cells (PGCs) results in the conversion of pluripotent epiblast cells into monopotent germ cell lineage. Blimp1/Prmt5 complex plays a critical role in the specification and maintenance of the early germ cell lineage. However, PGCs can be induced to dedifferentiate back to a pluripotent state as embryonic germ (EG) cells when exposed to exogenous signaling molecules, FGF-2, LIF and SCF. Here we show that Trichostatin A (TSA), an inhibitor of histone deacetylases, is a highly potent agent that can replace FGF-2 to induce dedifferentiation of PGCs into EG cells. A key early event during dedifferentiation of PGCs in response to FGF-2 or TSA is the down-regulation of Blimp1, which reverses and apparently relieves the cell fate restriction imposed by it. Notably, the targets of Blimp1, which include c-Myc and Klf-4, which represent two of the key factors known to promote reprogramming of somatic cells to pluripotent state, are up-regulated. We also found early activation of the LIF/Stat-3 signaling pathway with the translocation of Stat-3 into the nucleus. By contrast, while Prmt5 is retained in EG cells, it translocates from the nucleus to the cytoplasm where it probably has an independent role in regulating pluripotency. We propose that dedifferentiation of PGCs into EG cells may provide significant mechanistic insights on early events associated with reprogramming of committed cells to a pluripotent state. | 18,953,407 |
Structures of SRP54 and SRP19, the two proteins that organize the ribonucleic core of the signal recognition particle from Pyrococcus furiosus. | In all organisms the Signal Recognition Particle (SRP), binds to signal sequences of proteins destined for secretion or membrane insertion as they emerge from translating ribosomes. In Archaea and Eucarya, the conserved ribonucleoproteic core is composed of two proteins, the accessory protein SRP19, the essential GTPase SRP54, and an evolutionarily conserved and essential SRP RNA. Through the GTP-dependent interaction between the SRP and its cognate receptor SR, ribosomes harboring nascent polypeptidic chains destined for secretion are dynamically transferred to the protein translocation apparatus at the membrane. We present here high-resolution X-ray structures of SRP54 and SRP19, the two RNA binding components forming the core of the signal recognition particle from the hyper-thermophilic archaeon Pyrococcus furiosus (Pfu). The 2.5 A resolution structure of free Pfu-SRP54 is the first showing the complete domain organization of a GDP bound full-length SRP54 subunit. In its ras-like GTPase domain, GDP is found tightly associated with the protein. The flexible linker that separates the GTPase core from the hydrophobic signal sequence binding M domain, adopts a purely alpha-helical structure and acts as an articulated arm allowing the M domain to explore multiple regions as it scans for signal peptides as they emerge from the ribosomal tunnel. This linker is structurally coupled to the GTPase catalytic site and likely to propagate conformational changes occurring in the M domain through the SRP RNA upon signal sequence binding. Two different 1.8 A resolution crystal structures of free Pfu-SRP19 reveal a compact, rigid and well-folded protein even in absence of its obligate SRP RNA partner. Comparison with other SRP19*SRP RNA structures suggests the rearrangement of a disordered loop upon binding with the RNA through a reciprocal induced-fit mechanism and supports the idea that SRP19 acts as a molecular scaffold and a chaperone, assisting the SRP RNA in adopting the conformation required for its optimal interaction with the essential subunit SRP54, and proper assembly of a functional SRP. | 18,953,414 |
Mammary tumors initiated by constitutive Cdk2 activation contain an invasive basal-like component. | The basal-like subtype of breast cancer is associated with invasiveness, high rates of postsurgical recurrence, and poor prognosis. Aside from inactivation of the BRCA1 tumor-suppressor gene, little is known concerning the mechanisms that cause basal breast cancer or the mechanisms responsible for its invasiveness. Here, we show that the heterogeneous mouse mammary tumor virus-cyclin D1-Cdk2 (MMTV-D1K2) transgenic mouse mammary tumors contain regions of spindle-shaped cells expressing both luminal and myoepithelial markers. Cell lines cultured from these tumors exhibit the same luminal/myoepithelial mixed-lineage phenotype that is associated with human basal-like breast cancer and express a number of myoepithelial markers including cytokeratin 14, P-cadherin, alpha smooth muscle actin, and nestin. The MMTV-D1K2 tumor-derived cell lines form highly invasive tumors when injected into mouse mammary glands. Invasion is associated with E-cadherin localization to the cytoplasm or loss of E-cadherin expression. Cytoplasmic E-cadherin correlates with lack of colony formation in vitro and beta-catenin and p120(ctn) localization to the cytoplasm. The data suggest that the invasiveness of these cell lines results from a combination of factors including mislocalization of E-cadherin, beta-catenin, and p120(ctn) to the cytoplasm. Nestin expression and E-cadherin mislocalization were also observed in human basal-like breast cancer cell lines, suggesting that these results are relevant to human tumors. Together, these results suggest that abnormal Cdk2 activation may contribute to the formation of basal-like breast cancers. | 18,953,433 |
Prostate gland biopsies and prostatectomies: an Ontario community hospital experience. | Transrectal ultrasound-guided core biopsies of the prostate gland and prostatectomies have become common procedures at many community hospitals in Canada, especially in the era of serum prostate-specific antigen (PSA) screening for prostate cancer. The Gleason grading of prostate cancer in biopsies and prostatectomies is a major determinant used for treatment planning. There is evidence in the literature that suggests important discordance between community hospital pathologists and urological pathologists with respect to the Gleason grading of prostate cancer. Our objective was to determine the diagnostic rates and Gleason scoring patterns for prostate gland biopsies and prostatectomies at our institution compared with the literature. We conducted a retrospective review of all prostate gland biopsies and prostatectomies performed at the Grey Bruce Health Services from January 2005 to September 2005. We collected data from 194 biopsies and 44 prostatectomies. We obtained prebiopsy serum PSA levels and digital rectal exam results for all patients from urologists' office records. The average age for men having biopsies was 65.8 (standard deviation [SD] 8.6) years, and the average prebiopsy serum PSA level was 8.7 (median 7.1, SD 6.2) mug/L. The rates of diagnosis from prostate gland biopsies of benign (17.6%), high-grade prostatic intraepithelial neoplasia (11.0%), atypical small acinar proliferation suspicious for invasive malignancy (13.2%) and invasive prostatic adenocarcinoma (58.2%) at our institution were significantly different than those reported in the literature (p < 0.001). We observed a significant variation in the rates of these diagnoses among the community hospital pathologists in our study (p = 0.004). There was a strong correlation between the increasing number of positive core biopsy sites and increasing Gleason scores in biopsies (p < 0.001). There was also a strong correlation between increasing pre-biopsy serum PSA levels and increasing Gleason scores in biopsies (p < 0.001). A substantial proportion (21.9%) of the biopsies given the Gleason score of 6 had a Gleason score of 7 in the prostatectomy specimen. Our results showed a significant difference in prostate gland biopsy categorical diagnoses compared with the literature. There were also significant differences in categorical diagnoses of prostate gland biopsies among the community hospital pathologists in our study. The data identify a strong positive correlation between the increasing number of positive core biopsy sites and increasing Gleason scores in biopsies, as well as a strong positive correlation between increasing prebiopsy serum PSA levels and increasing Gleason scores in biopsies that revealed cancer. We would encourage other community hospital pathologists, in collaboration with their urologists, to review periodically their prostate gland pathology practices in an attempt to improve the uniformity of diagnoses. | 18,953,449 |
Leptin levels recover normally in healthy older adults after acute diet-induced weight loss. | Involuntary weight loss affects 20% of community dwelling older adults. The underlying mechanism for this disorder is unknown. Objective is to determine if failure of older persons to regain weight is associated with elevated pro-inflammatory cytokine and leptin levels. Prospective diet intervention study. University of Washington Medical Center from 2001-2005. Twenty-one younger (18-35 years old) and nineteen older (>or= 70 years old) men and women. Each subject was placed for two weeks on a weight-maintaining diet, followed in sequence by 2 weeks of 30% caloric restriction, then 4 weeks of ad libitum food intake. Plasma leptin levels, fasting serum pro-inflammatory cytokine levels, and peripheral blood mononuclear cell cytokine levels were measured. Leptin levels in the two cohorts decreased after caloric restriction and increased after ad-libitum food consumption resumed. Plasma TNF alpha levels were higher in older subjects compared to younger adults. However, there was no association between changes in TNF alpha levels and changes in AUC leptin. Leptin levels in healthy older individuals responded appropriately in a compensatory manner to changes in body weight. These data do not support a cytokine dependent elevation in leptin levels as being responsible for the failure of older adults to regain weight. | 18,953,464 |
An investigation of the effects of saccharides on the memory performance of middle-aged adults. | To investigate the effects of glucose, or a combination of saccharides, or a placebo on the memory performance of middle-aged adults. A double-blind, placebo controlled design was used. A population-based sample of 45 men and women (aged 40-63 years) completed a series of memory tasks following administration of a single dose of either glucose, a combination of saccharides or placebo. Memory tasks included immediate and delayed recall, recognition, short-term memory, working memory, and a test of general cognitive ability. There were no statistically significant effects of treatments on any of the outcome measures. The pattern of means in the combination of saccharides group suggests potential enhancement effects of memory performance in middle-aged adults that deserves further investigation. | 18,953,465 |
Multidetector computed tomography for preoperative evaluation of vascular anatomy in living renal donors. | Currently, multidetector computed tomographic (MDCT) angiography has become a noninvasive alternative imaging modality to catheter renal angiography for the evaluation of renal vascular anatomy in living renal donors. In this study, we investigated the diagnostic accuracy of 16-slice MDCT in the preoperative assessment of living renal donors. Fifty-nine consecutive living renal donors (32 men, 27 women) underwent MDCT angiography followed by open donor nephrectomy. All MDCT studies were performed by using a 16-slice MDCT scanner with the same protocol consisting of arterial and nephrographic phases followed by conventional abdominal radiography. The MDCT images were assessed retrospectively for the number and branching pattern of the renal arteries and for the number and presence of major or minor variants of the renal veins. The results were compared with open surgical results. The sensitivity and specificity of MDCT for the detection of anatomic variants of renal arteries including the accessory arteries (n = 9), early arterial branching (n = 7) and major renal venous anomalies including the accessory renal veins (n = 3), late venous confluence (n = 4), circumaortic (n = 2) or retroaortic (n = 3) left renal veins were 100%. However, the sensitivity for identification of minor venous variants was 79%. All of three ureteral duplications were correctly identified at excretory phase conventional abdominal radiography. Sixteen-slice MDCT is highly accurate for the identification of anatomic variants of renal arteries and veins. Dual-phase MDCT angiography including arterial and nephrographic phases followed by conventional abdominal radiography enables complete assessment of renal donors without significant increase of radiation dose. However, the evaluation of minor venous variants may be problematic because of their small diameters and poor opacification. | 18,953,477 |
Prevalence of hepatitis B virus genotypes in chronic carriers in Santiago, Chile. | The eight genotypes (designated A-H) of hepatitis B virus (HBV) display distinctive geographical distribution worldwide, with genotypes A, D and F frequently detected in South America. To determine the prevalence of HBV genotypes in Santiago, Chile, 131 samples from chronic carriers were used for PCR amplification, and genotyping was performed by RFLP. The results indicated that genotype F was the most prevalent among HBV carries (84% of the cases), whereas genotypes A, B, C and D were found at a prevalence of 3.8, 3.8, 6.1, and 2.3%, respectively. We discuss these data in the complex scenario of HBV epidemiology. | 18,953,483 |
Serum total selenium status in Greek adults and its relation to age. The ATTICA study cohort. | The trace element selenium is an essential micronutrient for human health and its low levels in serum are implicated in the pathogenesis of several chronic diseases. Therefore, the determination of total selenium in serum may contribute to the assessment of the health and nutritional status of certain populations. The objective of the present work was to determine total selenium in the serum of 506 healthy volunteers that participated in the ATTICA study. Selenium was determined in serum by using the technique of inductively coupled plasma mass spectrometry. The mean serum selenium concentration was determined to be 91.8 +/- 33.7 microg/L (N = 506); 87.6% of women and 88.5% of men had serum selenium concentration below 125 microg/L, the cutoff considered to be required for optimal glutathione peroxidase activity. No association was found between serum selenium levels and the gender of the participants while a significant decline of selenium with age (p < 0.0001) was observed. According to our results, no anthropometric, lifestyle, nutritional, or biochemical indices were able to affect the association between serum selenium and age. This result may indicate that other factors such as selenium distribution as well as retention may be affecting the relationship between serum selenium and age. | 18,953,500 |
Serum zinc, plasma ghrelin, leptin levels, selected biochemical parameters and nutritional status in malnourished hemodialysis patients. | This study was performed to investigate the serum zinc (Zn), plasma ghrelin, leptin levels and nutritional status, and to evaluate the potential association between malnutrition and these investigated parameters in malnourished hemodialysis (HD) patients. Fifteen malnourished HD patients, aged 42.9 +/- 2.11 years, who underwent the HD for 46.44 +/- 7.1 months and 15 healthy volunteers, aged 41.0 +/- 2.17 years, were included in this study. The nutritional status of the subjects was determined by the subjective global assessment (SGA). Anthropometric measurements were taken by bioelectrical impedance after HD. Blood samples were collected for the analysis of zinc (Zn), ghrelin, leptin, and selected blood parameters. The HD patients consumed less energy and nutrients than controls. In HD patients, body weight, body mass index (BMI) (p < 0.001), basal metabolic rate (BMR), body fat, lean body mass (LBM), serum Zn, copper (Cu) (p < 0.05), sodium (Na) (p < 0.01), glucose (p < 0.05), albumin (p < 0.01), total cholesterol (p < 0.001), and ghrelin (p < 0.05) were lower whereas body water ratio (p < 0.001), serum potassium (K) (p < 0.01), inorganic phosphorous (Pi), blood urea nitrogen, creatinine (p < 0.001), and plasma insulin (p < 0.05) levels were higher than the controls. No difference existed between HD patients and controls regarding plasma leptin levels. There were positive correlations for body weight-fasting glucose and body weight-leptin (p < 0.05), body weight-BMI and body weight-LBM (p < 0.01); body fat-leptin (p < 0.05); BMI-fasting glucose, BMI-leptin, and BMI-body fat (p < 0.05); albumin-hemoglobin and albumin-insulin (p < 0.05). Negative correlation was found for SGA score-ghrelin (p < 0.05). Malnutrition in HD patients may result from inadequate energy and nutrient intake and low Zn and ghrelin levels. Zinc supplementation to the diets of HD patients may be of value to prevent the malnutrition. | 18,953,507 |
Arteriovenous malformation of the pancreas: assessment of clinical and multislice CT features. | This study was undertaken to analyze the clinical and CT features of arteriovenous malformation (AVM) of the pancreas. Seven lesions in six consecutive patients (one woman and five men, mean age 51 years) with AVM of the pancreas who underwent multiphase contrast-enhanced CT with 0.5 or 1-mm collimation were retrospectively studied. CT images were evaluated and correlated with angiographic findings by two radiologists. In four patients, the lesions were incidental findings. Two patients presented with abdominal pain and gastrointestinal bleeding, respectively. Serum amylase levels were within normal limits in all patients. The mean size of the lesions was 32.1 mm (3.0-97.3 mm). Conglomeration of strong nodular stains and early enhancement of the portal venous system were observed for all the lesions. The diagnosis of AVM of the pancreas was retrospectively established for all lesions, but was prospectively established for four lesions. The feeding arteries of all lesions were depicted, showing agreement with those observed by angiography performed for four lesions. One lesion showed pseudocyst formation, haziness around the lesion, and strong enhancement of the duodenal wall. Multiphase CT examination using multislice CT is useful for diagnosis of AVM of the pancreas, including identification of the feeding arteries. | 18,953,516 |
[Semen analysis: spermiogram according to WHO criteria]. | Semen analysis plays a key role in diagnostics of male infertility. Semen analysis should be done according to WHO guidelines (1999), which are currently under revision. Standard procedures of semen analysis include evaluation of sperm concentration, motility, morphology, and vitality as well as determination of round cells, leukocytes, and sperm antibodies. Analysis of biochemical markers is optional. Several methods of sperm preparation are available for assisted reproduction procedures. Patients should be asked to remain abstinent for at least 48 h and a maximum of 7 days prior to ejaculation.Special focus has to be on quality control programs in andrological laboratories based on WHO guidelines. Only by means of standardized semen analysis the andrologist is capable of counseling infertile couples and diagnosing andrological deficits to finally determine therapeutic strategies including techniques of assisted reproduction. | 18,953,523 |
Variability in motor learning: relocating, channeling and reducing noise. | Variability in motor performance decreases with practice but is never entirely eliminated, due in part to inherent motor noise. The present study develops a method that quantifies how performers can shape their performance to minimize the effects of motor noise on the result of the movement. Adopting a statistical approach on sets of data, the method quantifies three components of variability (tolerance, noise, and covariation) as costs with respect to optimal performance. T-Cost quantifies how much the result could be improved if the location of the data were optimal, N-Cost compares actual results to results with optimal dispersion at the same location, and C-Cost represents how much improvement stands to be gained if the data covaried optimally. The TNC-Cost analysis is applied to examine the learning of a throwing task that participants practiced for 6 or 15 days. Using a virtual set-up, 15 participants threw a pendular projectile in a simulated concentric force field to hit a target. Two variables, angle and velocity at release, fully determined the projectile's trajectory and thereby the accuracy of the throw. The task is redundant and the successful solutions define a nonlinear manifold. Analysis of experimental results indicated that all three components were present and that all three decreased across practice. Changes in T-Cost were considerable at the beginning of practice; C-Cost and N-Cost diminished more slowly, with N-Cost remaining the highest. These results showed that performance variability can be reduced by three routes: by tuning tolerance, covariation and noise in execution. We speculate that by exploiting T-Cost and C-Cost, participants minimize the effects of inevitable intrinsic noise. | 18,953,531 |
Plant voltage-dependent anion channels are involved in host defense against Pseudomonas cichorii and in Bax-induced cell death. | The voltage-dependent anion channel (VDAC) is a major outer mitochondrial membrane protein. It is well documented that VDAC plays an important role in apoptosis, a kind of programmed cell death, in mammalian systems. However, little is known about the role of the plant counterpart during the process of plant-specific cell death such as pathogen-induced hypersensitive response. To address this issue, we isolated three VDAC full-length cDNAs (NtVDAC1-3) from Nicotiana tabacum. The deduced products, NtVDACs, share 78-85% identity and retain the conserved eukaryotic mitochondrial porin signature distal to their C-terminal regions. Mitochondrial localization of three NtVDACs in plant cells was confirmed via a green fluorescent protein fusion method. Then, we addressed the main issue concerning pathogenesis relation. The N. benthamiana orthologues of NtVDACs were upregulated by challenge with the non-host pathogen Pseudomonas cichorii, but not after challenge with the virulent pathogen P. syringae pv. tabaci. Both the pharmaceutical inhibition of VDAC and silencing of NbVDACs genes compromised the non-host resistance against P. cichorii, suggesting the involvement of VDACs in defense against non-host pathogen. Involvement of NbVDACs in Bax-mediated cell death was also verified using a similar approach. | 18,953,543 |
Quantitative parameters to compare image quality of non-invasive coronary angiography with 16-slice, 64-slice and dual-source computed tomography. | Multi-slice computed tomography (MSCT) is a non-invasive modality to visualize coronary arteries with an overall good image quality. Improved spatial and temporal resolution of 64-slice and dual-source computed tomography (DSCT) scanners are supposed to have a positive impact on diagnostic accuracy and image quality. However, quantitative parameters to compare image quality of 16-slice, 64-slice MSCT and DSCT are missing. A total of 256 CT examinations were evaluated (Siemens, Sensation 16: n = 90; Siemens Sensation 64: n = 91; Siemens Definition: n = 75). Mean Hounsfield units (HU) were measured in the cavum of the left ventricle (LV), the ascending aorta (Ao), the left ventricular myocardium (My) and the proximal part of the left main (LM), the left anterior descending artery (LAD), the right coronary artery (RCA) and the circumflex artery (CX). Moreover, the ratio of intraluminal attenuation (HU) to myocardial attenuation was assessed for all coronary arteries. Clinical data [body mass index (BMI), gender, heart rate] were accessible for all patients. Mean attenuation (CA) of the coronary arteries was significantly higher for DSCT in comparison to 64- and 16-slice MSCT within the RCA [347 +/- 13 vs. 254 +/- 14 (64-MSCT) vs. 233 +/- 11 (16-MSCT) HU], LM (362 +/- 11/275 +/- 12/262 +/- 9), LAD (332 +/- 17/248 +/- 19/219 +/- 14) and LCX (310 +/- 12/210 +/- 13/221 +/- 10, all p < 0.05), whereas there was no significant difference between DSCT and 64-MSCT for the LV, the Ao and My. Heart rate had a significant impact on CA ratio in 16-slice and 64-slice CT only (p < 0.05). BMI had no impact on the CA ratio in DSCT only (p < 0.001). Improved spatial and temporal resolution of dual-source CT is associated with better opacification of the coronary arteries and a better contrast with the myocardium, which is independent of heart rate. In comparison to MSCT, opacification of the coronary arteries at DSCT is not affected by BMI. The main advantage of DSCT lies with the heart rate independency, which might have a positive impact on the diagnostic accuracy. | 18,953,544 |
Evaluation of the integrity of the deltoid ligament in supination external rotation ankle fractures: a systematic review of the literature. | Review the literature concerning modalities to evaluate the integrity of the deltoid ligament in patients with supination external rotation ankle fractures. The electronic databases Pubmed/Medline, CINAHL and Embase were searched from 1987 to November 2007 to identify all published original studies concerning diagnostic modalities to evaluate the integrity of the deltoid ligament in adult ankle fractures. This review included nine studies involving 423 ankle fractures. Three trails investigated medial tenderness; two studies, ecchymosis; two studies, swelling; one study, an injury radiograph; six studies, a type of radiographic stress view; one study, the Lauge-Hansen classification; one study, MRI; and one article studied arthroscopy in the evaluation of the deltoid ligament integrity. Swelling, ecchymosis, medial tenderness, initial injury radiographs and the Lauge-Hansen classification are less adequate predictors of the integrity of the deltoid ligament. Manual or the less painful variant, the gravity external rotation stress radiographs are considered the gold standard. The amount of medial clear space widening indicative of a positive external rotation stress test has been somewhat variable in the literature but > or =5 mm is generally regarded as most reliable. Achieving adequate external rotation of the foot when obtaining stress radiographs is more important than positioning the ankle in the appropriate degree of ankle flexion. The amount of applied force necessary when performing an external rotation stress radiograph is not well defined and mainly determined by the patient's pain level. The indication for surgery should not be based on the absolute value of one parameter but on the combination of several parameters. If nonoperative treatment is chosen despite a positive stress radiograph, close follow-up is critical because subluxation of the ankle joint is still possible. MRI could be useful in individual cases. | 18,953,550 |
Influence of cosmetically tinted soft contact lenses on higher-order wavefront aberrations and visual performance. | To investigate the influence of cosmetically tinted soft contact lenses on ocular higher-order aberrations and visual performance, and to analyze the relationship between these parameters after the lens wear. In 44 eyes of 22 subjects, visual acuity, contrast sensitivity under photopic and mesopic conditions, and ocular higher-order aberrations were evaluated before and after wearing the tinted soft contact lenses (1-day Acuvue Colours; Vistakon, Jacksonville, FL). Contrast sensitivity under a photopic condition was determined at 3, 6, 12, and 18 cycles per degree, and the area under the log contrast sensitivity function (AULCSF) was calculated. Mesopic contrast sensitivity with and without glare was assessed. Ocular higher-order aberrations for a 4-mm pupil were measured, and coma-like, spherical-like, and total higher-order aberrations were determined. The tinted contact lens wearing resulted in significant decreases in log contrast sensitivity at all spatial frequencies (P < 0.05) and AULCSF (P < 0.0001), although 100% contrast visual acuity did not change. Log mesopic contrast sensitivity with and without glare was also reduced significantly by the lens wear (P < 0.0001). The contact lens wear significantly increased coma-like, spherical-like, and total higher-order aberrations (P < 0.0001). The induced changes in higher-order aberrations were analyzed in relation to the changes in contrast sensitivity function. Although the changes in coma-like and spherical-like aberrations did not correlate significantly with those in AULCSF (P > 0.05), the changes in total higher-order aberrations showed a significant correlation with those in AULCSF (P < 0.05). On the other hand, there was no significant relationship between the changes in higher-order aberrations and the changes in log mesopic contrast sensitivity with and without glare (P > 0.05). Cosmetically tinted contact lenses increase ocular higher-order aberrations and worsen contrast sensitivity under both photopic and mesopic conditions. Increases in higher-order aberrations are responsible for decreased contrast sensitivity under the photopic condition. Tinted contact lens wearers should be sufficiently informed about the possible reduction in optical quality of the eye and quality of vision. | 18,953,556 |
Human error in strabismus surgery: quantification with a sensitivity analysis. | Reoperations are frequently necessary in strabismus surgery. The goal of this study was to analyze human-error related factors that introduce variability in the results of strabismus surgery in a systematic fashion. We identified the primary factors that influence the outcome of strabismus surgery. For each of the human-error related factors we quantified variation with clinical assessments: measurement of the angle of strabismus, surgical strategy and surgical accuracy. Firstly, six patients were examined by six orthoptists, and accuracy of prism cover tests was assessed. Secondly, a questionnaire with sample cases (10 degrees, 15 degrees and 20 degrees of infantile esotropia) was put to orthoptists, to determine variation in current surgical strategy. Finally, photographs made during surgery were analyzed to assess surgical accuracy. The influence of human-error related factors was related to the influence of inter-patient differences with a mechanical model. The relative contribution of all factors was assessed with a sensitivity analysis, and results were compared to clinical studies. The surgical trajectory of strabismus surgery could be modeled mathematically. Measurement of angle of strabismus, surgical technique, anatomy and physiology were considered. Variations in the human-error related factors were: (1) the latent angle at distant fixation was measured with a 90% confidence interval of 5 degrees , and comprised 20% of the total variance of the postoperative angle, (2) orthoptists decided for bilateral recessions of, respectively, 7.3 +/- 1.7 mm (total amount of two recessions), 9.1 +/- 1.2 mm and 10.3 +/- 1.3 mm, which comprised 15% of the total variance, and (3) surgical accuracy was estimated at +/-0.5 mm, which comprised 20% of the total variance. The human error in strabismus surgery could be quantified with a sensitivity analysis. Approximately half of the reoperations in strabismus surgery are caused by inaccuracy in the measurement of the angle of strabismus, variability in surgical strategy and imprecise surgery. | 18,953,557 |
Depressive symptoms and self-reported occupational injury in small and medium-sized companies. | This survey was designed to determine whether depressive symptoms had an effect on the risk of self-reported occupational injury in South Korea. We conducted a prospective follow-up survey of workers at 44 small- to medium-sized companies classified into manufacturing or service businesses; 1,350 questionnaires were used in the final analysis. The first survey requested information regarding personal characteristics, work characteristics, and depressive symptoms (CES-D); the second survey queried participants in the first survey about self-reported occupational injuries (including minor scratches or cuts) experienced in the previous 4 months. Risk ratios (RRs) were calculated through Poisson regression analysis. The number of occupational injuries during the previous 4 months served as the dependent variable, and depressive symptoms served as the independent variable. After adjustment for demographic factors, the RRs were 1.75 (95% CI: 1.41-2.18) and 2.68 (95% CI: 1.98-3.64) in male and female, respectively. Additional adjustment for work-related variables did not alter the RR considerably in females (2.65; 95% CI: 1.95-3.59). Among the male workers, however, the RR was not significant (1.21; 95% CI: 0.95-1.55). On the other hand, when the analysis was limited to blue-collar workers, after adjustment for demographic and work-related factors, the RRs remained significant in both genders (male: 1.34; 95% CI: 1.03-1.74; female: 2.04; 95% CI: 1.41-2.95). We found that the risk of self-reported occupational injury experience was higher in workers who reported depressive symptoms. Additional study using objective data is required to confirm our results. | 18,953,561 |
Impact of the exercise mode on heart rate recovery after maximal exercise. | Heart rate recovery 1 min after exercise termination (HRR-1) is a prognostic predictor. However, the influence of the exercise mode on HRR-1 is incompletely characterised. Twenty-nine young and healthy subjects and 16 elderly patients with chronic heart failure underwent cardiopulmonary exercise testing using cycle ergometer and treadmill ramp protocols in random order. HRR-1 and heart rate recovery 2 and 3 min after exercise (HRR-2, HRR-3) during active recovery and peak oxygen consumption (peak VO(2)) were measured. In both healthy subjects (32 +/- 14 vs. 27 +/- 10 bpm) and HF patients (19 +/- 8 vs. 14 +/- 9 bpm), HRR-1 was faster after cycle exercise (p = 0.029; p for between group difference 0.94). In contrast, HRR-2 and HRR-3 were similar after both tests in both groups. Peak VO(2) was lower during cycle as compared to treadmill exercise in both groups. In conclusion, in both healthy subjects and HF patients, HRR-1 depends on the mode of exercise as peak VO(2) does. | 18,953,564 |
Molecular studies of BKCa channels in intracranial arteries: presence and localization. | Large conductance calcium-activated potassium channels (BK(ca)) are crucial for the regulation of cerebral vascular basal tone and might be involved in cerebral vasodilation relevant to migraine and stroke. We studied the differential gene expression of mRNA transcript levels and protein expression of the BK(Ca) channel in rat basilar, middle cerebral, and middle meningeal arteries by reverse transcription polymerase chain reaction (RT-PCR), quantitative real-time PCR, and Western blotting. Distribution patterns were investigated using in situ hybridization and immunofluorescence studies. RT-PCR and quantitative real-time PCR detected the expression of the BK(Ca) channel mRNA transcript in rat basilar, middle cerebral, and middle meningeal arteries, with the transcript being expressed more abundantly in rat basilar arteries than in middle cerebral and middle meningeal arteries. Western blotting detected the BK(Ca) channel protein in rat basilar and middle cerebral arteries. In situ hybridization and immunofluorescence studies confirmed that the BK(Ca) channel mRNA and protein expression was localized to smooth muscle cells in all three intracranial arteries. The data thus suggest the presence and localization of both mRNA and protein expression of the BK(Ca) channel in the smooth muscle cell layer in rat basilar, middle cerebral, and middle meningeal arteries. | 18,953,570 |
Whole-tree sap flow is substantially diminished by leaf herbivory. | Ecohydrological models consider the relationship between tree size and structure (especially leaf area index) and water use but generally treat herbivory as a source of unwanted noise in the data. Little is known of how insect damage to leaves influences whole-plant water use in trees. Water use is driven by environmental demand and the total leaf area through which transpiration can occur, but the effects of insects are expected to be complex. Different kinds of insects could have different effects; for example, chewing insects reduce leaf area, whereas sucking and tissue mining insects reduce leaf function without reducing area. Further, plants respond to herbivory in a range of ways, such as by altering leaf production or abscising leaves. We examined the effect of insects on Eucalyptus blakelyi in a woodland near Canberra, Australia, using sap flow velocity as a measure of whole-plant water use. We applied insecticide to 16 trees matched to an untreated control group. After 6 months, we examined the effects on sap flow velocity and crown condition. There was a general increase in sap flow velocity as trees produced leaves over the growing season, but the increase in sap flow for trees without insecticide protection was half that of the protected trees (increase: 4.4 vs. 9.0 cm/h, respectively). This dramatic effect on sap flow was consistent with effects on crown condition. Unprotected trees had 20% less leaf mass per unit stem in the crown. In addition, unprotected trees had a 20% greater loss of leaf functional area from necrosis. It should be noted that these effects were detected in a year in which there was not an outbreak of the psyllids (Homoptera) that commonly cause severe leaf damage to this tree species. It is predicted that the effect in a psyllid outbreak year would be even more substantial. This result underscores the significant impact that insect herbivores can have on an ecological process of significance to the ecosystem, namely, the movement of water from the soil to the atmosphere. | 18,953,575 |
A randomized, phase II study of preoperative plus postoperative imatinib in GIST: evidence of rapid radiographic response and temporal induction of tumor cell apoptosis. | Gastrointestinal stromal tumor (GIST) is the most common sarcoma arising in the gastrointestinal (GI) tract. Imatinib mesylate (imatinib) is efficacious in treating advanced and metastatic GIST. Patients undergoing resection of GIST realize a highly variable median disease-free survival (DFS). In the absence of prospective data, we conducted a randomized, phase II study to assess the safety and efficacy of preoperative and postoperative imatinib for the treatment of GIST. Nineteen GIST patients undergoing surgical resection were randomized to receive 3, 5, or 7 days of preoperative imatinib (600 mg daily). Patients received postoperative imatinib for 2 years. Perioperative adverse events were compared with those in an imatinib-naïve historical control. The efficacy of imatinib was assessed by (18)fluorodeoxyglucose positron emission tomography ((18)FDG-PET), dynamic computed tomography (dCT), terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, and DFS. Imatinib did not affect surgical morbidity as compared with an imatinib-naïve cohort (p >/= 0.1). Most patients responded to preoperative imatinib by (18)FDG-PET and dCT (69% and 71%, respectively). Tumor cell apoptosis increased by an average of 12% (range 0-33%) and correlated with the duration of preoperative imatinib (p = 0.04). Median DFS of patients treated with surgery and imatinib was 46 months (range 10-46 months). Tumor size was a predictor of recurrence after postoperative imatinib (p = 0.02). Imatinib appears to be safe and may be considered for patients undergoing surgical resection of their GIST. Radiographic response and tumor cell apoptosis occur within the first week of imatinib therapy. | 18,953,611 |
Physical activity behaviors in women with newly diagnosed ductal carcinoma-in-situ. | Epidemiological evidence suggests that physical activity may affect breast cancer risk and other health outcomes. Little information is available regarding changes in activity after diagnosis and treatment of in-situ cancer. We enrolled 487 women with newly diagnosed ductal carcinoma-in-situ (DCIS) in a longitudinal cohort study. Exercise behaviors were assessed at enrollment and at 18 months. Changes in exercise frequency over time were compared, and the impact of demographic and treatment-related variables was evaluated. Enrollment and 18-month exercise data were available for 391 women (80%). At enrollment, most women performed strenuous physical activity infrequently, and only half engaged in any type of exercise more than twice a week. Overall activity patterns did not change greatly over the course of the study. However, logistic regression modeling of changes in exercise revealed that women who underwent unilateral or bilateral mastectomy (hazard ratio [HR], 2.4; 95% confidence interval [95% CI], 1.3-4.4) and those who were anxious at enrollment (HR, 2.1; 95% CI, 1.1-4.1) were statistically significantly more likely to decrease exercise levels, and women who worked were significantly more likely to increase exercise over the course of the study (HR, 1.9; 95% CI, 1.1-3.3). Nonsignificant variables included age, reconstructive surgery, depressive symptoms, financial status, education, and tamoxifen use. A large proportion of women with newly diagnosed DCIS were inactive and remained so over time. Women who underwent mastectomy, as well as women who were more anxious, were more likely to decrease their level of physical activity. Women with DCIS might benefit from targeted interventions to increase physical activity. | 18,953,612 |
Genotype phenotype correlations of cardiac beta-myosin heavy chain mutations in Indian patients with hypertrophic and dilated cardiomyopathy. | The aim of the current study was to determine the frequency of mutations in the beta-myosin heavy chain gene (MYH7) in a cohort of hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) and their families, and to investigate correlations between genotype and phenotype. About 130 consecutive patients diagnosed with HCM or DCM (69 with HCM and 61 with DCM) attending the cardiology clinic of Post Graduate Institute of Medical Education and Research were screened for mutations in the MYH7 gene. The control group for genetic studies consisted of 100 healthy subjects. We report 14 mutations in 6 probands (5 probands in HCM and 1 proband in DCM) and their family members. Out of these 6 mutations, 3 are new and are being reported for the first time. One known mutation (p.Gly716Arg) was found to be "de novo" which resulted in severe asymmetric septal hypertrophy (31 mm) and resulted in the sudden cardiac death (SCD) of the proband at the age of 21 years. Further, a DCM causing novel mutation p.Gly377Ser was identified which resulted in the milder phenotype. The present study shows that there is genetic and phenotypic heterogeneity of cardiomyopathies in Indian population. Further, the location and type of mutation in a given sarcomeric gene determines the severity and phenotypic plasticity in cardiomyopathies. | 18,953,637 |
Developing a university-workforce partnership to address rural and frontier MCH training needs: the Rocky Mountain Public Health Education Consortium (RMPHEC). | The objective of the article is to provide the socio-cultural, political, economic, and geographic conditions that justified a regional effort for training maternal and child health (MCH) professionals in the Rocky Mountain region, describe a historical account of factors that led to the development of the Rocky Mountain Public Health Education Consortium (RMPHEC), and present RMPHEC as a replicable model developed to enhance practice/academic partnerships among state, tribal, and public health agencies and universities to enhance public health capacity and MCH outcomes. This article provides a description of the development of the RMPHEC, the impetus that drove the Consortium's development, the process used to create it, and its management and programs. Beginning in 1997, local, regional, and federal efforts encouraged stronger MCH training and continuing education in the Rocky Mountain Region. By 1998, the RMPHEC was established to respond to the growing needs of MCH professionals in the region by enhancing workforce development through various programs, including the MCH Certificate Program, MCH Institutes, and distance learning products as well as establishing a place for professionals and MCH agencies to discuss new ideas and opportunities for the region. Finally over the last decade local, state, regional, and federal efforts have encouraged a synergy of MCH resources, opportunities, and training within the region because of the health disparities among MCH populations in the region. The RMPHEC was founded to provide training and continuing education to MCH professionals in the region and as a venue to bring regional MCH organizations together to discuss current opportunities and challenges. RMPHEC is a consortium model that can be replicated in other underserved regions, looking to strengthen MCH training and continuing education. | 18,953,642 |
Acculturation among three racial/ethnic groups of host and immigrant adolescents. | This study compares Latino host, Latino immigrant, Asian-American host, Asian-American immigrant and European-American host groups of adolescents with respect to four acculturation-related variables: ethnic identity exploration, ethnic identity affirmation/belonging, outgroup orientation, and American identity. Using the five ethno-generational categories as a grouping variable, we conducted analyses of 313 survey responses to the acculturation items at two time periods, 9 weeks apart. Results showed that differences among the three host racial/ethnic groups can best be explained by a group dominance perspective, whereby the two racial/ethnic minority groups are more similar to each other than they are to the European-American group. Furthermore, the relationship between American identity and ethnic identity components is stronger among the three host groups, as compared to the immigrant groups. Implications for future research with adolescent members of the host group whose heritage culture is non-European are drawn. | 18,953,649 |
Cytogenetic and Y chromosome microdeletion screening studies in infertile males with Oligozoospermia and Azoospermia in Southeast Turkey. | In view of the genetic risks for the next generation, the importance of careful evaluation of karyotypes and AZF microdeletions in male infertility prior to assisted reproduction is evident. In the present study, it is aimed to investigate the frequency and types of both major chromosomal abnormalities by using standard cytogenetic methods and Y chromosome microdeletions of infertile males with azoospermia and oligozoospermia to give appropriate genetic counseling before assisted reproduction techniques in southeast Turkey. A total of 80 infertile males (52 were azoospermic, 25 oligospermic and 3 asthenospermic) were studied for the cytogenetic evaluation and molecular AZF screening program prior to use of assisted reproduction techniques. A detailed history was taken for each man. Karyotyping was performed on peripheral blood lymphocytes according to standard methods. Polymerase chain reaction (PCR) amplification by using 15 Y-specific sequence-tagged sites of AZF region was performed to screen the microdeletions in the AZF region of Y chromosome. Of 80 cases, 71 had normal karyotype (46,XY). The total prevalence of chromosomal abnormalities was found to be 11.2% (9/80), including seven patients with Klinefelter syndromes and two patients with balanced autosomal rearrangements. All of the patients with Klinefelter Syndrome had azoospermia, but carriers with translocation had oligospermia. The deletions of Y chromosome were seen in one patient (1.3%) with features of normal karyotype and azoospermia. Microdeletions were seen in the AZFc and AZFd regions. Neither AZFa nor AZFb microdeletions were detected. The occurrence of chromosomal anomalies and Y chromosome microdeletions among infertile males strongly suggests the need for routine genetic testing and counseling prior to employment of assisted reproduction techniques. | 18,953,646 |
Egg distributions of insect parasitoids: modelling and analysis of temporal data with host density dependence. | A simple numerical procedure is presented for the problem of estimating the parameters of models for the distribution of eggs oviposited in a host. The modelling is extended to incorporate both host density and time dependence to produce a remarkably parsimonious structure with only seven parameters to describe a data set of over 3,000 observations. This is further refined using a mixed model to accommodate several large outliers. Both models show that the level of superparasitism declines with increasing host density, and the rate declines over time. It is proposed that the differing behaviours represented by the mixed model may reflect a balance between behavioural strategies of different selective benefit. | 18,953,656 |
Prediction of protein structural classes using hybrid properties. | In this paper, amino acid compositions are combined with some protein sequence properties (physiochemical properties) to predict protein structural classes. We are able to predict protein structural classes using a mathematical model that combines the nearest neighbor algorithm (NNA), mRMR (minimum redundancy, maximum relevance), and feature forward searching strategy. Jackknife cross-validation is used to evaluate the prediction accuracy. As a result, the prediction success rate improves to 68.8%, which is better than the 62.2% obtained when using only amino acid compositions. Therefore, we conclude that the physiochemical properties are factors that contribute to the protein folding phenomena and the most contributing features are found to be the amino acid composition. We expect that prediction accuracy will improve further as more sequence information comes to light. A web server for predicting the protein structural classes is available at http://app3.biosino.org:8080/liwenjin/index.jsp. | 18,953,662 |
Pili in Gram-negative and Gram-positive bacteria - structure, assembly and their role in disease. | Many bacterial species possess long filamentous structures known as pili or fimbriae extending from their surfaces. Despite the diversity in pilus structure and biogenesis, pili in Gram-negative bacteria are typically formed by non-covalent homopolymerization of major pilus subunit proteins (pilins), which generates the pilus shaft. Additional pilins may be added to the fiber and often function as host cell adhesins. Some pili are also involved in biofilm formation, phage transduction, DNA uptake and a special form of bacterial cell movement, known as 'twitching motility'. In contrast, the more recently discovered pili in Gram-positive bacteria are formed by covalent polymerization of pilin subunits in a process that requires a dedicated sortase enzyme. Minor pilins are added to the fiber and play a major role in host cell colonization.This review gives an overview of the structure, assembly and function of the best-characterized pili of both Gram-negative and Gram-positive bacteria. | 18,953,686 |
Tonsillectomy and breast cancer risk in the Western New York Diet Study. | Exposures during early life may affect risk of breast cancer. History of tonsillectomy has recently been associated with risk of several cancers, including cancer of the breast. We conducted a population-based case-control study of women living in Western New York from 1986 to 1991. Cases had incident, primary, pathologically confirmed breast cancer and were recruited through all major hospitals in the region (n = 740). Population-based controls (n = 810) were randomly sampled from among drivers' license holders from Department of Motor Vehicles records (<65 yrs) and from Health Care Finance Administration records (> or =65 yrs). Participants were interviewed with regard to diet, anthropometrics, demographics, medical, and reproductive history. Unconditional logistic regression models stratified by menopausal status were used to estimate multivariate odds ratios (OR) and 95% confidence intervals (95% CI). A history of tonsillectomy was associated with increased breast cancer risk among premenopausal (OR 1.50, 95% CI: 1.08-2.08) but not postmenopausal women (OR 1.05, 95% CI: 0.79-1.38). Our findings add to accumulating data implicating tonsillectomy in risk of cancer. Tonsillectomy may be an indicator for conditions of chronic inflammation and/or reduced efficiency of immune function. Our study also provides additional evidence that early life exposures may affect premenopausal breast cancer risk. | 18,953,693 |
Dendritic cell subtypes as primary targets of vaccines: the emerging role and cross-talk of pattern recognition receptors. | Preventive vaccination is the most successful approach against infectious diseases and has a great impact on world health. Vaccines operate through the activation of innate immunity that helps to stimulate antigen-specific T- and B-lymphocytes. These events are orchestrated by dendritic cells (DCs) that are able to sample foreign structures and concomitantly sense 'danger signals'. Thus, DCs provide a functional link between innate and acquired immunity, and due to their regulatory potential are referred to as natural adjuvants. Human conventional and plasmacytoid DCs express different sets of well-characterized Toll-like membrane receptors (TLRs) that recognize a broad range of conserved molecular patterns of pathogens. The recently discovered cytosolic Nod-like receptors (NLRs) and RIG-like helicases (RLHs) also turned out to participate in pathogen recognition and modulation of immune responses through interacting signaling pathways. As a result of their collaboration, the TLR, NLR and RLH recognition systems induce the secretion of different combinations of cytokines that play a fundamental role in T-cell activation and instruction. Ligands of the innate recognition systems emerge as new adjuvants for vaccine design, whereas manipulation of the signaling pathways mediated by these receptors offers new avenues for fine tuning immune responses and optimizing immunotherapies. | 18,953,714 |
Maintenance of serological memory. | Long-lived plasma cells are key to maintaining long-term humoral immunity after infection or vaccination. Some vaccines and/or infections induce antibody levels that remain stable for the life of the individual. However, the mechanism whereby these long-lived plasma cells are maintained over long periods of time remains an open question. Furthermore, given a finite number of sustainable plasma cells within the bone marrow, it is also unclear how space for newly induced plasma cells is generated without compromising the pre-existing repertoire. Here we review the current understanding of these important issues. | 18,953,719 |
Inhibition of bacterial oxidases by formamide and analogs. | The enzymatic activity of Paracoccus denitrificans cytochrome c oxidase (COX) and Escherichia coli cytochrome b(o) ubiquinol oxidase (QOX) was determined in the presence of formamide, N,N-dimethyl formamide and N,N-dimethyl acetamide. Formamide was found to inhibit the enzyme activity of the oxidases most significantly, whereas the other two compounds inhibited the activity to a lesser extent. The effects of formamide and analogs on enzyme activity were very similar for COX and QOX, indicating that the mechanism of inhibition might be the same for both of these oxidases. The inhibition kinetics followed a non-competitive mechanism. Studies using proteoliposomes of COX and QOX containing the electron entry site of the enzyme directed towards the outside of the vesicles showed that the effect of inhibition by formamide was higher when the inhibitor was present on the outside of the proteoliposome compared to when it was present only in the aqueous core. This indicates that inhibition of enzyme activity by formamide possibly predominantly involves blocking of the water exit pathway in the oxidases. | 18,953,727 |
Neuroprotection of GST, an extract of traditional Chinese herb, against ischemic brain injury induced by transient brain ischemia and reperfusion in rat hippocampus. | In this study, we investigated the effect of GST, an extract of Chinese traditional herb, on transient brain ischemia/reperfusion-induced neuronal cell death. Immunoblotting was used to detect the phosphorylation of MLK, JNK and c-jun. Transient (15 minutes) brain ischemia was induced by the four-vessel occlusion in Sprague-Dawley rats. GST was administrated to the SD rats 20 minutes before ischemia or 1 hour after ischemia. Our data showed that the pretreatment of GST could inhibit phosphorylation of MLK, JNK and c-jun. Moreover, GST showed potent neuroprotective effects on ischemic brain damage in vivo and administration of it 1 hour after ischemia also achieved the protective effects. These results indicate that GST has a prominent neuroprotection action against brain ischemic damage and provides a promising therapeutic approach for ischemic brain injury. | 18,953,737 |
Stability and relative validity of the Multiple Sclerosis Impact Profile (MSIP). | To examine the stability and relative validity of the Multiple Sclerosis Impact Profile (MSIP) in criterion-related groups. The MSIP is a disease-targeted health impact measure based on a selection of International Classification of Functioning, Disability and Health (ICF) aspects selected by 98 patients and medical and non-medical health professionals. Data were obtained from a postal survey of 377 individuals with Multiple Sclerosis (MS) attending the MS centre of the University Medical Center Groningen (UH) and 153 subjects from the MS patients' association. Stability was tested with t-tests for paired samples and intraclass correlation coefficients for repeated measures in a sample of 251 individuals from the UH sample. The Relative Validity (RV) was estimated using the Short Form Questionnaire (SF-36), the World Health Organization Quality of Life-BREF (WHOQOL-BREF), the Disability and Impact Profile (DIP), the Impact on Autonomy Questionnaire (IPAQ) and the Groningen Activity Restriction Scale (GARS). These indicate that the MSIP is a stable measure in time. MSIP scales showed satisfactory and strong RV. In general, the domain-specific activities and participation measures (GARS and IPAQ) performed equally or slightly better than the comparable MSIP-scales, while the MSIP performed better than the multidimensional health impact measures (SF-36, DIP and WHOQOL-BREF). The MSIP demonstrated good stability and RV compared to generic health impact and domain-specific measures. | 18,953,748 |
Extensive-stage small-cell lung cancer: evolution of systemic therapy and future directions. | Extensive-stage small-cell lung cancer (ES-SCLC) is one of the most lethal malignancies, with a median overall survival of only 8-10 months with first-line chemotherapy despite response rates of 60%-80%. In the second-line setting, the prognosis is even more limited, with only 20%-30% of patients having a response and a median survival measured in weeks to months. This article will review systemic chemotherapy in first- and second-line treatment of patients with ES-SCLC and discuss novel therapeutic agents, cytotoxic and "targeted," with an emphasis on recently completed clinical trials and ongoing investigations. | 18,953,759 |
Waste processing and health. A position document of the Italian Association of Epidemiology (AIE) - May 2008. | This is a position document of the Italian Epidemiological Association (AIE) on the health hazards of waste disposal. The main objectives of the document are: 1) to support the decision makers on the safety of the existing waste treatment and disposal plants and of the planned new plants; b) to recommend protective actions in favour of populations exposed to toxic agents linked to illegal waste treatment and disposal; c) to signal circumstances that require the adoption of surveillance plan or ad hoc studies in order to unveil possible health effects associated to the environmental exposure to toxic agents derived from waste treatment and disposal. The evaluations presented in this document are based on the available scientific literature. AIE recommends the adoption of preventive policies to contain both the production of waste and the need to dispose it. AIE also recommends the participation and involvement of the population in all phases of waste management, from the decisional to the operational ones. | 18,953,763 |
A preliminary study investigating class characteristics in the Gurmukhi handwriting of 1st and 2nd generation Punjabis. | Gurmukhi is a written script of the Punjabi language spoken by 104 million people worldwide. It has been previously shown in a study of Punjabi residents to contain several unique class characteristics. In this paper these class characteristics and others were analysed in both 1st generation and 2nd generation Punjabi decedents residing in the United Kingdom. Using the Pearson Chi-squared test, eight characteristic features were found to be statistically different in the Gurmukhi handwriting of the two populations (p > 0.01). Additionally there are several changes in previously identified class characteristics, such as script type and angularity of characters, between the 1st generation and 2nd generation Punjabi populations. These class characteristics may be of value to forensic document examiners and allow them to identify the population and the generation of the writer of a suspect document. | 18,953,800 |
[Intraoperative cranial nerves monitoring under partial neuromuscular relaxation during cerebellopontine angle tumor resection]. | To evaluate the efficacy of multiple cranial nerves monitoring under partial Seventy elective neuromuscular relaxation during cerebellopontine angle (CPA) tumor resection. patients undergoing CPA tumor resection via microneurosurgery were randomly allocated to 2 equal groups: Group FN receiving intraoperative facial nerve (NF) monitoring and Group MN receiving monitoring of multiple nerves: trigeminal nerve, glossopharyngeal nerve, accessory nerve or hypoglossal nerve other than the FN which were considered at risk by the neurosurgeon preoperatively. The manipulation procedure were modified according to cranial nerves monitoring and neuromuscular relaxation was maintained at train of four stimulation (TOF)=3 by continuous vencronium infusion during the acoustic neuroma resection. The function of the cranial nerves monitored were evaluated preoperatively and 8 days postoperatively. Discernable and legible images of electromyographic wave complex were obtained during cranial nerve mapping and monitoring under intraoperative partial neuromuscular relaxation form all the patients. The facial nerve function of 4 patients exacerbated (from H-B grade I-II to grade III-IV) in both groups, and one new glossopharyngeal nerve function deficiency was found in Group FN, and one new hypoglossal nerve function deficiency was found in Group MN postoperatively. Intraoperative cranial nerves monitoring under partial neuromuscular relaxation is feasible. Multiple cranial nerves combined with facial nerve monitoring seems unable to increase the short-term protective effects of nerve function after CPA tumor resection. | 18,953,855 |
[Testosterone impairs insulin sensitivity in 3T3-L1 adipocytes and the related nongenomic mechanisms]. | To investigate the influence of rapid nongenomic effect of androgen on the insulin sensitivity of mature adipocytes and the molecular mechanism thereof. Fetal mice [corrected] preadipocytes of the line 3T3-L1 were cultured to develop into mature adipocytes. 3T3-L1 adipocytes were pretreated with testosterone of the concentration of 10-9 to approximately 10(-5) mol/L for a short-time 0-30 minutes) or a long-time (24 hours). Insulin (Ins) 200 microl at the concentration 100 micromol/L and 2-deoxy [3H] glucose were added to examine the glucose uptake. Phosphorylation and protein expression of Ins receptor (InsR) and its downstream signaling molecules (Akt and GSK3beta) were analyzed by Western blotting. The Ins-stimulated glucose uptake after the pretreatment of testosterone for 30 min and 24 h decreased gradually in response to the increasing of the concentration of testosterone with the nadir both at the testosterone concentration of 10(-5) mol/L (both P < 0.05). The phosphorylation levels of InsR, Akt, and GSK3Pbeta were significantly down-regulated by adding of testosterone at the concentration of 10(-6) mol/L for 3-30 minutes (all P < 0.05) or by adding of testosterone at the concentrations of 10(-7) - 10(-6) mol/L for 24 hours (all P < 0.05). The protein expression levels of InsR, Akt, and GSK3Pbeta, however, were not significantly affected by testosterone treatment. Rapid nongenomic effect of androgen may contribute to the insulin resistance in adipocytes. | 18,953,857 |
[Enhanced expression of caveolin-1 in articular chondrocytes in osteoarthritis]. | To study the expression level of caveolin-1 in articular chondrocytes in patients with osteoarthritis (OA), and whether catabolic factor IL-1beta stimulate caveolin-1 expression in articular chondrocytes. In human OA cartilage, caveolin-1 mRNA was investigated by quantitative real-time RT-PCR while caveolin-1 protein was detected by immunohistologic analysis in 8 cases. OA model was prepared by unilateral anterior cruciate ligament and medial collateral ligament transection in 20 rats. In cultured OA chondrocytes, caveolin-1 mRNA expression was studied by RT-PCR and quantitative real-time RT-PCR, and caveolin-1 protein was analyzed by Western blotting. In 6 of 8 OA cases, human OA articular cartilage, higher expression levels of both caveolin-1 mRNA and caveolin-1 protein were found in advanced degenerated cartilage than less degenerated cartilage of the same joints. In rat OA model, upregulated caveolin-1 expression was found, which was associated with the degree of cartilage destruction. IL-1beta (10 ng/ml) upregulated caveolin-1 mRNA/protein expression in cultured OA chondrocytes for at least 48 hours. Enhanced expression level of caveolin-1 is associated with cartilage degeneration in OA. IL-1beta stimulates caveolin-1 expression in articular chondrocytes, which may be responsible for OA development. | 18,953,858 |
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