title stringlengths 0 1.13k | abstract stringlengths 1 15.7k | PMID int64 22 36.5M |
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Negative brain: an integrative review on the neural processes activated by unpleasant stimuli. | Evolutionary pressure has led the nervous system to guarantee rapid and intense responses to negative events (dangerous, harmful or repugnant). Thus, the 'negative brain' (the set of neural mechanisms triggered by unpleasant or negative stimuli) is equipped with several specific characteristics. This review organizes the current data on the human negative brain in three blocks. Firstly, the "Input mechanisms" block describes those structures responsible for the rapid distribution of all sensory information. Secondly, the "Evaluation systems" block refers to the key pieces: those responsible for evaluating negative consequences of stimulation and deciding which response is the most appropriate for coping with them. Thirdly, the "Associated and output processes" block describes how evaluative elements may interact with other brain structures to modulate attention, store and recover situational information, activate defense/withdrawal motor programs (or plan new actions) and develop autonomic/motor actions to cope with the unpleasant event. Finally, an integrative summary that serves as a tentative model of the negative brain is provided. | 18,727,941 |
Usefulness of cell-penetrating peptides to improve intestinal insulin absorption. | Cell-penetrating peptides (CPPs) are a useful tool for delivering therapeutic macromolecules across cell membranes. We previously devised an approach using CPPs without intermolecular cross-linking and showed the efficient delivery of insulin from the intestine to the systemic circulation using a typical CPP, oligoarginine. However, this approach required relatively high doses of the CPP. Therefore, this study aimed to identify CPPs that are more effective for the delivery of insulin and do not induce toxic effects on the intestine. In this study, we examined the effects of various types of CPPs including arginine-rich peptides and amphipathic peptides that aid insulin absorption from rat ileal segments. Among these peptides, coadministration of insulin with R8, penetratin, pVEC, and RRL helix significantly increased ileal insulin absorption compared with insulin administration alone. In the case of R8, the D-form of the peptide had stronger absorption enhancing ability than the L-form. In contrast, the other three peptides exerted a more significant effect when the L-forms were applied, and L-penetratin had the strongest ability to enhance intestinal insulin absorption. Meanwhile, in a physical mixture of CPP and insulin, aggregates formed in the solution when high concentrations of CPPs were present. L-penetratin enhanced insulin absorption even when administered in an aggregated solution. We then showed that aggregates of L-penetratin and insulin were broken down in the presence of intestinal degradation enzymes. Thus, among CPPs used in this study, L-penetratin had the strongest ability to improve insulin intestinal absorption. | 18,727,945 |
Selective resistance of taurine-fed mice to isoniazide-potentiated seizures: in vivo functional test for the activity of glutamic acid decarboxylase. | Taurine, 2-aminoethanesulfonic acid, is one of the most abundant free amino acids especially in excitable tissues, with wide physiological actions. We have previously reported that in mice, supplementation of the drinking water with taurine induces alterations in the inhibitory GABAergic system. In taurine-fed mice we found that the expression level of glutamic acid decarboxylase (GAD), the enzyme responsible for GABA synthesis, is elevated. Increased expression of GAD was accompanied by increased levels of GABA. Here, we investigated pharmacologically the functional significance of taurine-induced increase in GAD expression by determining the threshold for kainic acid-induced seizures after partial inhibition of GAD activity with isoniazide. We found that taurine-fed mice have elevated GAD expression and showed a higher threshold for seizure onset when compared with age-matched controls. Thus, taurine-fed mice have a functional increase in GAD activity which offers some protection in this seizure model. Furthermore, this pharmacological manipulation can be used to determine the level of GAD activity in other model systems that show alterations in GAD expression. | 18,727,952 |
Reversible regulation of metastasis by ROS-generating mtDNA mutations. | It has been controversial whether mtDNA mutations are responsible for oncogenic transformation (normal cells to develop tumors), and for malignant progression (tumor cells to develop metastases). To clarify this issue, we created trans-mitochondrial cybrids with mtDNA exchanged between mouse tumor cells that express different metastatic phenotypes. The G13997A mutation in the ND6 gene of mtDNA from high metastatic tumor cells reversibly controlled development of metastases by overproduction of reactive oxygen species (ROS), but did not control development of tumors. The mtDNA-mediated reversible control of metastasis reveals a novel function of mtDNA, and suggests that ROS scavengers may be therapeutically effective in suppressing metastasis. | 18,727,959 |
Impact of runoff on superficial femoral artery endoluminal interventions for rest pain and tissue loss. | While aggressive endoluminal therapy for superficial femoral artery (SFA) occlusive disease is commonplace, the implications of runoff on long-term outcomes of these interventions in patients with rest pain and tissue loss is unclear. Runoff is known to negatively effect graft patency. The aim of this study is to examine the impact of distal runoff on long-term outcomes of SFA interventions for critical ischemia. A prospective database of patients undergoing endovascular treatment of the SFA between 1986 and 2007 was queried. Patients with Rutherford symptom classification 4, 5, and 6 were selected. Patients with concomitant tibial interventions were excluded. Pre-operative angiograms were reviewed in all cases to assess distal popliteal and tibial runoff and were scored according to modified Society of Vascular Surgery criteria for both vessels such that a higher score implies worse runoff (minimum 1 and maximum 19). Three runoff score groups were identified: <5 (good), 5-10 (compromised), and >10 (poor). Kaplan-Meier survival analyses were performed to assess time-dependent outcomes. Multivariate and factor analyses were performed. Three hundred six limbs in 241 patients (57% male, mean age 68 years) underwent endovascular treatment for critical ischemia (44% rest pain and 56% tissue loss.) Technical success was 96% with 61% SFA undergoing angioplasty, 37% SFA primary stenting and 2% SFA an atherectomy. Overall mortality was 1% and overall morbidity was 16% at 90 days after the procedure. At 5 years, vessels with compromised and poor runoff had significantly worse cumulative patency (82 +/- 9%, 56 +/- 4%, and 52 +/- 7% for good, compromised, and poor runoffs, respectively, mean +/- standard error of the mean [SEM]). Freedom from recurrent symptoms (65 +/- 8%, 39 +/- 9%, and 18 +/- 9% for good, compromised, and poor runoffs, respectively) and limb salvage (65 +/- 5%, 41 +/- 4%, and 20 +/- 6% for Good, Compromised, and Poor runoffs, respectively) were incrementally curtailed by worsening runoff with significant decreases as runoff category deteriorated. In patients presenting with rest pain and tissue loss who are treated with SFA percutaneous interventions, patency is negatively affected by compromised and poor runoffs in keeping with the bypass literature. More importantly, freedom from recurrent symptoms and limb salvage are incrementally curtailed as runoff scores worsen. These findings are consistent with the bypass literature. | 18,727,964 |
First report of a late type III endoleak from fabric tears of a Zenith stent graft. | We report a case of a late type III endoleak from a hole in the fabric of the main body of a Zenith bifurcated endograft 7 years after implantation. Abdominal pain and a rapidly expanding aneurysm were eventually followed by rupture. The defect was detected at open surgery, whereas no evidence of endoleak was found at preoperative computed tomography (CT) or angiogram. The defect was repaired by a relining procedure with an Excluder stent graft. The patient, however, died 3 weeks after admission. | 18,727,968 |
Early Palma procedure after iliac vein injury in abdominal penetrating trauma. | Ligation for penetrating abdominal vein trauma may have better outcome than a vascular reconstruction in an unstable patient. However, symptoms of chronic venous insufficiency may appear over time. We describe our surgical experience with 4 patients who underwent iliac vein ligation followed by venous bypass with a modified Palma derivation between 48 and 240 hours after sustaining penetrating abdominal trauma with concomitant iliac vein injury. Patients were assessed for venous symptoms and conduit patency with continuous wave Doppler and duplex scanning. One graft occluded acutely and the remaining three remain patent with functioning valves. In order to preserve venous outflow after severe iliac vein injury, we think that venous ligation as a part of damage control surgery followed by a modified Palma operation may prevent chronic symptoms of venous outflow obstruction without compromising an already injured patient. | 18,727,974 |
The weaker sex: is being male a legally cognizable defect, impairment, or disability? | Compared with women, men die from cancer and coronary artery disease in disproportionately higher numbers and are more susceptible to a host of emotional and developmental disorders. The authors of this article consider what scientific proof or evidence would be required to legally recognize "being male" as a disability, based on the overwhelming number of physical deficiencies to which males are genetically predisposed. The article summarizes major scientific findings on male health problems and explores various laws and policies that might be implicated by treatment of males as a special category recognized by the law. How the law creates categories of individuals and the reasons why these categories are created for legal classification are reviewed. In addition, the potential for a "maleness" defense in the context of criminal law and procedure is assessed. Lastly, the authors examine the policy implications of treating men as a disabled class, and consider how judges, juries, and legislators would view a scientifically based approach to the creation of a class. Given the many false starts in the past, in which the law had embraced what later was shown to be bad science, substantial historical baggage will have to be overcome to convince judges, juries, and legislators that science has now got it in the sense of having established a valid, causal, genetic or biological determinant for behavior. The consideration of a "male deficiency" theory under the law would have to rely on a more inclusive view of legal "disability" and a willingness to allow technologic advances in genetics to inform our understanding of criminal behavior. | 18,727,986 |
Wastewater treatment plants (WWTPs) as a source of sediment contamination by toxic organic pollutants and fecal sterols in a semi-enclosed bay in Korea. | Toxic organic contaminants and a macrobenthic community were assayed in sediments collected near a wastewater treatment plant (WWTP) outfall to assess the impact of WWTP discharges on an aquatic environment. Average concentrations of toxic organic contaminants in sediments from 20 locations were 96.7ng TEQ/kg dry matter for PCDD/Fs, 1.84ng TEQ/kg dry matter for dioxin-like PCBs, 29.1microg/kg dry matter for PBDEs, 411microg/kg dry matter for nonylphenols, 1021microg/kg dry matter for fecal sterols, and 928microg/kg dry matter for PAHs. Concentrations of all the organic contaminants and fecal sterols varied widely and there was a clear decrease in concentration gradients with increasing distances from the WWTP outfall. This result suggests that WWTP activities contribute to contamination by organic chemicals. A survey of benthic organisms showed the dominance of a few polychaete species, indicating a deterioration of the macrobenthic community by the WWTP discharge. Non-parametric multidimensional scaling (MDS) ordination and Spearman correlation analyses showed that organic contamination is associated with the benthic community structure. For polychaete species, the sensitive species for organic contaminants was Paraprionospio pinnata, while contaminant-tolerant species were Spiochaetopterus koreana and Capitella capitata. BIOENV analyses of all locations suggested PCDDs and PCDFs as the major contaminants influencing the structure of the macrobenthic community. The present study highlights that continuous WWTP discharges contribute to severe organic contamination and risks for the benthic community in an aquatic ecosystem. | 18,727,999 |
Inhibition of protein tyrosine phosphatase 1B and alkaline phosphatase by bis(maltolato)oxovanadium (IV). | Vanadate has been recognized as a specific and potent phosphatase inhibitor since its structure is similar to that of phosphate. In this study, we measured the inhibition of glutathione S-transferase-tagged protein tyrosine phosphatase 1B (GST-PTP1B) and alkaline phosphatase (ALP) by the insulin enhancing compounds, bis(maltolato)oxovanadium(IV) (BMOV). The results showed that the activity of GST-PTP1B was reversibly inhibited by solutions of BMOV with an IC(50) value of 0.86+/-0.02 microM. Steady state kinetic studies showed that inhibition of GST-PTP1B by BMOV was of a mixed competitive and noncompetitive type. In addition, incubation of GST-PTP1B with BMOV showed a time-dependent biphasic inactivation of the protein. On the other hand, the inhibitory behavior of BMOV on ALP activity was reversible and competitive with an IC(50) value of 32.1+/-0.6 microM. Incubation with BMOV did not show biphasic inactivation of ALP. The reversible inhibition of GST-PTP1B by BMOV is more potent than that of ALP, but solutions of BMOV inhibited both enzymes. This data support the suggestion that mechanisms for the inhibitory effects of BMOV on GST-PTP1B and ALP are very different. | 18,728,000 |
Tyrosine residues as redox cofactors in human hemoglobin: implications for engineering nontoxic blood substitutes. | Respiratory proteins such as myoglobin and hemoglobin can, under oxidative conditions, form ferryl heme iron and protein-based free radicals. Ferryl myoglobin can safely be returned to the ferric oxidation state by electron donation from exogenous reductants via a mechanism that involves two distinct pathways. In addition to direct transfer between the electron donor and ferryl heme edge, there is a second pathway that involves "through-protein" electron transfer via a tyrosine residue (tyrosine 103, sperm whale myoglobin). Here we show that the heterogeneous subunits of human hemoglobin, the alpha and beta chains, display significantly different kinetics for ferryl reduction by exogenous reductants. By using selected hemoglobin mutants, we show that the alpha chain possesses two electron transfer pathways, similar to myoglobin. Furthermore, tyrosine 42 is shown to be a critical component of the high affinity, through-protein electron transfer pathway. We also show that the beta chain of hemoglobin, lacking the homologous tyrosine, does not possess this through-protein electron transfer pathway. However, such a pathway can be engineered into the protein by mutation of a specific phenylalanine residue to a tyrosine. High affinity through-protein electron transfer pathways, whether native or engineered, enhance the kinetics of ferryl removal by reductants, particularly at low reductant concentrations. Ferryl iron has been suggested to be a major cause of the oxidative toxicity of hemoglobin-based blood substitutes. Engineering hemoglobin with enhanced rates of ferryl removal, as we show here, is therefore likely to result in molecules better suited for in vivo oxygen delivery. | 18,728,007 |
Phospholipase Cgamma2 mediates RANKL-stimulated lymph node organogenesis and osteoclastogenesis. | Phospholipase Cgamma2 (PLCgamma2) is an important signaling effector of multiple receptors in the immune system. Here we show that PLCgamma2-deficient mice displayed impaired lymph node organogenesis but normal splenic structure and Peyer's patches. Receptor activator of NF-kappaB ligand (RANKL) is a tumor necrosis factor family cytokine and is essential for lymph node organogenesis. Importantly, PLCgamma2 deficiency severely impaired RANKL signaling, resulting in marked reduction of RANKL-induced activation of MAPKs, p38 and JNK, but not ERK. The lack of PLCgamma2 markedly diminished RANKL-induced activation of NF-kappaB, AP-1, and NFATc1. Moreover, PLCgamma2 deficiency impaired RANKL-mediated biological function, leading to failure of the PLCgamma2-deficient bone marrow macrophage precursors to differentiate into osteoclasts after RANKL stimulation. Re-introduction of PLCgamma2 but not PLCgamma1 restores RANKL-mediated osteoclast differentiation of PLCgamma2-deficient bone marrow-derived monocyte/macrophage. Taken together, PLCgamma2 is essential for RANK signaling, and its deficiency leads to defective lymph node organogenesis and osteoclast differentiation. | 18,728,019 |
Congenital atresia of the left coronary artery--myocardial revascularization in two children. | Two patients with congenital atresia of the left coronary artery ostium underwent myocardial revascularization at the age of three years and three months, respectively. The patients were admitted to the hospital with a clinical history of sudden chest pain or short apnea not necessitating resuscitation. Non-invasive examinations and hemodynamic studies revealed dysfunction of the left ventricle and ostial atresia of the left coronary artery. Surgical revascularization-bypass grafts were performed using the left internal mammary artery and saphenous vein graft in the first case and the left internal mammary artery in the second child. Both patients survived surgery and good patency of the grafts was confirmed by coronary angiograms during hospital stay. These cases are interesting because of their rarity and diagnostic and therapeutic difficulties. | 18,728,035 |
Evidence of epistasis between interleukin 1 and selenoprotein-S with susceptibility to rheumatoid arthritis. | Selenoprotein-S (SELS) is involved in the stress response within the endoplasmic reticulum (ER) and inflammation. Recently, promoter variants in the SELS gene were shown to be associated with plasma levels of interleukin (IL)6, IL1beta and tumour necrosis factor (TNF). It was hypothesised that these variants could influence rheumatoid arthritis (RA) susceptibility and may interact with functional single nucleotide polymorphisms (SNPs) in the genes for IL1, IL6 and TNF. Genotyping was performed in 988 unrelated healthy controls and 965 patients with RA. Stratified analysis was used to test for interactions. Single gene effects and evidence of epistasis were investigated using the Mantel-Haenszel (M-H) test and the linkage disequilibrium (LD)-based statistic. No association of SELS -105 genotype and RA susceptibility was detected. Stratification of SELS -105 genotypes by IL1 -511 genotypes showed that the disease risk (comparing AA/GA to GG at the SELS -105 locus) in individuals with the GG/AG genotype at the IL1beta -511 locus was significantly lower than that in individuals having the AA genotype at the IL1beta -511 locus (odds ratio (OR): 0.9 and 2.3, respectively; p = 0.004 by M-H test). Significant epistasis was also detected using the LD-based statistic (p = <0.001). No interaction was observed between SELS -105 and IL6 or TNF variants. Our results reveal evidence of strong epistasis in two genes in the IL1 production pathway and highlight the potential importance of gene-gene interactions in the pathogenesis of RA. | 18,728,048 |
Sudden cardiac death and left ventricular ejection fraction during long-term follow-up after acute myocardial infarction in the primary percutaneous coronary intervention era: results from the HIJAMI-II registry. | To determine the incidence of sudden cardiac death (SCD) according to left ventricular ejection fraction (LVEF) in survivors of myocardial infarction (MI) in the primary percutaneous coronary intervention (PCI) era. A multicentre observational prospective registered cohort study. 18 medical centres in Japan. 4122 consecutive patients (mean age 66 (SD 12) years, 73.7% male) with acute MI, who were discharged alive. The primary end-point was SCD, and a secondary end-point was death from any cause. Patients were categorised into three groups: LVEF >40% (n = 3416), LVEF < or =40% and >30% (n = 507) and LVEF < or =30% (n = 199). Among all patients, 77.8% received PCI and 3.7% received coronary artery bypass graft surgery. During an average follow-up of 4.1 years, SCD was 1.2% and mortality was 13.1%. Patients with LVEF < or =30% and LVEF < or =40% and >30% were at increased risk for SCD (HR 5.99, 95% CI 2.73 to 13.14, p<0.001, HR 3.37, 95% CI 1.74 to 6.50, p<0.001, respectively), and mortality (HR 3.85, 95% CI 2.96 to 5.00, p<0.001, HR 2.06, 95% CI 1.66 to 2.57, p<0.001, respectively), compared to patients with LVEF >40%. Kaplan-Meier estimates of SCD in patients with LVEF < or =30% were 2.9%, 5.1% and 5.1% at 1, 3 and 5 years, respectively. There is a low incidence of SCD in survivors of MI in the primary PCI era, although LVEF is a predictor of increased risk for SCD. | 18,728,065 |
Autistic phenotypes and genetic testing: state-of-the-art for the clinical geneticist. | Autism spectrum disorders represent a group of developmental disorders with strong genetic underpinnings. Several cytogenetic abnormalities or de novo mutations able to cause autism have recently been uncovered. In this study, the literature was reviewed to highlight genotype-phenotype correlations between causal gene mutations or cytogenetic abnormalities and behavioural or morphological phenotypes. Based on this information, a set of practical guidelines is proposed to help clinical geneticists pursue targeted genetic testing for patients with autism whose clinical phenotype is suggestive of a specific genetic or genomic aetiology. | 18,728,070 |
Sibutramine-associated QT interval prolongation and cardiac arrest. | To report on a probable association between sibutramine and QT interval prolongation leading to ventricular fibrillation and cardiac arrest. A previously well 51-year-old woman with obesity but no other relevant past medical history or cardiac risk factors was prescribed sibutramine (initial dose 10 mg daily, increased to 15 mg daily after 10 wk). Four months after initiation of therapy, the woman developed ventricular fibrillation and was successfully resuscitated. On admission, an electrocardiogram (ECG) demonstrated sinus tachycardia without any ischemic changes and a prolonged QTc interval (545 msec). A subsequent coronary angiogram revealed normal coronary arteries and no other abnormalities. Her QTc interval returned to normal (432 msec) by day 2 and remained within normal limits (<440 msec) thereafter. Due to a favorable neurologic recovery and the absence of any cardiac structural abnormality, the patient was readmitted for implantation of an automatic implantable cardioverter-defibrillator on day 35 and remained well from a cardiac and neurologic standpoint at a 2-year follow-up examination. Sibutramine acts centrally to inhibit noradrenaline, dopamine, and serotonin reuptake, thereby sharing similar actions of other QT interval-prolonging drugs. Therefore, sibutramine might be anticipated to also share a tendency to QT interval prolongation. The current prescribing information for sibutramine does not specifically list any precautions or adverse reactions related to QT interval prolongation. QT interval prolongation associated with sibutramine in this case is considered probable based on the Naranjo probability scale. Clinicians prescribing sibutramine should monitor their patients for ECG abnormalities and be cautious in coprescribing drugs known to prolong the QT interval. | 18,728,104 |
Effects of feedback frequency and timing on acquisition, retention, and transfer of speech skills in acquired apraxia of speech. | Two studies examined speech skill learning in persons with apraxia of speech (AOS). Motor-learning research shows that delaying or reducing the frequency of feedback promotes retention and transfer of skills. By contrast, immediate or frequent feedback promotes temporary performance enhancement but interferes with retention and transfer. These principles were tested in the context of a common treatment for AOS. Two studies (N = 4, N = 2) employed single-subject treatment designs to examine acquisition and retention of speech skills in adults with AOS under different feedback conditions. Reduced-frequency or delayed feedback enhanced learning in 3 participants with AOS. Feedback manipulation was not an influential variable in 3 other cases in which stimulus-complexity effects may have masked treatment effects. These findings demonstrate that individuals with AOS can benefit from structured intervention. They provide qualified support for reduction and delay of feedback, although interaction with other factors such as stimulus complexity or task difficulty needs further exploration. This study adds to the growing body of literature investigating the use of principles of motor learning in treating AOS and provides impetus for consideration of pre-treatment variables that affect outcome in treatment studies. | 18,728,115 |
Polymorphisms in the adiponutrin gene are associated with increased insulin secretion and obesity. | The insulin responsive adiponutrin or patatin-like phospholipase 3 (PNPLA3, previously ADPN) gene shows association with obesity and in vitro adipocyte lipolysis. This study aimed to replicate the association between PNPLA3 variants and obesity, and to investigate their effect on insulin resistance and beta-cell function. rs738409 (Met148Ile) and rs2072907 (C to G) were genotyped using TaqMan allelic discrimination assay in a Swedish population-based sample (n=1811). Oral glucose tolerance test (OGTT) with data from three time points (0, 30, and 120 min) were available from individuals under the age of 50 years (n=973). Both variant alleles were associated with decreased prevalence of obesity (P<0.05); odds ratio 0.75 (0.61-0.93) per carried Ile-allele for rs738409 and 0.80 (0.64-1.00) per carried G-allele for rs2072907. For obesity as a quantitative trait, there was no association in the whole population, but in obese subjects body mass index (BMI; P=0.023) and waist (P=0.0098) were higher in carriers of the Ile-allele. The Ile-carriers also displayed decreased insulin secretion in response to OGTT (30 min insulin; P=0.007, insulinogenic index; P=0.0051) with no significant differences in fasting plasma glucose (P=0.31), beta-cell function (disposition index; P=0.17) or homeostasis model of assessment insulin resistance (HOMA-IR; P=0.063). The correlation between BMI and HOMA-IR differed (Met/X versus Ile/Ile, P=0.028), Met-allele carriers were seemingly more insulin resistant at a lower BMI. The rs2072907 variant shows similar results for insulin secretion. The significance of this finding remained after adjusting for age, gender, and level of self-reported leisure-time physical activity. We confirm the association between PNPLA3 and obesity. In addition, the rs738409 variant was associated with insulin secretion. There seems to be a differential effect of the Ile-allele depending on the degree of obesity, possibly as a consequence of insulin resistance. | 18,728,122 |
Comparison of two extracorporeal shock wave therapy techniques for the treatment of painful subcalcaneal spur. A randomized controlled study. | To describe and compare two extracorporeal shock wave therapy techniques for the treatment of painful subcalcaneal spur. Random assignment to two groups of treatment with two and eight months follow-up. The data were collected in outpatients. Forty-five subjects with a history of at least six months of heel pain were studied. Each subject received a three-session ultrasound-guided extracorporeal shock wave therapy (performed weekly). Perpendicular technique was used in group A (n=22, mean age 59.3 +/- 12 years) and tangential technique was used in group B (n= 23, mean age 58.8 +/- 12.3 years). Mayo Clinical Scoring System was used to evaluate each subject before the treatment and at two and eight months follow-up. Mayo Clinical Scoring System pretreatment scores were homogeneous between the groups (group A 55.2 +/-18.7; group B 53.5 +/- 20; P>0.05). In both groups there was a significant (P<0.05) increase in the Mayo Clinical Scoring System score at two months (group A 83.9 +/- 13.7; group B 80 +/- 15,8) and eight months (group A 90 +/- 10.5; group B 90.2 +/-8.7) follow-up. No significant differences were obtained comparing the Mayo Clinical Scoring System scores of the two groups at two and eight months follow-up. There was no difference between the two techniques of using extracorporeal shock wave therapy. The tangential technique was found to be better tolerated as regards treatment-induced pain, allowing higher energy dosages to be used. | 18,728,131 |
Neuropsychological predictors of powered wheelchair use: a prospective follow-up study. | To investigate (1) rates of powered wheelchair use and level of user-rated functional performance at one-month follow-up, and (2) whether psychological variables were prospectively predictive of outcome. Prospective follow-up study. UK hospital-based regional rehabilitation and mobility centre. Volunteer adults with impaired mobility. Of 155 approached, 103 had baseline assessments. Of these, 81 (79%) provided outcome data. Mean age was 65.6 years (SD = 13.5); 55% were male. Rate of day-to-day powerchair use, and users' perceptions of how well the powerchair allowed them to perform functional tasks. Among those with indoor-only chairs, 48% were 'less frequent' users; this rose to 72% among those with indoor/outdoor chairs. Excluding environmental reasons, rate of indoor use was predicted by baseline measures of verbal recall (P<0.001), figure copying (P=0.003) and global cognition (P=0.021). Among those with indoor/outdoor chairs, total rate of use was predicted by verbal recall (P= 0.001). Participants reported that the powerchair was effective in meeting their functional needs. Powered wheelchair use was predicted by cognitive measures. Rates of use were relatively low, despite users' reports that the powerchair facilitated their everyday functioning well. | 18,728,137 |
Renal dysfunction in acute stroke: an independent predictor of long-term all combined vascular events and overall mortality. | Acute stroke is the third leading cause of death in western societies after ischemic heart disease and cancer. Although it is an emergency disease sharing the same atherosclerotic risk factors with ischemic heart disease, the association of renal function and stroke is poorly investigated. The present study aims at assessing renal function status in patients with acute stroke and investigate any prognostic significance on the outcome. This is a prospective study of hospitalized first-ever stroke patients over 10 years. The study population comprised 1350 patients admitted within 24 h from stroke onset and followed up for 1 to 120 months or until death. Patients were divided in 3 groups on the basis of the estimated Glomerular Filtration Rate (eGFR) that was calculated from the abbreviated equation of the Modification Diet for Renal Disease in ml/min/1.73 m(2) of body surface area: Group-A comprised patients who had eGFR > 60, group-B those with 30 <or= eGFR <or= 60 and group-C patients with eGFR < 30. Patients with Acute Kidney Injury (AKI) were excluded from the study. The main outcome measures were overall mortality and the composite new cardiovascular events (myocardial infarction, recurrent stroke, vascular death) among the 3 groups during the follow-up period. Almost 1/3 (28.08%) of our acute stroke patients presented with moderate (group B) or severe (group C) renal dysfunction as estimated by eGFR. After adjusting for basic demographic, stroke risk factors and stroke severity on admission, eGFR was an independent predictor of stroke mortality at 10 years. Patients in groups B and C had an increased probability of death during follow-up: Hazard ratio = 1.21 with 95% CI 1.01-1.46, p < 0.05 and Hazard ratio = 1.76 with 95% CI 1.14-2.73, p < 0.05 respectively, compared to patients belonging to group A. The probability of death from any cause was significantly different among groups (log rank test 55.4, p = 0.001) during the follow-up period: in group-A patients it was 62.8 (95% CI 57.6-68.1), in group-B 77.3 (95% CI 68.5-86.1) and in group-C 89.2 (95% CI 75.1-100). During the follow-up period 336 new cardiovascular events occurred. The probability to have a new composite cardiovascular event was also significantly different among the 3 groups (log rank test 21.1, p = 0.001): in group-A patients it was 45.2 (95% CI 38.7-51.7), in group-B 67.4 (95% CI 56.2-78.6) and in group-C 77.6 (95% CI 53.5-100). Renal function on admission appears to be a significant independent prognostic factor for long term mortality and new cardiovascular morbidity over a 10-year period. | 18,728,156 |
EPAC and PKA allow cAMP dual control over DNA-PK nuclear translocation. | We identify a compartmentalized signaling system that identifies a functional role for the GTP exchange factor, exchange protein activated by cAMP (EPAC) coupled to Rap2 in the nucleus. In this system, cAMP regulates the nuclear/cytoplasmic trafficking of DNA-dependent protein kinase (DNA-PK), a critical kinase that acts to repair double-stranded breaks (DSBs) in damaged DNA and to phosphorylate the cell survival kinase, PKB/Akt. Intersecting regulatory inputs for cAMP employ EPAC to transduce positive effects, namely the Rap2-dependent nuclear exit and activation of DNA-PK, whereas protein kinase A (PKA) provides the negative input by antagonizing these actions. We identify this as a compartmentalized regulatory system where modulation of cAMP input into the stimulatory, EPAC and inhibitory, PKA intersecting arms is provided by spatially discrete, cAMP degradation systems. The distribution of DNA-PK between nuclear and cytoplasmic compartments can thus potentially be influenced by relative inputs of cAMP signaling through the EPAC and PKA pathways. Through this signaling system EPAC activation can thereby impact on the Ser-473 phosphorylation status of PKB/Akt and the repair of etoposide-induced DSBs. | 18,728,186 |
Mass incarceration can explain population increases in TB and multidrug-resistant TB in European and central Asian countries. | Several microlevel studies have pinpointed prisons as an important site for tuberculosis (TB) and multidrug-resistant TB in European and central Asian countries. To date, no comparative analyses have examined whether rises in incarceration rates can account for puzzling differences in TB trends among overall populations. Using longitudinal TB and cross-sectional multidrug-resistant TB data for 26 eastern European and central Asian countries, we examined whether and to what degree increases in incarceration account for differences in population TB and multidrug-resistant TB burdens. We find that each percentage point increase in incarceration rates relates to an increased TB incidence of 0.34% (population attributable risk, 95% C.I.: 0.10-0.58%, P < 0.01), after controlling for TB infrastructure; HIV prevalence; and several surveillance, economic, demographic, and political indicators. Net increases in incarceration account for a 20.5% increase in TB incidence or nearly three-fifths of the average total increase in TB incidence in the countries studied from 1991 to 2002. Although the number of prisoners is a significant determinant of differences in TB incidence and multidrug-resistant TB prevalence among countries, the rate of prison growth is a larger determinant of these outcomes, and its effect is exacerbated but not confounded by HIV. Differences in incarceration rates are a major determinant of differences in population TB outcomes among eastern European and central Asian countries, and treatment expansion alone does not appear to resolve the effect of mass incarceration on TB incidence. | 18,728,189 |
Evidence for an asialoglycoprotein receptor on nonparenchymal cells for O-linked glycoproteins. | B cell-activating factor receptor 3 (BR3)-Fc is an IgG1-receptor dimeric fusion protein that has multiple O-linked glycosylation sites and sialylation levels that can vary in the manufacturing process. Increased sialic acid levels resulted from increased site occupancy with the O-linked N-acetylgalactosamine (GalNAc-Gal), but because the ratio of sialic acid per mole of oligosaccharide remained approximately 1, this led to increased asialo terminal GalNAc. Previous studies have demonstrated an effect of terminal asialo Gal or GalNAc on the clearance of glycoproteins due to uptake and degradation by lectin receptors in the liver. However, the previous studies examined N-linked oligosaccharides, and there are less data regarding O-linked oligosaccharides. The objective of these studies was to determine the effects on the pharmacokinetics and distribution of the asialo terminal GalNAc and varying amounts of sialic acid residues on BR3-Fc. The results of the data presented here suggest that exposed Gal on the desialylated BR3-Fc led to rapid clearance due to uptake and degradation in the liver that was associated with nonparenchymal cells. It is interesting to note that the data indicated a decreased clearance and increased exposure of BR3-Fc as the sialic acid levels increased, even though increased sialic acid was associated with increased asialo GalNAc. Therefore, the exposed GalNAc did not seem to play a role in the clearance of BR3-Fc; although the Gal linked to the hydroxyl group at position 3 may have prevented an interaction. Because we did not see uptake of desialylated BR3-Fc in hepatocytes where the asialoglycoprotein receptor is localized, this nonparenchymal cell lectin may have preference for O-linked glycoproteins. | 18,728,239 |
Nonmelanoma skin cancer and risk for subsequent malignancy. | Individuals with a personal history of nonmelanoma skin cancer (NMSC) may have an increased risk of subsequent noncutaneous malignancies. To test this hypothesis, we carried out a community-based, prospective cohort study. In the CLUE (Give Us a Clue to Cancer and Heart Disease) II cohort, which was established in Washington County, MD, in 1989, the risk of new malignancies was compared among individuals with (n = 769) and without (n = 18,405) a personal history of NMSC (total n = 19,174) during a 16-year follow-up period. Pathologically confirmed NMSC (and other malignancies) were ascertained from the Washington County Cancer Registry. Cox regression analysis with time-dependent covariates was used to determine the hazard ratios (presented as multivariable-adjusted relative risks [RRs]) and 95% confidence intervals (CIs) of second primary malignancies associated with a previously confirmed NMSC diagnosis. All statistical tests were two-sided. The crude incidence rate (per 10,000 person-years) of subsequent cancers other than NMSC among participants with a positive personal history of NMSC was 293.5 and with a negative history was 77.8. Compared with persons with no personal history of NMSC, those with such a history had a statistically significantly increased risk of being diagnosed with a subsequent cancer other than NMSC (RR = 1.99, 95% CI = 1.70 to 2.33) after adjusting for age, sex, body mass index, smoking status, and educational level. The association was observed for both basal cell carcinoma (multivariable-adjusted RR = 2.03, 95% CI = 1.70 to 2.42) and squamous cell carcinoma (multivariable-adjusted RR = 1.97, 95% CI = 1.50 to 2.59) of the skin. NMSC was a statistically significantly stronger cancer risk factor in younger age groups than in older age groups (P for interaction = .022). This community-based, prospective cohort study provides evidence for an association between an NMSC diagnosis and an increased risk of subsequent cancer, even after adjusting for individual-level risk factors. | 18,728,282 |
Induction of apoptosis in human cancer cells by candidaspongiolide, a novel sponge polyketide. | Candidaspongiolide (CAN), a novel polyketide from a marine sponge, is the active component of a mixture that was found to be potently cytotoxic in the National Cancer Institute's 60-cell-line screen. Effects of CAN on U251 glioma and HCT116 colorectal cancer cells and on normal fibroblasts were assessed using radiolabeling studies to measure protein synthesis, clonogenic assays to measure cell survival, flow cytometry of annexin V- and propidium iodide-stained cells to measure apoptosis, and western blots in the presence or absence of specific inhibitors to assess accumulation and phosphorylation of potential downstream target proteins. CAN inhibited protein synthesis and potently induced apoptosis in both U251 and HCT116 cells, the latter in part by a caspase 12-dependent pathway. For example, 25%-30% of U251 or HCT116 cells became apoptotic after 24 hours of treatment with 100 nM CAN. CAN also rapidly induced sustained phosphorylation of eukaryotic translation initiation factor-2 (eIF2)-alpha at Ser51 and of the translation elongation factor eEF2 at Thr56, which could contribute to its dose-dependent inhibition of protein synthesis. Stable expression of dominant-negative eIF2alpha was sufficient to prevent CAN-induced eIF2alpha phosphorylation and induction of apoptosis but insufficient to prevent inhibition of protein synthesis. CAN induction of eIF2alpha phosphorylation did not occur by a classic endoplasmic reticulum stress pathway. However, an inhibitor of and small-interfering RNAs to the double-stranded RNA-dependent protein kinase PKR prevented CAN-mediated eIF2alpha phosphorylation and apoptosis, respectively. Although CAN inhibited protein synthesis in both cancer cells and normal human fibroblasts, it induced eIF2alpha phosphorylation and apoptosis only in cancer cells. CAN triggers PKR/eIF2alpha/caspase 12-dependent apoptosis and inhibits protein synthesis in cancer cells but only inhibits protein synthesis in normal cells. | 18,728,285 |
Relationship between perceived needs and assessed needs for services in community-dwelling older persons. | We examine the relationship between the perceived needs and assessed needs of community-dwelling seniors. Trained research assistants administered the Naturally Occurring Retirement Community Baseline Survey to 268 community-dwelling older adults in suburban Maryland. Perceived and assessed needs were measured in the domains of health and function (memory, health, functional needs, mobility, and financial management), mental health (depression and loneliness), sensory functioning (vision), and health behaviors (nutrition and exercise). In the areas of functional needs, mobility, financial management, loneliness, and vision, persons who scored as more needy were already utilizing significantly more services. Of persons not receiving services, participants in need of memory, physical health, functional, loneliness, and nutrition services were more likely to indicate they would use those services. Although there were significant relationships between assessed needs and perceived needs, there was also a high level of discrepancy, such that a substantial proportion of those participants screened as not needing services requested those services, and a sizable proportion of those who screened as needing services did not request them. The results also show a high prevalence of needs among older adults and yet low service use by those with needs for these services. Both assessed and perceived needs should be examined in future need assessment surveys. Further investigations into the nature of discrepancies will likely result in improvement in the methodologies of screening assessed and perceived needs. Services targeted to older adults must be made more available to those dwelling in the community. | 18,728,300 |
Effects of radiation quality on the calibration of kerma-area product meters in x-ray beams. | The calibration coefficients of kerma-area product meters significantly depend on the energy spectrum of the x-ray beam. This effect was examined by measuring the calibration coefficients for several radiation qualities in the range generally used in diagnostic x-ray imaging. The intention was to determine the calibration coefficients for other radiation qualities by interpolation between the measured values, relative to one or more suitable parameters. The x-ray tube voltage, total filtration and half-value thickness were examined as possible specifiers of the energy distribution. No single parameter provided an interpolation of calibration coefficients with the accuracy recommended by the ICRU and IAEA, except for a narrow range of radiation qualities. At least two of the parameters are needed to reliably specify the radiation quality for the interpolation of calibration coefficients. | 18,728,309 |
Prognostic implications of the NT-ProBNP level and left atrial size in non-ischemic dilated cardiomyopathy. | The ratio of peak early diastolic mitral inflow to annular velocity (E/E') and left atrial size could provide prognosis on congestive heart failure (CHF). N-terminal Pro B-type natriuretic peptide (NT-ProBNP) has also been useful for predicting adverse cardiac events. However, it is not clear how these parameters compare with conventional risk factors. Thus, we investigated whether E/E', left atrial dimension index (LADI) and NT-ProBNP would predict adverse events and add incremental value to conventional risk factors, even in non-ischemic advanced dilated cardiomyopathy (DCM). Both NT-ProBNP and echocardiography were evaluated in 105 patients. The cardiac events were defined as the composite of cardiac death and re-admission for CHF. At follow up, cardiac events occurred in 24 patients who had high NT-ProBNP and showed higher LADI and E/E'. In multivariate analysis, both NT-ProBNP and LADI, but not E/E', remained as independent predictors; patients with both increased LADI and NT-ProBNP had a 27-fold higher risk of cardiac events than those without any risk factors (p = 0.003). Moreover, LADI and NT-ProBNP showed a better incremental prognostic value over conventional risk factors (global chi-square increase from 7 to 17 to 49, p = 0.003, p < 0.001, respectively). Both NT-ProBNP and LADI might have the most predictable power, particularly in non-ischemic advanced DCM. | 18,728,335 |
Enamel tissue engineering using subcultured enamel organ epithelial cells in combination with dental pulp cells. | We describe a strategy for the in vitro engineering of enamel tissue using a novel technique for culturing enamel organ epithelial (EOE) cells isolated from the enamel organ using 3T3-J2 cells as a feeder layer. These subcultured EOE cells retain the capacity to produce enamel structures over a period of extended culture. In brief, enamel organs from 6-month-old porcine third molars were dissociated into single cells and subcultured on 3T3-J2 feeder cell layers. These subcultured EOE cells were then seeded onto a collagen sponge in combination with primary dental pulp cells isolated at an early stage of crown formation, and these constructs were transplanted into athymic rats. After 4 weeks, complex enamel-dentin structures were detected in the implants. These results show that our culture technique maintained ameloblast lineage cells that were able to produce enamel in vivo. This novel subculture technique provides an important tool for tooth tissue engineering. | 18,728,352 |
Activation of Sirt1 decreases adipocyte formation during osteoblast differentiation of mesenchymal stem cells. | Mesenchymal stem cells (MSC) can differentiate into osteoblasts, adipocytes, chondrocytes and myoblasts. It has been suggested that a reciprocal relationship exists between the differentiation of MSC into osteoblasts and adipocytes. Peroxisome proliferator-activated receptor gamma2 (PPARgamma2) is a key element for the differentiation into adipocytes. Activation of the nuclear protein deacetylase Sirt1 has recently been shown to decrease adipocyte development from preadipocytes via inhibition of PPARgamma2. In vitro, MSC differentiate to osteoblasts when exposed to bone-inducing medium. However, adipocytes are also developed. In the present study we have targeted Sirt1 to control adipocyte development during differentiation of MSC into osteoblasts. The finding that resveratrol and isonicotinamide markedly inhibited adipocyte and promoted osteoblast differentiation demonstrates an interesting alternative to PPARgamma antagonists. These results are important for the evolving field of cell-based tissue engineering, but may also be relevant in the search for new treatments of osteoporosis. | 18,728,353 |
[Evaluation of iQ200 automated urine microscopy analyzer]. | Microscopic examination of urine sediment is one of the most commonly performed tests in the clinical laboratory. However, manual microscopic sediment examination is labor-intensive, time-consuming and imprecise. In this study, we evaluated the analytical performance and clinical usefulness of a recently introduced image-based automated urinalysis system, Iris iQ200 (Iris Diagnostics, USA). We assessed the iQ200 for linearity, precision and carryover rate using patient's samples and quality control materials. On 337 urine samples, urine sediment analyses performed by the iQ200 were compared with manual microscopy results. The iQ200 showed a good linearity (r2>0.99) for all cellular components analyzed. Within-run and total CVs on urine specimens and quality control samples were less than 10% except for within-run CV for the samples with low concentration of the squamous epithelial cells. The carryover rates were 0.21% for RBCs and 1.92% for WBCs. The agreement rates within one grade between the iQ200 and manual microscopy for RBCs, WBCs, and squamous epithelial cells were 93.8%, 94.2% and 96.9%, respectively. Since the iQ200 showed a reliable analytical performance and good concordance with manual microscopy, it could be useful in the clinical practice as a screening procedure. | 18,728,375 |
Budding yeast 14-3-3 proteins contribute to the robustness of the DNA damage and spindle checkpoints. | Cells respond to DNA or mitotic spindle damage by activating specific pathways that halt the cell cycle to allow for possible repair. Here, we report that inactivation of one of the Saccharomyces cerevisiae 14-3-3 proteins, Bmh1, as well as the bmh1-S189P bmh2 mutant, failed to exhibit normal spindle damage-induced cell cycle delay and conferred hypersensitivity to benomyl or nocodazole. These defects were additive with those conferred by the bub2 and mad2 spindle checkpoint mutations. Following cdc13-1-induced DNA damage, the 14-3-3 response was additive with those provided by the Mec1 (ATR-related)-controlled Rad53 (CHK2-related) and Chk1 (CHK1-related) checkpoint pathways and also distinct from the PKA (Protein Kinase A)-controlled response. Therefore, the budding yeast 14-3-3 proteins contribute to the robustness of the two major mitotic checkpoints and, by doing so, may also ensure optimal coordination between the responses to two distinct types of damage. | 18,728,387 |
Mouse models for BRCA1 associated tumorigenesis: from fundamental insights to preclinical utility. | Germline mutations in BRCA1 result in a significant predisposition for breast and ovarian cancer, with frequent LOH of the remaining wild type allele. Soon after the identification of BRCA1, several different knockout mice were generated to study its biological function in vivo. BRCA1, which is involved in DNA double-strand break (DSB) repair, appeared to be essential for embryonic proliferation and survival during mid-gestation. In contrast to human mutation carriers however, heterozygous mouse mutants did not show spontaneous cancer development. Therefore, a number of conditional mouse models were developed. while tumors of these mice show varying degrees of similarity with their human counterparts, two mouse models develop mammary tumors that lack expression of estrogen and progesterone receptors and ERBB2. This 'triple negative' signature is a characteristic feature of BRCA1-associated breast cancers, which can therefore not be treated with endocrine agents or ERBB2-targeting therapeutics. Promising drugs for treating BRCA1-mutated tumors include platinum compounds and PARP inhibitors, which are specifically toxic to DSB repair deficient cells. Although encouraging results have been reported, recent findings indicate that BRCA1/2 deficient ovarian tumors can escape from such targeted treatment by genetic reversion. This resistance mechanism might be studied in future mouse tumor models based on Brca1 truncating mutations mimicking defined human founder mutations. | 18,728,395 |
Usp39 is essential for mitotic spindle checkpoint integrity and controls mRNA-levels of aurora B. | Accurate chromosome segregation relies on the mitotic spindle checkpoint. This checkpoint acts to restrict ubiquitin ligase activity of the Anaphase-promoting complex (APC/C) in mitosis until all chromosomes are bipolarly attached to the mitotic spindle. We performed a functional RNAi-based screen to identify De-ubiquitinating enzymes (Dubs) involved in mitotic progression. We identified Usp39 as a new factor required to maintain the spindle checkpoint and support successful cytokinesis. Strikingly, although Usp39 clearly contains an ubiquitin-protease domain, we show that Usp39 is entirely deprived of Dub activity. However, consistent wilt a previously described role for Usp39 in mRNA processing, we observed specific reduction in Aurora B-mRNA levels after depletion of Usp39. Although we find that exogenously expressed Aurora B cDNA is not sufficient to rescue the checkpoint defect of Usp39-depleted cells, Aurora B expression is restored. Our observations suggest Usp39 to be involved in splicing of Aurora B and other mRNAs that are essential for proper spindle checkpoint function. | 18,728,397 |
The suppressor of metastasis Nm23-H1 interacts with the Cdc42 Rho family member and the pleckstrin homology domain of oncoprotein Dbl-1 to suppress cell migration. | Tumor invasion and metastasis is regulated by a number of cellular molecules known to be involved in signaling and cytoskeletal rearrangement. One of these molecules is the suppressor of tumor metastasis Nm23-H1 which linked to invasiveness and metastatic potential of human cancers. Nm23-H1 expression is down-regulated in human melanoma and invasive breast carcinoma. Recent studies have shown an association between the Nm23-H1 and oncoprotein Dbl-1 which is associated with guanine exchange and belongs to a family of Guanine Exchange Factors (GEF). In this report we show a direct interaction in vitro and in human B cells and specifically identified the pleckstrin homology domain of Dbl-1 as the domain which binds to Nm23-H1. Furthermore, Nm23-H1 and Dbl-1 colocalized in the cytoplasm of COS-7 cells when expressed exogenously and showed predominant signals at the periphery of the cells particularly at the plasma membrane. Interestingly, Dbl-1 and Cdc42 expression rescued the suppressive activities of Nm23-H1 in cell migration assays. We show that Cdc42 a regulatory protein involved in cytoskeletal reorganization, cell growth and development can bind to Nm23-H1 and the kinase deficient mutant H118F but only weakly to the mutant P96S which lacks the ability to suppress cell migration and metastasis. Cdc42 also colocalized with Nm23-H1 and the Dbl-1 proteins as specific punctate signals in the cytoplasm and at the cell membrane. Nm23-H1 also lead to the reduction in membrane ruffles and protuberances when expressed with Dbl-1 and Cdc42. Surprisingly, Nm23-H1 interacted with Cdc42 as well as Rac1 but somewhat weaker with RhoA. These studies suggests that Nm23-H1 can negatively regulate cell migration and tumor metastasis by modulating the activity of Cdc42 and possibly other Rho family members through interaction with Dbl-1. | 18,728,402 |
Case study: the Stanford University School of Medicine and its teaching hospitals. | There is wide variation in the governance and organization of academic health centers (AHCs), often prompted by or associated with changes in leadership. Changes at AHCs are influenced by institutional priorities, economic factors, competing needs, and the personality and performance of leaders. No organizational model has uniform applicability, and it is important for each AHC to learn what works or does not on the basis of its experiences. This case study of the Stanford University School of Medicine and its teaching hospitals--which constitute Stanford's AHC, the Stanford University Medical Center--reflects responses to the consequences of a failed merger of the teaching hospitals and related clinical enterprises with those of the University of California-San Francisco School of Medicine that required a new definition of institutional priorities and directions. These were shaped by a strategic plan that helped define goals and objectives in education, research, patient care, and the necessary financial and administrative underpinnings needed. A governance model was created that made the medical school and its two major affiliated teaching hospitals partners; this arrangement requires collaboration and coordination that is highly dependent on the shared objectives of the institutional leaders involved. The case study provides the background factors and issues that led to these changes, how they were envisioned and implemented, the current status and challenges, and some lessons learned. Although the current model is working, future changes may be needed to respond to internal and external forces and changes in leadership. | 18,728,444 |
Comparison of complications in percutaneous coronary intervention patients mobilized at 3, 4, and 6 hours after femoral arterial sheath removal. | The purpose of this research study was to explore groin complication rates of patients mobilized at 3, 4, and 6 hours after femoral arterial sheath removal following a percutaneous coronary intervention procedure. Participants were recruited from those undergoing coronary angioplasty and coronary stent placement at a large public hospital in Brisbane, Queensland. Participants were randomly allocated to the 3, 4, or 6 hourly mobilization group. After removal of the femoral arterial sheath and again the next day, participants' groins were assessed for evidence of complications including hemorrhage, hematoma formation, and pseudoaneurysm. The results showed that the length of bed rest after arterial sheath removal had no significant effect on bleeding (F 304 = 5.39, P = 0.21) or hematoma formation (F 304 = 0.258, P = 0.612) at the groin puncture site for participants who mobilized at either 3, 4, or 6 hours after percutaneous coronary intervention arterial sheath removal. | 18,728,513 |
Adiponectin and insulin resistance in childhood obesity. | To measure adiponectin serum levels in Greek children and adolescents and correlate them with body fat and insulin resistance. Forty-six obese prepubertal children (19 M, 27 F) and 34 obese adolescents (17 M, 17 F) ages 9.33 +/- 1.57 and 13.6 +/- 1.42 years, respectively, and 43 matched control individuals were studied. Body mass index standard deviation score and percent body fat were measured by bioelectric impedance analysis. Fasting indices of insulin resistance (HOMA-IR and fasting glucose-to-insulin ratio) were calculated for all participants. Indices of insulin resistance derived from oral glucose tolerance tests were estimated in obese participants. Adiponectin was measured by enzyme-linked immunosorbent assay. (MEAN +/- SD):: Adiponectin serum levels were significantly lower in obese participants than in nonobese participants (8.11 +/- 3.80 vs 11.81 +/- 4.98 microg/mL, P < 0.001), in obese children than in nonobese children (8.86 +/- 3.86 vs 13.08 +/- 5.48 microg/mL, P < 0.001), in obese adolescents than in nonobese adolescents (7.04 +/- 3.43 vs 10.47 +/- 4.10 microg/mL, P = 0.002), and in obese adolescent boys than in obese adolescent girls (5.87 +/- 3.52 vs 8.31 +/- 3.16 microg/mL, P = 0.042). There were significant correlations between adiponectin and age, body mass index, body mass index standard deviation score, homeostasis model assessment for insulin resistance, and fasting glucose-to-insulin ratio. Adiponectin correlated with percent body fat after adjustment for sex. Adiponectin correlated significantly with several indices of insulin resistance, such as the areas under the curves for glucose and insulin, whole-body insulin sensitivity index, glucose 120', and insulin 30', in obese participants. Adiponectin was significantly lower in obese participants than in nonobese participants in general, and it correlated significantly with fasting indices of insulin resistance and with indices derived from oral glucose tolerance tests. It is worthwhile to further investigate the option of applying a simple measurement of serum adiponectin as a screening tool before applying more time-consuming techniques in young obese individuals. | 18,728,534 |
Endoscopic endonasal resection of anterior cranial base meningiomas. | The endonasal route may be feasible for the resection of anterior cranial base tumors that abut the paranasal sinuses. There are several case reports and mixed case series discussing this approach. Other than pituitary adenomas, there is a lack of literature describing the outcomes of endonasal approaches for single-tumor types such as meningiomas. In this study, we describe our current endoscopic endonasal technique and demonstrate the feasibility of using it to access anterior cranial base meningiomas from the back wall of the frontal sinus to the sella and laterally to the region of the midorbit. After this discussion, which includes key technical considerations and nuances, we address safety and efficacy by reporting the outcomes of our early experience with endoscopic endonasal resection of 35 anterior cranial base meningiomas. A total of 35 patients underwent endoscopic endonasal resection of anterior cranial base meningiomas from October 2002 to October 2005. Degree of resection by tumor location was as follows: 10 of the 12 (83%) patients with olfactory groove meningiomas planned for complete resection underwent gross total (seven of 12) or near-total (>95%) (three of 12) resection (67% of all 15 olfactory tumors); 12 of 13 patients (92%) with tuberculum meningiomas underwent gross (11 of 13) or near (>95%) (one of 13) total resection; five patients diagnosed with petroclival meningiomas had successful resection of the parasellar portion of their tumors with relief of visual symptoms (no patients underwent complete resection of their tumors via the endoscopic, endonasal approach); two giant petroclival meningiomas were debulked with 63 and 89% resection, respectively.All patients experienced resolution or improvement of visual symptoms. No patient experienced permanent worsening of vision after surgery. Only one (3%) patient without preoperative endocrine dysfunction experienced a new, permanent pituitary deficit, diabetes insipidus. One (3%) patient experienced a new neurological deficit after experiencing a hemorrhage 3 weeks after surgery. The postoperative cerebrospinal fluid leak rate was 40% (14 of 35) and varied by tumor location. All leaks were resolved without craniotomy. There were no cases of bacterial meningitis. One patient developed a superinfection of a sterile granuloma from a sinusitis 2 years after surgery. There were two cases of deep venous thrombosis and one pulmonary embolus. There were no operative or perioperative deaths. Cranial base meningiomas can be successfully managed via a purely endoscopic endonasal approach with acceptable morbidity and mortality rates. The extent of resection is guided by patient factors and symptoms, not by approach. This series had a high cerebrospinal fluid leak rate. With the evolution of new reconstruction techniques, these rates have been substantially reduced. | 18,728,567 |
Lower incidence of reoperation with longer shunt survival with adult ventriculoperitoneal shunts placed for hemorrhage-related hydrocephalus. | The incidence of reoperation for ventriculoperitoneal shunts (VPS) in adults, although lower than in pediatric patients, is not insignificant. We hypothesize that adult VPS placed for hemorrhage-related hydrocephalus have a lower incidence of reoperation than those placed for other types of hydrocephalus. We retrospectively reviewed all adult (>/= 20 yr) VPS initially placed from February 2001 to August 2006 at the University of Florida. We determined the incidence and time interval to reoperation. Follow-up was conducted by telephone interview and review of medical records. A total of 286 adult VPS were initially placed: 96 (34%) hemorrhage and 190 (66%) nonhemorrhage. A total of 15 (16%) hemorrhage patients underwent 22 shunt reoperations, compared with 50 (27%) nonhemorrhage patients who underwent 82 shunt reoperations (P = 0.0316). A Poisson regression analysis of the number of reoperations, factoring hemorrhage, age, and sex, demonstrated a significantly lower incidence of reoperation in hemorrhage patients (P = 0.0900). A Cox proportional hazards model analysis of time to first reoperation, factoring hemorrhage, age, and sex, demonstrated a significantly longer shunt survival in hemorrhage patients (P = 0.0404). Adult VPS placed for hemorrhage-related hydrocephalus have a significantly lower incidence of reoperation and significantly longer shunt survival. This result may be related to an incidence of transient shunt dependency in patients with hemorrhage-related hydrocephalus. However, the precise mechanism remains unclear. | 18,728,570 |
Internal carotid artery aneurysms occurring at the origin of fetal variant posterior cerebral arteries: surgical and endovascular experience. | A fetal variant posterior cerebral artery (fetal PCA) is an embryological remnant in which the PCA is primarily supplied via the anterior cerebral circulation. Internal carotid artery (ICA) aneurysms originating from the takeoff of fetal PCA vessels deserve special attention before surgical or endovascular obliteration because of a greater potential for ischemic injury. We present the first series of ICA-posterior communicating artery (PComA) aneurysms originating at the takeoff of fetal PCA vessels that were treated by surgical or endovascular intervention. A retrospective chart review was conducted for all patients who underwent surgical and endovascular treatment of an ICA-PComA aneurysm at Los Angeles County-University of Southern California Medical Center during a 15-year period (1991-2006) to identify cases with aneurysms originating from fetal variant PCAs. Data were retrospectively reviewed and analyzed. During a 15-year period, 271 patients were treated for 273 ICA-PComA aneurysms. Aneurysms occurring at the origin of fetal PCAs were identified in 30 patients (11%). There were 23 women (77%) and seven men (23%) (sex difference, P = 0.0035). Twenty-four patients underwent surgical clipping, whereas six patients underwent endovascular coiling. The mean aneurysm size was 7 mm. The mean ischemia time with temporary clipping (12 cases) was 4.5 minutes. Intraoperative rupture occurred in four surgical cases (17%). Postoperative angiography demonstrated occlusion of the fetal PCA in one case after clip ligation (3%), with an ensuing occipital infarct yet no clinical symptoms. ICA-PComA aneurysms originating from fetal PCA vessels may pose a more substantial risk for infarction and subsequent neurological sequelae with surgical or endovascular obliteration. Fetal variant circulations were identified at the PComA origin in 11% of ICA-PComA aneurysm patients and were more commonly encountered in women. The decision of surgical versus endovascular treatment of fetal PCA aneurysms must be carefully considered, given the greater potential for ischemic injury with parent vessel occlusion. | 18,728,604 |
The X-files in immunity: sex-based differences predispose immune responses. | Despite accumulating evidence in support of sex-based differences in innate and adaptive immune responses, in the susceptibility to infectious diseases and in the prevalence of autoimmune diseases, health research and clinical practice do not address these distinctions, and most research studies of immune responses do not stratify by sex. X-linked genes, hormones and societal context are among the many factors that contribute to disparate immune responses in males and females. It is crucial to address sex-based differences in disease pathogenesis and in the pharmacokinetics and pharmacodynamics of therapeutic medications to provide optimal disease management for both sexes. | 18,728,636 |
Therapeutic efficacy of a herpes simplex virus with radiation or temozolomide for intracranial glioblastoma after convection-enhanced delivery. | The herpes simplex virus-1 (HSV-1)-infected cell protein 0 (ICP0) is an E3 ubiquitin ligase implicated in cell cycle arrest and DNA repair inhibition. Convection-enhanced delivery (CED) of either the replication-defective, ICP0-producing HSV-1 mutant, d106, or the recombinant d109, devoid of all viral genome expression, was performed to determine the in vivo efficacy of ICP0 in combination with ionizing radiation (IR) or systemic temozolomide (TMZ) in the treatment of glioblastoma multiforme (GBM). Intracranial U87-MG xenografts were established in athymic nude mice. Animal survival was determined after mice underwent intracranial CED of either the replication-defective d106 or d109 viruses, or Hanks' balanced salt solution (HBSS), before a single session of whole-brain irradiation or TMZ treatment. Median survival for animals that underwent treatment with HBSS alone, d109 alone, d106 alone, HBSS + IR, HBSS + TMZ, d109 + IR, d106 + IR, and d106 + TMZ was 28, 35, 41, 39, 44, 39, 68 (P < 0.01), and 66 days (P < 0.01), respectively. Intracerebral d106 CED resulted in a significant increase in athymic nude mouse survival when combined with IR or TMZ. d106 CED allows for distribution of HSV-1 in human GBM xenografts and persistent viral infection. | 18,728,637 |
Ex vivo chemosensitivity testing and gene expression profiling predict response towards adjuvant gemcitabine treatment in pancreatic cancer. | Efficacy of chemotherapy for pancreatic cancer may be improved by tailoring it to individual chemosensitivity profiles. Identification of nonresponders before initiation of treatment may help to avoid side effects. In this study, primary pancreatic cancer cells were isolated from 18 patients undergoing pancreaticoduodenectomy for pancreatic cancer. Eight commonly used pancreatic cancer cell lines were used as controls. Ex vivo chemosensitivity for gemcitabine, 5-fluorouracil, mitomycin-C, cisplatinum, oxaliplatinum, paclitaxel and a combination of gemcitabine with oxaliplatinum or mitomycin-C was determined using a cellular ATP-based tumour chemosensitivity assay (ATP-TCA). Quantitative real-time-polymerase chain reaction was performed to determine RNA expression levels of genes implicated in chemoresistance. Chemosensitivity towards cytotoxic agents was highly variable in primary pancreatic cancer cells and pancreatic cancer cell lines. ATP-TCA results for gemcitabine correlated to the tissue expression of human equilibrative nucleoside transporter-1 (hENT1). Time to relapse in patients with gemcitabine-sensitive tumours was significantly higher than in patients with chemoresistant pancreatic cancers (P=0.01; 71 vs 269 days). Furthermore, time to relapse in gemcitabine-treated patients was related to hENT1 expression (P=0.0067). Thus, chemosensitivity testing using ATP-TCA in pancreatic cancer is feasible and correlated with time to relapse in gemcitabine-treated patients. This suggests that ATP-TCA testing could be used as a decision-making tool in the adjuvant treatment of pancreatic cancer. | 18,728,667 |
Calcipotriol/betamethasone dipropionate in the treatment of psoriasis vulgaris. | Psoriasis is one of the most common skin diseases. The mainstay of treatment for the vast majority of patients is topical therapy. A rising first-line treatment modality for psoriasis vulgaris is the two-compound ointment containing calcipotriol 50 mug/g plus betamethasone dipropionate 0.5 mg/g (Dovobet((R)), Daivobet((R)), Taclonex((R))), which combines a vitamin D analog and a corticosteroid. This innovative formulation preserves the activity and bioavailability of the two components and many clinical studies have demonstrated that it has a greater efficacy, tolerability, and a rapid onset of action compared with its individual ingredients or tacalcitol. | 18,728,704 |
Treatment of gastrointestinal stromal tumor: focus on imatinib mesylate. | Gastrointestinal stromal tumor (GIST) is a rare primary neoplasm of the gastrointestinal tract, mesentery, or omentum. In the past, surgery has been the only effective treatment. The diagnosis and treatment of GIST has been revolutionized over the past decade, since expression of the receptor tyrosine kinase KIT was shown to occur on these tumors. Mutations in this proto-oncogene commonly cause constitutive activation of the KIT tyrosine kinase receptor, an important factor in the pathogenesis of the disease. The development of specific tyrosine kinase inhibitors, such as imatinib mesylate, has led to a breakthrough in the treatment of advanced GIST. Treatment with this drug has led to significant improvements in survival, with overall response rates in excess of 80%. Side effects are common, but usually manageable. The success of this drug has led to further trials investigating its use in the pre- and postoperative situation. This review summarizes the current knowledge of GIST and imatinib treatment and possible future developments. | 18,728,705 |
Therapeutic options for chronic myeloid leukemia: focus on imatinib (Glivec, Gleevectrade mark). | Treatment options for chronic myeloid leukemia (CML) have changed dramatically during the last decades. Interferon-alpha treatment and stem cell transplantation (SCT) clearly improved survival over conventional chemotherapy and offered the possibility of complete and durable responses. With the advent of the small molecule inhibitor imatinib mesylate (Glivec((R)), Gleevectrade mark) targeting the causative Bcr-Abl oncoprotein, the era of molecular cancer therapy began with remarkable success especially in chronic phase patients. Today, imatinib is the first-line treatment for CML. However, imatinib does not appear to be capable to eliminate all leukemia cells in the patients and pre-existing as well as acquired resistance to the drug has been increasingly recognized. To overcome these problems, several strategies involving dose escalation, combinations with other agents, and novel Bcr-Abl inhibitors have been developed. | 18,728,706 |
Treatment of prostate cancer: therapeutic potential of targeted immunotherapy with APC8015. | The body's immune system has some capacity to recognize and attack cancerous growths, including prostate cancer. However, various intrinsic characteristics of tumor cells usually limit that capacity. Therapeutically administered immunologic stimuli, such as APC8015, an individualized, ex vivo stimulation of a patient's own antigen presenting cells (APC), are capable of boosting the anti-tumor response. Late phase clinical trials of APC8015 (now also called Sipuleucel-T) show evidence of slowing disease progression and increasing survival in advanced prostate cancer. Such immunotherapeutic approaches hold real promise to provide additional useful and welcome weapons against this common malignancy. | 18,728,723 |
Role of phosphodiesterase 5 in synaptic plasticity and memory. | Phosphodiesterases (PDEs) are enzymes that break down the phosphodiesteric bond of the cyclic nucleotides, cAMP and cGMP, second messengers that regulate many biological processes. PDEs participate in the regulation of signal transduction by means of a fine regulation of cyclic nucleotides so that the response to cell stimuli is both specific and activates the correct third messengers. Several PDE inhibitors have been developed and used as therapeutic agents because they increase cyclic nucleotide levels by blocking the PDE function. In particular, sildenafil, an inhibitor of PDE5, has been mainly used in the treatment of erectile dysfunction but is now also utilized against pulmonary hypertension. This review examines the physiological role of PDE5 in synaptic plasticity and memory and the use of PDE5 inhibitors as possible therapeutic agents against disorders of the central nervous system (CNS). | 18,728,748 |
Water Dynamics in Nafion Fuel Cell Membranes: the Effects of Confinement and Structural Changes on the Hydrogen Bond Network. | The complex environments experienced by water molecules in the hydrophilic channels of Nafion membranes are studied by ultrafast infrared pump-probe spectroscopy. A wavelength dependent study of the vibrational lifetime of the O-D stretch of dilute HOD in H(2)O confined in Nafion membranes provides evidence of two distinct ensembles of water molecules. While only two ensembles are present at each level of membrane hydration studied, the characteristics of the two ensembles change as the water content of the membrane changes. Time dependent anisotropy measurements show that the orientational motions of water molecules in Nafion membranes are significantly slower than in bulk water and that lower hydration levels result in slower orientational relaxation. Initial wavelength dependent results for the anisotropy show no clear variation in the time scale for orientational motion across a broad range of frequencies. The anisotropy decay is analyzed using a model based on restricted orientational diffusion within a hydrogen bond configuration followed by total reorientation through jump diffusion. | 18,728,757 |
Evaluation of two methods to estimate and monitor bird populations. | Effective management depends upon accurately estimating trends in abundance of bird populations over time, and in some cases estimating abundance. Two population estimation methods, double observer (DO) and double sampling (DS), have been advocated for avian population studies and the relative merits and short-comings of these methods remain an area of debate. We used simulations to evaluate the performances of these two population estimation methods under a range of realistic scenarios. For three hypothetical populations with different levels of clustering, we generated DO and DS population size estimates for a range of detection probabilities and survey proportions. Population estimates for both methods were centered on the true population size for all levels of population clustering and survey proportions when detection probabilities were greater than 20%. The DO method underestimated the population at detection probabilities less than 30% whereas the DS method remained essentially unbiased. The coverage probability of 95% confidence intervals for population estimates was slightly less than the nominal level for the DS method but was substantially below the nominal level for the DO method at high detection probabilities. Differences in observer detection probabilities did not affect the accuracy and precision of population estimates of the DO method. Population estimates for the DS method remained unbiased as the proportion of units intensively surveyed changed, but the variance of the estimates decreased with increasing proportion intensively surveyed. The DO and DS methods can be applied in many different settings and our evaluations provide important information on the performance of these two methods that can assist researchers in selecting the method most appropriate for their particular needs. | 18,728,775 |
Drug-selected human lung cancer stem cells: cytokine network, tumorigenic and metastatic properties. | Cancer stem cells (CSCs) are thought to be responsible for tumor regeneration after chemotherapy, although direct confirmation of this remains forthcoming. We therefore investigated whether drug treatment could enrich and maintain CSCs and whether the high tumorogenic and metastatic abilities of CSCs were based on their marked ability to produce growth and angiogenic factors and express their cognate receptors to stimulate tumor cell proliferation and stroma formation. Treatment of lung tumor cells with doxorubicin, cisplatin, or etoposide resulted in the selection of drug surviving cells (DSCs). These cells expressed CD133, CD117, SSEA-3, TRA1-81, Oct-4, and nuclear beta-catenin and lost expression of the differentiation markers cytokeratins 8/18 (CK 8/18). DSCs were able to grow as tumor spheres, maintain self-renewal capacity, and differentiate. Differentiated progenitors lost expression of CD133, gained CK 8/18 and acquired drug sensitivity. In the presence of drugs, differentiation of DSCs was abrogated allowing propagation of cells with CSC-like characteristics. Lung DSCs demonstrated high tumorogenic and metastatic potential following inoculation into SCID mice, which supported their classification as CSCs. Luminex analysis of human and murine cytokines in sonicated lysates of parental- and CSC-derived tumors revealed that CSC-derived tumors contained two- to three-fold higher levels of human angiogenic and growth factors (VEGF, bFGF, IL-6, IL-8, HGF, PDGF-BB, G-CSF, and SCGF-beta). CSCs also showed elevated levels of expression of human VEGFR2, FGFR2, CXCR1, 2 and 4 receptors. Moreover, human CSCs growing in SCID mice stimulated murine stroma to produce elevated levels of angiogenic and growth factors. These findings suggest that chemotherapy can lead to propagation of CSCs and prevention of their differentiation. The high tumorigenic and metastatic potentials of CSCs are associated with efficient cytokine network production that may represent a target for increased efficacy of cancer therapy. | 18,728,788 |
Prolonged cholinergic enrichment influences regional cortical activation in early Alzheimer's disease. | Neuroimaging studies of cholinesterase inhibitor (ChEI) treatment in Alzheimer's disease (AD) indicate that the short and long term actions of ChEIs are dissimilar. fMRI studies of the ChEI rivastigmine have focused on its short term action. In this exploratory study the effect of prolonged (20 weeks) rivastigmine treatment on regional brain activity was measured with fMRI in patients with mild AD. Eleven patients with probable AD and nine age-matched controls were assessed with a Pyramids and Palm Trees semantic association and an n-back working memory fMRI paradigm. In the patient group only, the assessment was repeated after 20 weeks of treatment. There was an increase in task-related brain activity after treatment with activations more like those of normal healthy elderly. Behaviorally, however, there were no significant differences between baseline and retest scores, with a range of performance probably reflecting variation in drug efficacy across patients. Variable patient response and drug dynamic/kinetic factors in small patient groups will inevitably bias (either way) the effect size of any relevant drug related changes in activation. Future studies should take drug response into account to provide more insight into the benefits of ChEI drugs at the individual level. | 18,728,791 |
Epidemiology and treatment of post-stroke depression. | Mood depression is a common and serious complication after stroke. According to epidemiological studies, nearly 30% of stroke patients develop depression, either in the early or in the late stages after stroke. Although depression may affect functional recovery and quality of life after stroke, such condition is often ignored. In fact, only a minority of patients is diagnosed and even fewer are treated in the common clinical practice. Moreover, the real benefits of antidepressant (AD) therapy in post-stroke depression have not been fully clarified. In fact, controlled studies on the effectiveness of ADs in post stroke depression (PSD) are relatively few. Today, data available suggest that ADs may be generally effective in improving mood, but guidelines for the optimal treatment and its length are still lacking. | 18,728,805 |
A review of ramelteon in the treatment of sleep disorders. | Ramelteon is a selective melatonin receptor (MT(1) and MT(2)) agonist that has been approved by the US Food and Drug Administration for the treatment of insomnia characterized by difficulty with sleep onset. It is the only approved sleep-promoting medication that does not have a direct sedating effect, but rather enhances sleep through effects on sleep regulatory mechanisms within the suprachiasmatic nucleus. Ramelteon has been shown to have no abuse liability and therefore is not scheduled by the U.S. Drug Enforcement Agency as a controlled substance. It is available as an 8 mg tablet, which should be taken approximately 30 minutes prior to bedtime. The FDA approval contains no limitation on how long the medication may be prescribed. | 18,728,808 |
Depression in Parkinson's disease: health risks, etiology, and treatment options. | Depression is found in about 30%-40% of all patients with Parkinson's disease (PD), but only a small percentage (about 20%) receive treatment. As a consequence, many PD patients suffer with reduced health-related quality of life. To address quality of life in depressed PD patients, we reviewed the literature on the health correlates of depression in PD (eg, cognitive function), etiology of depression in PD, and treatment options (ie, antidepressants, electroconvulsive therapy, and psychotherapy). The current review is unique in its focus on psychosocial aspects, as well as neuropathological factors, of depression in PD. Overall, we conclude that neurochemical (eg, serotonin) and psychosocial factors (eg, coping style, self-esteem, and social support) contribute to the affective disturbances found in this neuropsychiatric population. Therefore, we recommend that a multidisciplinary (eg, pharmacotherapeutic, psychoeducational, and/or psychotherapeutic) approach to treatment be taken with depressed PD patients. | 18,728,814 |
Zosyn (piperacillin/tazobactam) reformulation: Expanded compatibility and coadministration with lactated Ringer's solutions and selected aminoglycosides. | Zosyn((R)) , also known as Tazocin((R)) for injection, contains piperacillin and tazobactam and was approved by the US Food and Drug Administration in 1993 for the treatment of indicated serious infections. In 1995, United States Pharmacopoeia and European Pharmacopoeias reduced the particulate limit for injectables by 40%, based on general safety concerns. Wyeth attempted to control sporadic batch failures (associated with increased particulate formation) by shortening product expiration dating from 36 to 24 months and optimizing the stopper siliconization process. These modifications did not correct the problem completely. Wyeth reformulated Zosyn by incorporating two stabilizing functional excipients, ethylene diamine tetraacetic acid disodium salt (EDTA disodium) and sodium citrate, which solved the particulate formation problem. These two functional excipients also allowed for the first time Y-site coadministration of reformulated Zosyn product with amikacin and gentamicin at specific doses and concentrations, and with certain diluents, and the use of Ca(++) ion-containing Lactated Ringer's for admixture preparation. Reformulated Zosyn (approved 2005) may provide useful options of drug administration to healthcare professionals to lessen levels of particulates. Supportive data is provided for the expanded compatibility of reformulated Zosyn with different types of Ringer's solutions used globally and for the Y-site coadministration of amikacin and gentamicin aminoglycosides. | 18,728,835 |
Luminescence properties of Pt(II) complexes containing polypyridine ligands with extended aromatic moieties. | The luminescence properties of eleven Pt(II) complexes containing polypyridine ligands with extended aromatic moieties have been studied, both in acetonitrile fluid solution at 298 K and in butyronitrile rigid matrix at 77 K. For comparison purposes, also the phosphorescence properties of three free ligands at 77 K in butyronitrile have been investigated. The absorption spectra of all the compounds exhibit intense bands (epsilon in the range 10(4)-10(5) M(-1) cm(-1)) in the UV region, which are attributed to spin-allowed ligand-centered (LC) transitions, and moderately intense bands (epsilon in the range 10(3)-10(4) M(-1) cm(-1)) in the visible region, which receive contribution from both spin-allowed LC transitions and spin-allowed metal-to-ligand charge-transfer (MLCT) transitions. At low energy, less intense spin-forbidden MLCT bands are also present. At 77 K in rigid matrix, all the studied compounds exhibit structured and long-lived (lifetimes from 840 micros on the millisecond timescale) luminescence, which is attributed to triplet LC states in all cases. At room temperature in fluid solution the luminescence lifetime of all the compounds is largely shortened (nanosecond timescale), and most of the emission spectra are unstructured and red-shifted. For species exhibiting structured emission spectra even at room temperature, low luminescence quantum yields are always obtained (Phi < 10(4)), and their emission is assigned to triplet LC states, which mainly deactivate to the ground state by thermal-activated surface crossing to a closely-lying metal-centered (MC) triplet state. Compounds exhibiting unstructured emission show relatively high emission quantum yields (about 0.1) and their emission is assigned to a mixed LC/MLCT state. | 18,728,885 |
Prediction of dropout from respiratory symptoms and airflow limitation in a longitudinal respiratory study. | This study investigated the possibility that employees reporting respiratory symptoms were more likely than asymptomatic workers to dropout of a respiratory study carried out in Norwegian smelters. The study included 3924 employees in 24 Norwegian smelters. They were examined annually using a respiratory questionnaire and spirometry. The employees who did not meet for the follow-up within 18 months prior to the end of the study were considered dropouts. The data were analyzed using Cox regression for time-dependent covariates. The total and the median follow-up times were 16 997 and 4.9 years, respectively. The overall dropout rate was 44.5 [95% confidence interval (95% CI) 41.5-47.8 per 1000 person-years]. The hazard ratio (HR) for dropout was 1.38 (95% CI 1.15-1.66) for the workers reporting any respiratory symptom compared with the asymptomatic workers. The effect was the strongest among the employees who reported dyspnea, and it was stronger regarding symptoms at the last visit than for the baseline symptoms. Similarly, the hazard ratio for dropout for those with an airflow limitation [forced expiratory volume/forced vital capacity below the 5th percentile of the predicted value] was 1.31 (95% CI 1.01-1.69) when they were compared with employees without any airflow limitation. Respiratory symptoms and airflow limitation are important predictors of dropout from a longitudinal respiratory study. | 18,728,912 |
Predicting longitudinal patterns of psychological distress in older husband caregivers: further analysis of existing data. | Further analysis of existing data from a previous longitudinal study of older husband caregivers sought to determine whether primary objective and subjective stressors drawn from Pearlin's model of caregiving could predict three patterns of psychological distress observed in the sample over 1 year: (a) stable high (n=115), (b) stable low (n=44), and (c) rising (n=46). Results of discriminant function analyses show that subjective stressors (level of role overload, role captivity and relational deprivation) at baseline, distinguish the stable low group of husbands from the stable-high. The results suggest that there is considerable stability over time. Many husband caregivers report high-psychological distress and need help, whereas there is a need of preventive interventions to keep psychological distress low. Implications for singular interventions that target specific factors according to group membership are discussed. | 18,728,946 |
Perceived stress and resilience in Alzheimer's disease caregivers: testing moderation and mediation models of social support. | The study examined whether social support functioned as a protective, resilience factor among Alzheimer's disease (AD) caregivers. Moderation and mediation models were used to test social support amid stress and resilience. A cross-sectional analysis of self-reported data was conducted. Measures of demographics, perceived stress, family support, friend support, overall social support, and resilience were administered to caregiver attendees (N=229) of two AD caregiver conferences. Hierarchical regression analysis showed the compounded impact of predictors on resilience. Odds ratios generated probability of high resilience given high stress and social supports. Social support moderation and mediation were tested via distinct series of regression equations. Path analyses illustrated effects on the models for significant moderation and/or mediation. Stress negatively influenced and accounted for most variation in resilience. Social support positively influenced resilience, and caregivers with high family support had the highest probability of elevated resilience. Moderation was observed among all support factors. No social support fulfilled the complete mediation criteria. Evidence of social support as a protective, moderating factor yields implications for health care practitioners who deliver services to assist AD caregivers, particularly the promotion of identification and utilization of supportive familial and peer relations. | 18,728,949 |
Pulmonary function test in transfusion-dependent beta-thalassemia patients. | Beta-thalassaemia is the most common hemoglobinopathies in our region with treatment of regular blood transfusion. Iron overload and hemosiderosis can cause organ involvement. Recent studies have focused on pulmonary involvement and pathophysiology of lung damage. The goal of this study was to investigate the pulmonary abnormalities in thalassemic patients in relation with sign and symptoms and iron overload. The authors studied pulmonary function test (PFT) at the Adult Thalassemia Clinic in Tehran. The history of blood transfusion, iron chelation, respiratory problems, and drug usage was taken. Physical examination, PFT, arterial blood gas (ABG), and chest X-ray (CXR) were done. In total, 139 patients were studied. The mean age was 21.1 years and mean duration of transfusion was 18 years. It was found that 133 patients (95.7%) did not have respiratory problems and only 6 (4.3%) had some respiratory complaints. In CXR, 100 patients (89.3%) had normal lung pattern and others (10.7%) had variable degrees of abnormal lung pattern. In ABG, mean of Po(2) was 73.5% and mean of O(2) saturation was 90.6%. In PFT, 101 patients (72.7%) had restrictive pattern, 35 (25.1%) had normal pattern, and 3 (2.2%) had combined pattern. According to vital capacity, the patients were placed in five categories: 54 patients (38.8%) normal, 37 (26.6%) mild, 35 (25.3%) moderate, 10 (7.2%) severe, and 3 (2.1%) extremely severe pulmonary deficit. There was no statistical significance between PFT results with all variables studied, except duration of blood transfusion, which may be considered a indirect effect of iron load (p = .05, r = .361). According to these results, restrictive pattern was the most common finding (72.7%) in PFT, while 95.7% of patients had no respiratory complaint, and in the chest X-ray group, 89.3% had normal pattern. The authors conclude that the lung may be considered a site for organ damage, and alteration of pulmonary function may be expected in transfusion-dependent patients in spite of no pulmonary symptoms or normal CXR. In recent years, because of new iron chelating drugs, doctors can expect thalassemic patients to have a long life-time and need to increase their quality of life. One way to do this is to evaluate the respiratory system by PFT to prevent the squeal of pulmonary disease. | 18,728,979 |
Condom use and self-efficacy among female sex workers with steady partners in China. | This study attempted to determine the association of self-efficacy with condom-use practice and to explore reasons of not using condoms among female sex workers (FSWs) with steady partners in China. Data from 309 establishment-based FSWs with steady partners in one Chinese county were collected through a cross-sectional study. Consistent condom use with steady partners was lower than with clients in entertainment establishments. Condom-use self-efficacy was positively associated with condom-use communication and condom-use frequency with clients but not with steady partners. It was positively associated with condom-use intention and skill with clients and steady partners. However, it was not associated with appropriate use of condoms. Significant differences of reasons about not using condom were also observed between the two partner types. The results may represent an important challenge to STD and HIV intervention programs aimed at achieving consistent condom use in FSWs. Health workers should focus on psychosocial factors affecting inconsistent condom use among FSWs with steady partners in China. In addition, intervention programs that can promote FSWs' self-efficacy through condom-use skill training will still be necessary. | 18,728,985 |
Ecology of E. coli O157:H7 and Salmonella enterica in the primary vegetable production chain. | There is an increased concern that plants might be more important as a carrier for human enteric pathogens like E. coli O157:H7 and Salmonella enterica serovars than previously thought. This review summarizes the knowledge available on the ecology of E. coli O157:H7 and Salmonella enterica in the primary production chain of leafy green vegetables (in particular lettuce), including manure, manure-amended soil, and crop. Based on the available literature, suggestions are made for the control of these pathogens. The suggested approach of oligotrophication of agro-ecosystems fits in the wider approach to lower environmental emissions of nutrients from manure application and to enhance the suppression against plant pathogens. | 18,728,991 |
Apixaban, an oral, direct inhibitor of activated Factor Xa. | Apixaban is an oral, direct Factor Xa inhibitor that is being developed by Bristol-Myers Squibb Co and Pfizer Inc. Apixaban is currently undergoing phase III clinical trials for cerebrovascular ischemia, deep vein thrombosis and lung embolism, and phase II clinical trials for coronary artery disease. | 18,729,009 |
Preparing for biofilm studies in the field. | In their natural environments, microorganisms are under constant environmental selection to form biofilms. Using aquatic biofilms as an example, this unit illustrates general concepts in field biology and practical suggestions for designing, conducting, and analyzing biofilm experiments at varying distances from the laboratory. The unit also addresses an example of a special situation (space flight) where experimentation must be done by proxy through another individual or machine. | 18,729,052 |
Functional decoupling of BOLD and gamma-band amplitudes in human primary visual cortex. | Although functional magnetic resonance imaging is an important tool for measuring brain activity, the hemodynamic blood oxygenation level dependent (BOLD) response is only an indirect measure of neuronal activity. Converging evidence obtained from simultaneous recording of hemodynamic and electrical measures suggest that the best correlate of the BOLD response in primary visual cortex is gamma-band oscillations ( approximately 40 Hz). Here, we examined the coupling between BOLD and gamma-band amplitudes measured with magntoencephalography (MEG) in human primary visual cortex in 10 participants. In Experiment A, participants were exposed to grating stimuli at two contrast levels and two spatial frequencies and in Experiment B square and sine wave stimuli at two spatial frequencies. The amplitudes of both gamma-band oscillations and BOLD showed tuning with stimulus contrast and stimulus type; however, gamma-band oscillations showed a 300% increase across two spatial frequencies, whereas BOLD exhibited no change. This functional decoupling demonstrates that increased amplitude of gamma-band oscillations as measured with MEG is not sufficient to drive the subsequent BOLD response. | 18,729,078 |
Dose-dependent growth inhibition in vivo of PC-3 prostate cancer with a reduction in tumoral growth factors after therapy with GHRH antagonist MZ-J-7-138. | Antagonists of growth hormone-releasing hormone (GHRH) inhibit the growth of various cancers and affect tumoral growth factors. We investigated the effect of a new GHRH antagonist MZ-J-7-138 at doses of 1.25, 2.5, 5 and 10 microg/day s.c. on the growth of PC-3 human androgen independent prostate cancers xenografted s.c. into nude mice. Binding assays were used to investigate GHRH receptors. The levels of IGF-II and VEGF in tumors were measured by radioimmunoassays. Treatment with 2.5, 5, and 10 microg/day MZ-J-7-138 caused a significant dose-dependent growth reduction of PC-3 tumors. The greatest inhibition of 78% was obtained with 10 microg/day. The suppression of IGF-II protein levels in tumors was seen at all doses of MZ-J-7-138, but only 10 microg dose induced a significant inhibition. MZ-J-7-138 also reduced VEGF protein levels, the inhibition being significant at doses of 5 and 10 microg. Specific high affinity binding sites for GHRH were found on PC-3 tumors using (125)I-labeled GHRH antagonist JV-1-42. MZ-J-7-138 displaced radiolabeled JV-1-42 with an IC(50) of 0.32 nM indicating its high affinity to GHRH receptors. Real-time PCR analyses detected splice variant 1 (SV1) of GHRH receptor (GHRH-R) as well as pituitary type of GHRH-R and GHRH ligand. Our results demonstrate the efficacy of GHRH antagonist MZ-J-7-138 in suppressing growth of PC-3 prostate cancer at doses lower than previous antagonists. The reduction of levels of growth factors such as VEGF and IGF-II in tumors by GHRH antagonist was correlated with the suppression of tumor growth. | 18,729,085 |
Carotid angioplasty and stenting in octogenarians: is it safe? | Elderly patients have a higher risk of complications in carotid endarterectomy. The aim of the study was to evaluate whether carotid artery stenting (CAS) performed in octogenarians also increases the procedure related risk. 870 patients (male 626) mean age 70.9 +/- 9.3 years underwent 930 CAS for de novo lesions (n = 851) restenoses (n = 54) post radiation (n = 14) inflammatory arteritis (n = 9) post trauma aneurysms (n = 2). Indications for treatment: symptomatic carotid stenosis > or = 70% (n = 577) or asymptomatic stenosis > or = 80%. Patients were separated into two age groups: <80 years (749 patients, 806 CAS) and >80 years (121 patients, 124 CAS). 187 CAS performed without protection (N.P-) 6 patients >80 years, 743 with protection (NP+) (occlusion balloon: 334, filters: 404, reversal flow: 6) 118 patients >80 years. Data analysis included neurological complications, death and myocardial infarction (MI) rate at 30 days, anatomical particularities. Technical points will be described depending on the age of the patient. Technical success 804/806 in patients <80 years, 123/124 in patients >80 years (NS). 30 days outcomes: in the patient group <80 years we observed 9 TIA (1.1%) 3 without NP (1.7%) 6 with NP (0.9%), 5 minor strokes (0.6%) 2 without NP (1.1%) 3 with NP (0.5%), 3 major strokes: 2 without NP (1.1%) 1 with NP (0.2%), 5 deaths (0.6%) 2 without NP (1.1%) 3 with NP (0.5%). Death/stroke/MI: 14 (1.8%) 6 without NP (3.3%), 8 with NP (1.3%). In the group >80 years, we observed 2 TIA (1.7%) 1 without NP 1 with NP (0.92%) 1 minor stroke without NP (17%) no major stroke, no death. Death/stroke/MI 1 without NP (17%). CAS can be performed in elderly patients without higher risk than in younger patients. But good indications, a meticulous technique, protection devices are mandatory and some technical points must be pointed out to avoid neurological complications and failures. | 18,729,151 |
Neuroanatomy of the complex tibial organ of Stenopelmatus (Orthoptera: Ensifera: Stenopelmatidae). | Stenopelmatidae (or "Jerusalem crickets") belong to the atympanate Ensifera, lacking hearing organs in the foreleg tibiae. Their phylogenetic position is controversial, either as a taxon in Tettigonioidea or within the clade of Gryllacridoidea. Similarly, the origin of tibial auditory systems in Ensifera is controversial. Therefore, we investigated the neuronal structures of the proximal tibiae of Stenopelmatus spec. with the hypothesis that internal sensory structures are similar to those in tympanate Ensifera. In Stenopelmatus the complex tibial organ consists of three neuronal parts: the subgenual organ, the intermediate organ, and a third part with linearly arranged neurons. This tripartite organization is also found in tympanate Ensifera, verifying our hypothesis. The third part of the sense organ found in Stenopelmatus can be regarded by the criterion of position as homologous to auditory receptors of hearing Tettigonioidea. This crista acustica homolog is found serially in all thoracic leg pairs and contains 20 +/- 2 chordotonal neurons in the foreleg. The tibial organ was shown to be responsive to vibration, with a broad threshold of about 0.06 ms(-2) in a frequency range from 100-600 Hz. The central projection of tibial sensory neurons terminates into two equally sized lobes in the primary sensory neuropil, the medial ventral association center. The data are discussed comparatively to those of other Ensifera and mapped phylogenetically onto recently proposed phylogenies for Ensifera. The crista acustica homolog could represent a neuronal rudiment of a secondarily reduced ear, but neuronal features are also consistent with an evolutionary preadaptation. | 18,729,154 |
Complications of type 1 diabetes: new molecular findings. | Interventions targeting the treatment of diabetic complications have not been nearly as successful as initially estimated, despite a marked improvement in therapeutic options for diabetes. The need for understanding why some very promising interventions have failed demands a closer look at the pathomechanisms of the complications. Great strides have been made in understanding the pathology, and several important hypotheses have emerged in recent years. On this basis, Brownlee and coworkers suggested a unifying hypothesis integrating various mechanisms discussed in past years with an overproduction of reactive oxygen species as an initiating cause. This hypothesis and further hypotheses, as well as mechanisms, are highlighted in this article. The field of pathomechanisms of diabetic complications is very wide, and any attempt to completely cover it within a single article is unrealistic. Therefore, our purpose is to present the most relevant concepts underlying diabetic complications in an attempt to contribute to a better understanding and pinpoint areas that warrant further research. | 18,729,179 |
Tumor expressed PTHrP facilitates prostate cancer-induced osteoblastic lesions. | Expression of parathyroid hormone-related protein (PTHrP) correlates with prostate cancer skeletal progression; however, the impact of prostate cancer-derived PTHrP on the microenvironment and osteoblastic lesions in skeletal metastasis has not been completely elucidated. In this study, PTHrP overexpressing prostate cancer clones were stably established by transfection of full length rat PTHrP cDNA. Expression and secretion of PTHrP were verified by western blotting and IRMA assay. PTHrP overexpressing prostate cancer cells had higher growth rates in vitro, and generated larger tumors when inoculated subcutaneously into athymic mice. The impact of tumor-derived PTHrP on bone was investigated using a vossicle co-implant model. Histology revealed increased bone mass adjacent to PTHrP overexpressing tumor foci, with increased osteoblastogenesis, osteoclastogenesis and angiogenesis. In vitro analysis demonstrated pro-osteoclastic and pro-osteoblastic effects of PTHrP. PTHrP enhanced proliferation of bone marrow stromal cells and early osteoblast differentiation. PTHrP exerted a pro-angiogenic effect indirectly, as it increased angiogenesis but only in the presence of bone marrow stromal cells. These data suggest PTHrP plays a role in tumorigenesis in prostate cancer, and that PTHrP is a key mediator for communication and interactions between prostate cancer and the bone microenvironment. Prostate cancer-derived PTHrP is actively involved in osteoblastic skeletal progression. | 18,729,185 |
Diet diversity and the risk of squamous cell esophageal cancer. | A varied diet may have a favorable role against digestive tract cancers. We analyzed the relationship between diet diversity (i.e. measured by the number of different foods consumed at least once per week) and the risk of esophageal cancer. We considered data from a case-control study conducted between 1992 and 1997 in northern Italy on 304 squamous cell esophageal cancer cases below age 78 years and 743 controls admitted to hospital for acute, nonneoplastic conditions, unrelated to tobacco or alcohol consumption. There was a significant inverse association for total diet diversity: the multivariate odds ratio (OR), adjusted for age, sex, area of residence, education, tobacco smoking, alcohol drinking and non-alcohol energy intake was 0.42 (95% confidence interval, CI: 0.25-0.71) for subjects in the highest versus those in the lowest quartile of diversity. Inverse relations were also found for diversity within vegetables (OR = 0.34, 95% CI: 0.21-0.55) and fruits (OR = 0.51, 95% CI: 0.33-0.80). No significant association was found for meat and cereal diversity. These results add epidemiological support to the dietary guidelines recommending a more varied diet, particularly in fruit and vegetables, for esophageal cancer prevention. | 18,729,191 |
Bicontinuous cyclosporin a loaded water-AOT/Tween 85-isopropylmyristate microemulsion: structural characterization and dermal pharmacokinetics in vivo. | Topical delivery of Cyclosporin A (CysA) is of great interest for the treatment of autoimmune skin disorders. Microemulsion systems prepared by AOT/Tween85/isopropyl myristate (IPM)/water possessing a potentially improved skin bioavailability of CysA were designed. The structure of microemulsions was investigated by diffusion-ordered NMR spectroscopy (DOSY) and differential scanning calorimetry (DSC) measurements. The DOSY measurements indicated the presence of bicontinuous and water-in-oil microemulsions depending on microemulsion composition. The DSC measurement confirmed that the microemulsion containing 30.0 wt% water was bicontinuous type, in agreement with the DOSY findings. We also evaluated the therapeutic advantage of dermal administration of CysA in rat model. Local (subcutaneous and skin), systemic concentrations and organ distribution (liver and kidney) were evaluated serially following topical and oral application of the drug. In rat dermal applied with the bicontinuous microemulsion containing CysA, the deposition of the drug into skin and subcutaneous fat was respectively almost 30 and 15-fold higher than the concentrations compared with oral administration. Systemic distribution in blood, liver and kidney was much lower following topical administration than that of following oral administration. With high local concentrations and minimal distribution to other organs via the circulation, topical microemulsion vehicle loaded with CysA might deliver maximal therapeutic effect to local tissue while avoiding side effects seen with systemic therapy. The histopathological findings revealed that the new bicontinuous microemulsion was a safe vehicle for topical drug delivery of CysA. | 18,729,203 |
Germline transgenesis of zebrafish using the medaka Tol1 transposon system. | Tol1 is a DNA-based transposable element first identified from an albino mutant medaka fish. It has been demonstrated to function as an efficient gene transfer vector in mammalian cells. We now demonstrate Tol1 germline transgenesis in zebrafish. A construct containing the green fluorescence protein (GFP) reporter gene inserted between the Tol1 arms was microinjected together with Tol1 transposase mRNA into fertilized eggs. Sustained GFP expression was observed in 88% of 1-month-old fish, suggesting efficient transposon integration into somatic cells. Eleven of 24 adult GFP-positive fish yielded GFP-positive progeny. Sequencing analysis of Tol1 insertion sites in GFP-positive progeny confirmed Tol1 transposition-mediated integrations into zebrafish chromosomes. We also observed functional independence of the Tol1 transposase-substrate system from that of Tol2, another medaka-derived transposon. Coupled with its previously demonstrated maximal cargo capacity of >20 kb, Tol1 could serve as a useful addition to the zebrafish genetic engineering toolbox. | 18,729,212 |
Enhancer detection and developmental expression of zebrafish sprouty1, a member of the fgf8 synexpression group. | Signaling pathways mediated by receptor tyrosine kinases (RTKs) are under positive and negative regulation, and misregulation of RTK signaling results in developmental defects and malignancy. A major class of antagonists of Fgf and Egf signaling are the Sprouty proteins. Through an enhancer detection approach, we isolated the sprouty1 (spry1) gene, expressed in multiple developing organs during embryogenesis. We analyzed expression of spry1 between tail bud stage and 10 days postfertilization. From the tail bud stage on, transcript and reporter are detected in the craniofacial region and in the mid-hindbrain boundary, where expression persists until adulthood. Further expression domains are the telencephalon, hindbrain, dorsal diencephalon and epiphysis, branchial arches, pituitary, and the tubular gill epithelium. In the trunk spry1 is also prominently expressed in pronephros, the lateral line and tail fin. Sprouty1 acts in Fgf signaling downstream of Fgfr1, as its expression is abrogated through the small molecule inhibitor of this receptor, SU5402. | 18,729,221 |
A critical evaluation of specific aspects of joint development. | Synovial joint formation has been divided into two phases; the formation of the anlagen of the opposing bones and the interzone and the later formation of the joint cavity. Here we review current theories on the mechanism by which these events are achieved in the joints of the developing limb. | 18,729,226 |
Expression of protocadherin-1 (Pcdh1) during mouse development. | Protocadherin-1 (Pcdh1) is a member of the delta-protocadherin subgroup of non-clustered protocadherins. We studied the expression of Pcdh1 from the early embryonic to the adult stage of mouse development by semi-quantitative RT-PCR and in situ hybridization. Pcdh1 can be detected as early as embryonic day 9.5. In early embryogenesis, expression is especially prominent in blood vessels. During later development and in the adult mouse, organs derived from the embryonic gut, such as the esophagus, intestines, liver, lung, and submandibular gland, contain epithelia and other types of tissues that are Pcdh1-positive. Other positive organs include the brain, spinal cord, retina, peripheral ganglia, the inner ear, hair follicles, kidney, vagina, uterus, placenta, testis, prostate, and the seminal gland. The tight spatial and temporal regulation of Pcdh1 expression suggests that this protocadherin plays multiple roles not only during development but also in mature tissues and organs in the mouse. | 18,729,229 |
Expression of TMEM16 paralogs during murine embryogenesis. | The TMEM16 protein family has recently been identified through several different experimental strategies including bioinformatic and microarray-based approaches. In mice and humans, there exist 10 paralogs with each containing eight putative transmembrane domains and a conserved C-terminal domain of unknown function. Mutation of at least one member of this family is associated with a human disorder, and several members of this gene family are overexpressed in different types of cancer. Despite their apparent relevance to normal development and disease, little is known about the expression of TMEM16 paralogs during embryonic development. Here, we provide a phylogenetic analysis of mouse and human TMEM16 paralogs and report the expression of Tmem16a, Tmem16b, Tmem16c, Tmem16f, Tmem16h, Tmem16j, and Tmem16k during murine embryogenesis with an emphasis on the respiratory, digestive, skeletal, and integumentary systems. These data should encourage investigations into the functions of TMEM16 paralogs in vertebrate development. | 18,729,231 |
Antibodies against RNA hydrolyze RNA and DNA. | Immunization of animals with DNA leads to the production of anti-DNA antibodies (Abs) demonstrating both DNase and RNase activities. It is currently not known whether anti-RNA Abs can possess nuclease activities. In an attempt to address this question, we have shown that immunization of three rabbits with complex of RNA with methylated BSA (mBSA) stimulates production of IgGs with RNase and DNase activities belonging to IgGs, while polyclonal Abs from three non-immunized rabbits and three animals immunized with mBSA are catalytically inactive. Affinity chromatography of IgGs from the sera of autoimmune (AI) patients on DNA-cellulose usually demonstrates a number of fractions, all of which effectively hydrolyze both DNA and RNA, while rabbit catalytic IgGs were separated into Ab subfractions, some of which demonstrated only DNase activity, while others hydrolyzed RNA faster than DNA. The enzymic properties of the RNase and DNase IgGs from rabbits immunized with RNA distinguish them from all known canonical RNases and DNases and DNA- and RNA-hydrolyzing abzymes (Abzs) from patients with different AI diseases. In contrast to RNases and AI RNA-hydrolyzing Abs, rabbit RNase IgGs catalyze only the first step of the hydrolysis reaction but cannot hydrolyze the formed terminal 2',3'-cyclophosphate. The data indicate that Abzs of AI patients hydrolyzing nucleic acids in part may be Abs against RNA and its complexes with proteins. | 18,729,241 |
A one-year survey on the use of a powder from Rosa canina lito in acute exacerbations of chronic pain. | This pilot surveillance included 152 patients with acute exacerbations of chronic pain, 124 (Back group) with non-specific low back pain (NSLBP), 20 with NSLBP overridden by osteoarthritic pain (Knee-Hip group), and eight with specific LBP (included in the safety analysis). Patients were recommended the rose hip and seed powder Litozin at a dose providing up to 3 mg of galactolipid/day for up to 54 weeks. Clinical symptoms and well-being were assessed every 6 weeks. The patients also kept a diary of their pain and the requirement for rescue medication. Data were analysed by intention to treat with last observation carried forward. Only 77 patients completed the year of surveillance. Multivariate analysis suggested an appreciable overall improvement during the surveillance, irrespective of group, and this was reflected for most of the individual measures in repeated measures ANOVA. The degree and time-course of improvement echoed that seen in similar surveillances of patients receiving an aqueous extract of Harpagophytum. Multiple regression analyses indicated that percentage changes from baseline tended to be greater in patients with greater degrees of pain and disability, but were otherwise largely unrelated to the patients' characteristics. There were no serious adverse events. The rose hip and seed powder, Litozin, seems to deserve further, more definitive studies as a possible option in long-term management of NSLBP with or without osteoarthritic pain. | 18,729,248 |
Risk factors for neonatal infections in full-term babies in South Korea. | Since 1997, private postnatal care facilities (San-hu-jo-ri-won in Korean) have emerged to take the role of the family. As a result, neonates are now exposed to many people and are very vulnerable to infection. However, there has been no study on the influence of postnatal care facilities on neonatal infection. The aim of this study was to determine the risk factors of neonatal infection in full-term babies in Korea. We followed up 556 pregnant women and their babies for 4 weeks after their births at 2 hospitals in Seoul and Daejeon from October 2004 to September 2005. Among 512 full-term babies, 58 had infectious diseases. To determine the risk factors for infection, 53 infected neonates at 4-28 days of life and 413 healthy neonates were compared. The incidence of neonatal infection at 4 to 28 days after birth was 10.5%. After adjusting the related factors, the number of siblings (OR = 2.05, 95% CI = 1.13-3.71 for 1 or more) and postnatal care facilities or home aides (OR = 1.91, 95% CI = 1.07-3.45) were significant risk factors. Formula or mixed feeding (OR = 1.66, 95% CI = 0.91-3.04) increased the risk of neonatal infection but it was not statistically significant. When the newborns had siblings, stayed at postnatal care facilities, or were cared for by home aides, the risk of neonatal infections significantly increased. Further research on the feeding effect on neonatal infection and evaluation of prevention efforts are needed. | 18,729,294 |
Antenatal cognitive-behavioral therapy for prevention of postpartum depression: a pilot study. | To examine the efficacy of cognitive-behavioral therapy (CBT) for the prevention of postpartum depression (PPD) in "at risk" women. We recruited 927 pregnant women in 6 obstetric and gynecology clinics and screened them using Beck Depression Inventory (BDI). Ninety-nine of the screened women who had significantly high scores in BDI (a score above 16) were selected for the study. They were contacted through by telephone, and 27 who had consented to participate in the study were interviewed via SCID-IV-I. Twenty-seven eligible women were randomly assigned to the CBT intervention (n = 15) and control condition (n = 12). All participants were required to complete written questionnaires, assessing demographic characteristics, depressive symptoms, negative thoughts, dyadic communication satisfaction, and global marital satisfaction prior to treatment and approximately 1 month postpartum. The 15 women in the CBT condition received 9 bi-weekly 1-hour individual CBT sessions, targeting and modifying negative patterns of thinking and behaviors occurring in the context of the dyadic relationship. The analysis of covariance (ANCOVA) showed that there were significant differences in all postpartum measures between the 2 groups, indicating that our antenatal intervention with CBT was effective in reducing depressive symptoms and improving marital satisfaction, which lasted until the postpartum period. Our pilot study has provided preliminary empirical evidence that antenatal CBT intervention can be an effective preventive treatment for PPD. Further study in this direction was suggested. | 18,729,297 |
Maternal depression predicts maternal use of corporal punishment in children with attention-deficit/hyperactivity disorder. | We sought to determine if maternal depression contributed to the use of corporal punishment in children with attention-deficit/hyperactivity disorder (ADHD). The data were gathered through chart review of clinic-referred children with ADHD and their mothers who were evaluated at a psychiatric clinic located in a large academic medical center in Seoul, Korea. Daily records kept by parents and 13 items from the Physical Assault of the Parent-Child Conflict Tactics Scales (CTSPC) were used to assess corporal punishment. Ninety-one children with ADHD and their mothers were included in this study. Mothers who used corporal punishment showed significantly higher scores on the Beck Depression Inventory (t = -2.952, df = 89, p < 0.01) than mothers who did not. Moreover, maternal depression contributed to the use of corporal punishment in ADHD children (Nagelkerke R2 = 0.102, p < 0.05). Maternal depression contributes to the use of corporal punishment with children with ADHD. Assessment and management of the maternal depression should be an important focus of evaluation of children with ADHD. | 18,729,299 |
Iatrogenic gastric dilatation: a rare and transient cause of hepatic-portal venous gas. | Gas in the portal veins is rare and in most cases is associated with serious diseases and poor clinical outcome. A case of gas in the hepatic-portal veins with gastric dilatation, as shown by CT-scanning for abdominal trauma, is reported. The condition was clinically benign and resolved spontaneously. An abdominal CT scan documented the findings. | 18,729,313 |
A spindle cell predominant pancreatic solid-pseudopapillary tumor. | A hitherto unrecognized variant of solid-pseudopapillary tumor (SPT) of the pancreas is reported. The tumor presented in the pancreatic tail of a 44-year-old female patient. It was a well-defined, solid nodule measuring 25 mm in diameter, with homogenous tan gray cut surface. Histologically, the neoplasm was mostly composed of sheets of spindle cells. No cellular atypia and mitosis was identified. The periphery of the tumor showed typical feature of SPT. Immunohistochemically, the tumor cells were positive for vimentin, CD10, CD56, beta-catenin, and alpha1-antichymotrypsin, but negative for cytokeratin, chromogranin, synaptophysin and S-100 protein. Ultrastructurally, the tumor showed a few acinar spaces with microvilli between tumor cells. This case is peculiar in that the tumor did not show gross cystic change and predominantly consists of spindle shaped tumor cells, so may cause difficult diagnostic problem. | 18,729,314 |
Critical assessment of QSAR models of environmental toxicity against Tetrahymena pyriformis: focusing on applicability domain and overfitting by variable selection. | The estimation of the accuracy of predictions is a critical problem in QSAR modeling. The "distance to model" can be defined as a metric that defines the similarity between the training set molecules and the test set compound for the given property in the context of a specific model. It could be expressed in many different ways, e.g., using Tanimoto coefficient, leverage, correlation in space of models, etc. In this paper we have used mixtures of Gaussian distributions as well as statistical tests to evaluate six types of distances to models with respect to their ability to discriminate compounds with small and large prediction errors. The analysis was performed for twelve QSAR models of aqueous toxicity against T. pyriformis obtained with different machine-learning methods and various types of descriptors. The distances to model based on standard deviation of predicted toxicity calculated from the ensemble of models afforded the best results. This distance also successfully discriminated molecules with low and large prediction errors for a mechanism-based model developed using log P and the Maximum Acceptor Superdelocalizability descriptors. Thus, the distance to model metric could also be used to augment mechanistic QSAR models by estimating their prediction errors. Moreover, the accuracy of prediction is mainly determined by the training set data distribution in the chemistry and activity spaces but not by QSAR approaches used to develop the models. We have shown that incorrect validation of a model may result in the wrong estimation of its performance and suggested how this problem could be circumvented. The toxicity of 3182 and 48774 molecules from the EPA High Production Volume (HPV) Challenge Program and EINECS (European chemical Substances Information System), respectively, was predicted, and the accuracy of prediction was estimated. The developed models are available online at http://www.qspr.org site. | 18,729,318 |
Synthesis of platinum nanowheels using a bicellar template. | Disk-like surfactant bicelles provide a unique meso-structured reaction environment for templating the wet-chemical reduction of platinum(II) salt by ascorbic acid to produce platinum nanowheels. The Pt wheels are 496 +/-55 nm in diameter and possess thickened centers and radial dendritic nanosheets (about 2-nm in thickness) culminating in flared dendritic rims. The structural features of the platinum wheels arise from confined growth of platinum within the bilayer that is also limited at edges of the bicelles. The size of CTAB/FC7 bicelles is observed to evolve with the addition of Pt(II) complex and ascorbic acid. Synthetic control is demonstrated by varying the reaction parameters including metal salt concentration, temperature, and total surfactant concentration. This study opens up opportunities for the use of other inhomogeneous soft templates for synthesizing metals, metal alloys, and possibly semiconductors with complex nanostructures. | 18,729,320 |
DNA interaction with antitumor polyamine analogues: a comparison with biogenic polyamines. | Biogenic polyamines, putrescine, spermidine, and spermine, are ubiquitous cellular cations and exert multiple biological functions. Polyamine analogues mimic biogenic polyamines at macromolecular level but are unable to substitute for natural polyamines and maintain cell proliferation, indicating biomedical applications. The mechanistic differences in DNA binding mode between natural and synthetic polyamines have not been explored. The aim of this study was to examine the interaction of calf thymus DNA with three polyamine analogues, 1,11-diamino-4,8-diazaundecane (333), 3,7,11,15-tetrazaheptadecane x 4 HCl (BE-333), and 3,7,11,15,19-pentazahenicosane x 5 HCl (BE-3333), using FTIR, UV-visible, and CD spectroscopy. Polyamine analogues bind with guanine and backbone PO2 group as major targets in DNA, whereas biogenic polyamines bind to major and minor grooves as well as to phosphate groups. Weaker interaction with DNA was observed for analogues with respect to biogenic polyamines, with K(333) = 1.90 (+/-0.5) x 10(4) M(-1), K(BE-333) = 6.4 (+/-1.7) x 10(4) M(-1), K(BE-3333) = 4.7 (+/-1.4) x 10(4) M(-1) compared to K(Spm) = 2.3 (+/-1.1) x 10(5) M(-1), K(Spd) = 1.4 (+/-0.6) x 10(5) M(-1), and K(Put) = 1.02 (+/-0.5) x 10(5) M(-1). A partial B- to A-DNA transition was also provoked by analogues. These data suggest distinct differences in the binding of natural and synthetic polyamines with DNA. | 18,729,321 |
Lyotropic liquid-crystalline mesophases of [Zn(H2O)6](NO3)2-C12EO10-CTAB-H2O and [Zn(H2O)6](NO3)2-C12EO10-SDS-H2O systems. | The mixture of two surfactants (C12EO10-CTAB and C12EO10-SDS) forms lyotropic liquid-crystalline (LLC) mesophases with [Zn(H2O)6](NO3)2 in the presence of a minimum concentration of 1.75 H2O per C12EO10. The metal ion/C12EO10 mole ratio can be increased up to 8.0, which is a record high metal ion density in an LLC mesophase. The metal ion concentration can be increased in the medium by increasing the CTAB/C12EO10 or SDS/C12EO10 mole ratio at the expense of the stability of the LLC mesophase. The structure and some thermal properties of the new mesophase have been investigated using XRD, POM, FTIR, and Raman techniques. | 18,729,333 |
Light-induced biocidal action of conjugated polyelectrolytes supported on colloids. | A series of water soluble, cationic conjugated polyelectrolytes (CPEs) with backbones based on a poly(phenylene ethynylene) repeat unit structure and tetraakylammonium side groups exhibit a profound light-induced biocidal effect. The present study examines the biocidal activity of the CPEs, correlating this activity with the photophysical properties of the polymers. The photophysical properties of the CPEs are studied in solution, and the results demonstrate that direct excitation produces a triplet excited-state in moderate yield, and the triplet is shown to be effective at sensitizing the production of singlet oxygen. Using the polymers in a format where they are physisorbed or covalently grafted to the surface of colloidal silica particles (5 and 30 microm diameter), we demonstrate that they exhibit light-activated biocidal activity, effectively killing Cobetia marina and Pseudomonas aeruginosa. The light-induced biocidal activity is also correlated with a requirement for oxygen suggesting that interfacial generation of singlet oxygen is the crucial step in the light-induced biocidal activity. | 18,729,335 |
Theoretical study on the phenyl torsional potentials of trans-diphenyldiphosphene. | The phenyl torsional potentials of trans-diphenyldiphosphene ( trans-phosphobenzene; t-DPP), which is an analogue of trans-azobenzene ( t-AZB), have been examined by means of ab initio complete active space self-consistent field (CASSCF) calculations. Though the electronic structures of t-DPP are similar to those of t-AZB, the phenyl torsional potentials are different from each other. In S 0, the potential energy curve of t-DPP has double minima at nonplanar conformations with C 2 and C i symmetries, while that of t-AZB has only minimum at a planar conformation with C 2 h . In S 1, the phenyl torsion of t-AZB is impeded from a planar geometry more than that in S 0. On the other hand, the phenyl torsion of t-DPP is promoted so that the phenyl groups are perpendicularly twisted against the PP double bond around the Franck-Condon region. Comments on the experimental findings of realistic diphosphenes protected by bulky substituents are also made. | 18,729,342 |
Binding of ADP in the mitochondrial ADP/ATP carrier is driven by an electrostatic funnel. | The ADP/ATP carrier (AAC) is a membrane protein of paramount importance for the energy-fueling function of the mitochondria, transporting ADP from the intermembrane space to the matrix and ATP in the opposite direction. On the basis of the high-resolution, 2.2-A structure of the bovine carrier, a total of 0.53 micros of classical molecular dynamics simulations were conducted in a realistic membrane environment to decipher the early events of ADP (3-) translocation across the inner membrane of the mitochondria. Examination of apo-AAC underscores the impermeable nature of the carrier, impeding passive transport of permeants toward the matrix. The electrostatic funnel illuminated from three-dimensional mapping of the electrostatic potential forms a privileged passageway anticipated to drive the diphosphate nucleotide rapidly toward the bottom of the internal cavity. This conjecture is verified in the light of repeated, independent numerical experiments, whereby the permeant is dropped near the mouth of the mitochondrial carrier. Systematic association of ADP (3-) to the crevice of the AAC, an early event in its transport across the inner membrane, is accompanied by the formation of an intricate network of noncovalent bonds. Simulations relying on the use of an adaptive biasing force reveal for the first time that the proposed binding site corresponds to a minimum of the free energy landscape delineating the translocation of ADP (3-) in the carrier. The present work paves the way to the design of novel nucleotides and new experiments aimed at unveiling key structural features in the chronology of ADP/ATP transport across the mitochondrial membrane. | 18,729,359 |
UV absorption cross-sections of a series of dimethylbenzaldehydes. | The ultraviolet absorption cross-sections of 2,4-, 2,5-, 2,6-, 3,4- and 3,5- dimethylbenzaldehydes are reported in the wavelength range 240-320 nm. The measurements were carried out in the temperature range 318-363 K using two different experimental systems (D 2 lamp-monochromator and D 2 lamp-diode array). The absorption spectra of the five aldehydes have been found to exhibit relatively high absorption cross-sections in the region of the tropospheric interest with maxima around 290 nm. This work provides the first UV cross-section measurements for these aromatic aldehydes. The obtained cross-section values enable us to estimate the tropospheric photolysis lifetimes of these compounds. The results suggest that photolysis could be an important removal process for these species in the troposphere. | 18,729,433 |
Cyclic ruthenium-alkylidene catalysts for ring-expansion metathesis polymerization. | A series of cyclic Ru-alkylidene catalysts have been prepared and evaluated for their efficiency in ring-expansion metathesis polymerization (REMP). The catalyst structures feature chelating tethers extending from one N-atom of an N-heterocyclic carbene (NHC) ligand to the Ru metal center. The catalyst design is modular in nature, which provided access to Ru complexes having varying tether lengths, as well as electronically different NHC ligands. Structural impacts of the tether length were unveiled through (1)H NMR spectroscopy as well as single-crystal X-ray analyses. Catalyst activities were evaluated via polymerization of cyclooctene, and key data are provided regarding propagation rates, intramolecular chain transfer, and catalyst stabilities, three areas necessary for the efficient synthesis of cyclic poly(olefin)s via REMP. From these studies, it was determined that while increasing the tether length of the catalyst leads to enhanced rates of polymerization, shorter tethers were found to facilitate intramolecular chain transfer and release of catalyst from the polymer. Electronic modification of the NHC via backbone saturation was found to enhance polymerization rates to a greater extent than did homologation of the tether. Overall, cyclic Ru complexes bearing 5- or 6-carbon tethers and saturated NHC ligands were found to be readily synthesized, bench-stable, and highly active catalysts for REMP. | 18,729,450 |
Nectar Flavonol rhamnosides are floral markers of acacia (Robinia pseudacacia) honey. | With the objective of finding floral markers for the determination of the botanical origin of acacia (robinia) honey, the phytochemicals present in nectar collected from Robinia pseudacacia flowers were analyzed by high-performance liquid chromatography-tandem mass spectrometry. Eight flavonoid glycosides were detected and characterized as kaempferol combinations with rhamnose and hexose. Acacia honey produced in the same location where the nectar was collected contained nectar-derived kaempferol rhamnosides. This is the first time that flavonoid glycosides have been found as honey constituents. Differences in the stability of nectar flavonoids during honey elaboration and ripening in the hive were shown to be due to hydrolytic enzymatic activity and to oxidation probably related to hydrogen peroxide (glucose-oxidase) activity. Acacia honeys contained propolis-derived flavonoid aglycones (468-4348 microg/100 g) and hydroxycinnamic acid derivatives (281-3249 microg/100 g). In addition, nectar-derived kaempferol glycosides were detected in all of the acacia honey samples analyzed (100-800 microg/100 g). These flavonoids were not detected in any of the different honey samples analyzed previously from different floral origins other than acacia. Finding flavonoid glycosides in honey related to floral origin is particularly relevant as it considerably enlarges the number of possible suitable markers to be used for the determination of the floral origin of honeys. | 18,729,455 |
Fractionation of honey carbohydrates using pressurized liquid extraction with activated charcoal. | This article describes the development of a new procedure that combines the use of activated charcoal and pressurized liquid extraction (PLE) to obtain enriched fractions of di- and trisaccharides from honey. Honey was adsorbed onto activated charcoal and packed into a PLE extraction cell. Optimum results were obtained at 10 MPa and 40 degrees C using two consecutive PLE cycles: first, 1:99 (v/v) ethanol/water for 5 min and second, 50:50 (v/v) ethanol/water for 10 min. Di- and trisaccharide fractions were enriched after PLE treatment, accounting for 73% and 8% of total carbohydrates, respectively. This procedure was also compared with other methodologies reported in the literature for the fractionation of honey carbohydrates (yeast treatment and extraction from activated charcoal). While the removal of monosaccharides was more efficient with yeast treatment, recovery of di- and trisaccharides was higher when either the PLE or the activated charcoal treatment was used. PLE was found to be the faster technique; it also required less solvent volume and minimized handling of the sample. | 18,729,462 |
Mathematical model for mixing reactants in a capillary microreactor by transverse diffusion of laminar flow profiles. | Transverse diffusion of laminar flow profiles (TDLFP) was recently suggested as a generic approach for mixing reactants inside a capillary microreactor. Conceptually, solutions of reactants are injected inside the capillary by high pressure as a series of consecutive plugs. Because of the laminar nature of the flow inside the capillary, the nondiffused plugs have parabolic profiles with predominantly longitudinal interfaces between the plugs. After the injection, the reactants are mixed by transverse diffusion across the longitudinal interfaces. TDLFP-based mixing is still in its infancy as only the principle was proved. Here, we develop the theory of TDLFP and introduce a dimensionless parameter, York number, which can be used in predicting the quality of TDLFP-based mixing. The theory uses a single simplifying assumption that the longitudinal diffusion is negligible; this assumption is readily satisfied. We then develop a numerical model of TDLFP and use it to simulate the concentration profiles of three reactants mixed by TDLFP in the capillary. The correlation between the York number and quality of mixing is analyzed. Two ways of improving the quality of TDLFP-based mixing are suggested and studied: (i) increasing the longitudinal interface between the plugs by a long last plug of a solvent and (ii) "shaking" the injected reactants by a series of alternating negative and positive pressure pulses. The developed theory and computational simulation of TDLFP will stimulate the practical use of capillary microreactors. | 18,729,469 |
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