title stringlengths 0 1.13k | abstract stringlengths 1 15.7k | PMID int64 22 36.5M |
|---|---|---|
Circulating 25-hydroxyvitamin D, VDR polymorphisms, and survival in advanced non-small-cell lung cancer. | We showed previously that in early-stage non-small-cell lung cancer (NSCLC), serum vitamin D levels and VDR polymorphisms were associated with survival. We hypothesized that vitamin D levels and VDR polymorphisms may also affect survival among patients with advanced NSCLC. We evaluated the relationship between circulating 25-hydroxyvitamin D levels; VDR polymorphisms, including Cdx-2 G>A (rs11568820), FokI C>T (rs10735810), and BsmI C>T (rs144410); and overall survival among patients with advanced NSCLC. Analyses of survival outcomes were performed using the log-rank test and Cox proportional hazards models, adjusting for sex, stage, and performance status. There were 294 patients and 233 deaths, with median follow-up of 42 months. We found no difference in survival by circulating vitamin D level. The C/C genotype of the FokI polymorphism was associated with improved survival: median survival for C/C was 21.4 months, for C/T was 12.1 months, and for T/T was 15.6 months (log-rank P = .005). There were no significant effects on survival by the Cdx-2 or BsMI polymorphism. However, having increasing numbers of protective alleles was associated with improved survival (adjusted hazard ratio for two or more v zero to one protective alleles, 0.57; 95% CI, 0.41 to 0.79; P = .0008). On haplotype analysis, the G-T-C (Cdx-2-FokI-BsmI) haplotype was associated with worse survival compared with the most common haplotype of G-C-T (adjusted hazard ratio, 1.61; 95% CI, 1.21 to 2.14; P = .001). There was no main effect of vitamin D level on overall survival in the advanced NSCLC population. The T allele of the VDR FokI>T polymorphism and the G-T-C (Cdx-2-FokI-BsmI) haplotype were associated with worse survival. | 18,936,471 |
Cost-effectiveness of nurse-led disease management for heart failure in an ethnically diverse urban community. | Randomized, controlled trials have shown that nurse-led disease management for patients with heart failure can reduce hospitalizations. Less is known about the cost-effectiveness of these interventions. To estimate the cost-effectiveness of a nurse-led disease management intervention over 12 months, implemented in a randomized, controlled effectiveness trial. Cost-effectiveness analysis conducted alongside a randomized trial. Medical costs from administrative records, and self-reported quality of life and nonmedical costs from patient surveys. Patients with systolic dysfunction recruited from ambulatory clinics in Harlem, New York. 12 months. Societal and payer. 12-month program that involved 1 face-to-face encounter with a nurse and regular telephone follow-up. Quality of life as measured by the Health Utilities Index Mark 3 and EuroQol-5D and cost-effectiveness as measured by the incremental cost-effectiveness ratio (ICER). Costs and quality of life were higher in the nurse-managed group than the usual care group. The ICERs over 12 months were $17,543 per EuroQol-5D-based quality-adjusted life-year (QALY) and $15,169 per Health Utilities Index Mark 3-based QALY (in 2001 U.S. dollars). From a payer perspective, the ICER ranged from $3673 to $4495 per QALY. Applying national prices in place of New York City prices yielded a societal ICER of $13,460 to $15,556 per QALY. Cost-effectiveness acceptability curves suggest that the intervention was most likely cost-effective for patients with less severe (New York Heart Association classes I to II) heart failure. The trial was conducted in an ethnically diverse, inner-city neighborhood; thus, results may not be generalizable to other communities. Over 12 months, the nurse-led disease management program was a reasonably cost-effective way to reduce the burden of heart failure in this community. | 18,936,502 |
Primary care interventions to promote breastfeeding: U.S. Preventive Services Task Force recommendation statement. | Update of a 2003 U.S. Preventive Services Task Force (USPSTF) recommendation on counseling to promote breastfeeding. The USPSTF evaluated the results of a systematic review, conducted by the Tufts-New England Medical Center Evidence-based Practice Center, of literature published since January 2007 on primary care-initiated, -conducted, or -referable activities to promote and support breastfeeding. The USPSTF recommends interventions during pregnancy and after birth to promote and support breastfeeding (Grade B recommendation). | 18,936,503 |
A rare case of posterior urethral valve and pleural effusion in Down syndrome with successful intrauterine shunt. | Posterior urethral valve or pleural effusion accompanied with Down syndrome have been described previously; however, there is no reported case of posterior urethral valve and pleural effusion with Down syndrome. A 45-year-old multigravida woman was transferred due to bilateral fetal hydrothorax, polyhydramnios, and threatened preterm labor at 32 weeks' gestation. Transabdominal ultrasonography revealed additional abnormality, posterior urethral valve. Amniocentesis was repeated due to intense amniotic fluid and patient's dyspnea. Ultrasound-guided thoracoamniotic shunt and vesicoamniotic shunt were done successfully. At 33 weeks' gestation, intrauterine infection was suspected by the laboratory findings of amniotic fluid. A 2.25-kg male baby with characteristic phenotypic findings of Down syndrome was delivered by Cesarean section. Cytogenetic analysis after birth revealed a karyotype of 47,XY,+21. The present case reinforces the notions that fetuses with multiple anomalies, like congenital pleural effusion and posterior urethral valve, are at risk of chromosomal abnormalities, in spite of their low possibilities of association with chromosomal abnormalities. | 18,936,544 |
Elective use of aortic balloon occlusion in cesarean hysterectomy for placenta previa percreta. | Only few reports are available on the use of aortic balloon catheter for cesarean hysterectomy in placenta previa percreta. A 32-year-old woman with placenta previa percreta underwent cesarean hysterectomy at 34 weeks of gestation. Before starting the surgery, an aortic occlusion balloon catheter (30 mm balloon, 5 Fr) was inserted. For total hysterectomy, the aortic balloon catheter was inflated and there was a sudden and dramatic reduction in blood loss, and the surgery was completed safely. An aortic occlusion was sustained for 80 min, with blood loss estimated at 3,200 ml. The postoperative course was uneventful. At 3 months after the operation, the mother and baby remained healthy. An aortic balloon is rapidly and easily inserted, and is an option for major hemorrhage in placenta previa percreta. | 18,936,549 |
Dialysis and the elderly: an underestimated problem. | In developed countries, the incidence of end-stage renal failure is constantly increasing, and uremia will soon be a disease typically found in mature and elderly adults. Almost invariably, the physical condition of the elderly patient with terminal uremia is extremely poor, and therapeutic approach complex. Frequent co-morbidity, treatment with many different drugs, the high risk of iatrogenic damage, advanced age and socio-environmental conditions further complicate the management of these patients. While replacement therapy may become necessary, peritoneal dialysis may have advantages over hemodialysis. Peritoneal dialysis causes less hemodynamic stress, does not necessitate vascular access and allows mobility, although it incurs a high incidence of peritonitis and vascular disease. Where hemodialysis is the only feasible treatment, procedures used for vascular access are frequently followed by several complications, representing an important cause of morbidity and hospitalization. In addition, even if it may improve the patient's quality of life, vascular condition, intradialytic hypotension, heart disease, intestinal bleeding and amyloidotic arthropathy are critical aspects of dialysis in the elderly patient. Therefore, particular attention from clinicians and administrators is required and the best possible strategies must be identified in order to provide effective and appropriate services to address these special patients' needs. | 18,936,550 |
Are Surgisis biomeshes effective in reducing recurrences after laparoscopic repair of large hiatal hernias? | Prosthetic repair is frequently advocated after repair of large hiatal hernias, and biomeshes have been proposed to help reduce the high recurrence rate. All patients undergoing laparoscopic repair of primary or recurrent large hiatal hernia, and with intraoperative finding of weak diaphragmatic pillars, as judged by the surgeon, were included, from June 2004 to July 2005, in a prospective observational study. In these patients, Surgisis biomeshes were employed to assist the repair. Six patients (4 for primary and 2 for recurrent hernia) received biomesh hiatoplasty. Four had mild dysphagia at 1 month that disappeared at the next follow-up. Three had slow radiologic transit through the esophagogastric junction, still present in 1 patient at 1 year. One patient had hernia recurrence 6 months after surgery and 2 other patients had radiologic recurrence of a small hernia at 1-year follow-up; in all 3, the recurrence was small and asymptomatic and none were reoperated. The short-term recurrence rate using biomesh for the laparoscopic repair of large hiatal hernias in patients with weak diaphragmatic pillars was high at 50%. Postoperative morbidity and mesh-related complications were almost absent. Biomeshes can be safely used as on lay reinforcement in hiatoplasty, but do not reduce the hiatal recurrence rate. | 18,936,659 |
Endoscopy-assisted transanal division of an apical pouch bridge after restorative proctocolectomy with a J-shaped ileal pouch. | Restorative proctocolectomy and J-shaped ileal pouch-anal anastomosis have been performed as a standard operation for ulcerative colitis. However, functional problems are sometimes troublesome in the postoperative period. The J pouch was constructed from 2 ileal limbs using the gastrointestinal anastomosis (GIA) stapler. A residual mucosal bridge remained because the stapler had a safety margin at the top of the cartridge. Apical pouch bridge is a residual septum above the ileoanal anastomosis. There are several reports of so-called apical pouch bridge syndrome due to outlet obstruction of the J-shaped ileal pouch by an apical bridge. Division of this septum can resolve the outlet obstruction. We describe a successful endoscopic procedure for division of an apical pouch bridge. An Endo-GIA stapler was introduced into the ileal pouch alongside the endoscope, and division of the apical bridge required a few firings of the Endo-GIA stapler under transanal endoscopic guidance. The symptoms related to the apical pouch bridge were resolved completely without creation of an ileostomy. | 18,936,672 |
Phenotypic alterations in ductal carcinoma in situ-associated myoepithelial cells: biologic and diagnostic implications. | Recent molecular studies have indicated that ductal carcinoma in situ (DCIS)-associated myoepithelial cells (MECs) show differences from MECs in normal breast tissue. Such alterations may influence the progression of DCIS to invasive cancer. The purpose of this study was to investigate further phenotypic alterations in DCIS-associated MECs. Paraffin sections of 101 cases of DCIS (56 without and 45 with associated invasive carcinoma) were immunostained for 7 MEC markers: smooth muscle actin, smooth muscle myosin heavy chain (SMMHC), calponin, p63, cytokeratin (CK) 5/6, CD10, and p75. In each case, the distribution and intensity of staining for each marker in DCIS-associated MECs was compared with that in MECs surrounding normal ductal-lobular structures on the same slide. In 85 cases (84.2%), DCIS-associated MECs showed decreased expression of one or more MEC markers when compared with normal MECs. The proportion of cases that showed reduced expression was 76.5% for SMMHC, 34.0% for CD10, 30.2% for CK5/6, 17.4% for calponin, 12.6% for p63, 4.2% for p75, and 1% for smooth muscle actin. Reduced MEC expression of SMMHC was significantly more frequent in high grade than in non-high-grade DCIS (84.8% vs. 61.5% of cases, P=0.01). We conclude that DCIS-associated MECs show immunophenotypic differences from MECs surrounding normal mammary ductal-lobular structures. The biologic significance of this remains to be determined. However, these results indicate that the sensitivity of some MEC markers is lower in DCIS-associated MECs than in normal MECs. This observation should be taken into consideration when selecting MEC markers to help distinguish in situ from invasive breast carcinomas. | 18,936,688 |
Continuous hemofiltration in pigs with hyperdynamic septic shock affects cardiac repolarization. | Sepsis has been defined as the systemic host response to infection with an overwhelming systemic production of both proinflammatory and anti-inflammatory mediators. Continuous hemofiltration has been suggested as possible therapeutic option that may remove the inflammatory mediators. However, hemodialysis and hemofiltration were reported to influence cardiac electrophysiologic parameters and to increase the arrhythmogenic risk. We hypothesize that sepsis affects electrophysiologic properties of the pig heart and that the effects of sepsis are modified by hemofiltration. Laboratory animal experiments. Animal research laboratory at university medical school. Forty domestic pigs of either gender. In anesthetized, mechanically ventilated, and instrumented pigs sepsis was induced by fecal peritonitis and continued for 22 hours. Conventional or high-volume hemofiltration was applied for the last 10 hours of this period. Electrocardiogram was recorded before and 22 hours after induction of peritonitis. RR, QT, and QTc intervals were significantly shortened by sepsis. The plasma levels of interleukin-6 and tumor necrosis factor-alpha were increased in sepsis. High-volume hemofiltration blunted the sepsis-induced increase in tumor necrosis factor-alpha. Action potentials were recorded in isolated ventricular tissues obtained at the end of in vivo experiments. Action potential durations were significantly shortened in septic preparations at all stimulation cycle lengths tested. Both conventional and high-volume hemofiltrations lead to further shortening of action potential durations measured afterward in vitro. This action potential duration shortening was reversed by septic hemofiltrates obtained previously by conventional or high-volume hemofiltration. Tumor necrosis factor-alpha (500 ng/L) had no effect on action potential durations in vitro. In a clinically relevant porcine model of hyperdynamic septic shock, both sepsis and continuous hemofiltration shortened duration of cardiac repolarization. The continuous hemofiltration was not associated with an increased prevalence of ventricular arrhythmias. Tumor necrosis factor-alpha or interleukin-6 did not contribute to the observed changes in action potential durations. | 18,936,693 |
Presence of crystalline lens as a protective factor for the late development of open angle glaucoma after vitrectomy. | To evaluate the late development of open angle glaucoma (OAG) after vitrectomy and to compare the rate of postvitrectomy OAG development in phakic and pseudophakic eyes. Retrospective case series of 101 eyes of 101 patients who had vitrectomy for idiopathic epiretinal membrane or idiopathic macular hole with a follow-up duration of more than 6 months. Eligible patients were assessed for new development of OAG during the follow-up period. Patients were separated into two groups based on the lens status at the end of the vitrectomy for statistical analysis using Kaplan-Meier survival analysis with log-rank test and Cox regression analysis. The mean follow-up duration was 51 months (range, 6-80 months). Of the 101 eyes, 8 (7.9%) eyes developed OAG during the follow-up period. Phakic eyes were less likely to develop OAG after vitrectomy compared with pseudophakic eyes, with 2% and 13%, respectively (log-rank test, P = 0.025). The result remained statistically significant after adjustment for age, refractive error and the use of gas tamponade (adjusted odds ratio = 0.09, P = 0.038). The presence of the crystalline lens may be protective against the late development of OAG after vitrectomy. | 18,936,722 |
[Receptors for advanced glycation end products and their physiological and clinical significance]. | The receptor for advanced glycation end products (RAGE) is a multiligand cell-surface protein and belongs to the immunoglobulin superfamily. RAGE is expressed by different cell types, including macrophages, lymphocytes, endothelial, neuronal, and smooth muscle cells. In addition to advanced glycation end products (AGEs), RAGE binds amphoterin, S100/calgranulin, amyloid, transthyretin, and a leukocyte integrin, Mac-1. Engagement of RAGE in intracellular signaling leads to the activation of the proinflammatory transcription factor NF-kappaB to sustained cellular dysfunction and tissue destruction. In this study a pivotal role of RAGE in the progression of various diseases, i.e. diabetes, inflammation, neurodegeneration, tumors, vascular injury, atherosclerosis, and septic shock, is presented. | 18,936,727 |
Regeneration, health status and quality of life after rhG-CSF-stimulated stem cell collection in healthy donors: a cross-sectional study. | Mobilized allogeneic PBPC are increasingly used instead of BM for allogeneic stem cell grafting. Although the short-term safety profile of recombinant human (rh)G-CSF seems acceptable, only minimal data on long-term safety are available. We therefore reviewed data on 171 sibling donors (M/F: 98/73) with respect to side effects of rhG-CSF and PBPC collection and impact on quality of life (QoL) and health status. In a cross-sectional study, we investigated the actual QoL and health status of the donors as well as the need for medical treatment since PBPC donation by a questionnaire that was sent to 151 donors. Ninety-five (64%) of the addressed donors responded to the questionnaire, but only 69 (46%) of them reported on their actual health status and QoL, which was good to very good in the majority of them. Two donors developed malignancies in the post-donation course. In general, PBPC collection after rhG-CSF mobilization was well tolerated by the responding donors. Although the reported events in medical history after PBPC donation do not seem to be associated with rhG-CSF administration or the collection procedure, a lifelong follow-up of donors should be obligatory. | 18,936,736 |
Targeting and tinkering with interaction networks. | Biological interaction networks have been in the scientific limelight for nearly a decade. Increasingly, the concept of network biology and its various applications are becoming more commonplace in the community. Recent years have seen networks move from pretty pictures with limited application to solid concepts that are increasingly used to understand the fundamentals of biology. They are no longer merely results of postgenome analysis projects, but are now the starting point of many of the most exciting new scientific developments. We discuss here recent progress in identifying and understanding interaction networks, new tools that use them in predictive ways in exciting areas of biology, and how they have become the focus of many efforts to study, design and tinker with biological systems, with applications in biomedicine, bioengineering, ecology and beyond. | 18,936,751 |
Inflammatory caspases are critical for enhanced cell death in the target tissue of Sjögren's syndrome before disease onset. | To date, little is known about why exocrine glands are subject to immune cell infiltrations in Sjögren's syndrome (SjS). Studies with SjS-prone C57BL/6.NOD-Aec1Aec2 mice showed altered glandular homeostasis in the submandibular glands (SMX) at 8 weeks before disease onset and suggested the potential involvement of inflammatory caspases (caspase-11 and -1). To determine whether inflammatory caspases are critical for the increased epithelial cell death before SjS-like disease, we investigated molecular events involving caspase-11/caspase-1 axis. Our results revealed concurrent upregulation of caspase-11 in macrophages, STAT-1 activity, caspase-1 activity and apoptotic epithelial cells in the SMX of C57BL/6.NOD-Aec1Aec2 at 8 weeks. Caspase-1, a critical factor for interleukin (IL)-1beta and IL-18 secretion, resulted in an elevated level of IL-18 in saliva. Interestingly, TUNEL-positive cells in the SMX of C57BL/6.NOD-Aec1Aec2 were not colocalized with caspase-11, indicating that caspase-11 functions in a noncell autonomous manner. Increased apoptosis of a human salivary gland (HSG) cell line occurred only in the presence of lipopolysaccharide (LPS-) and interferon (IFN)-gamma-stimulated human monocytic THP-1 cells, which was reversed when caspase-1 in THP-1 cells was targeted by siRNA. Taken together, our study discovered that inflammatory caspases are essential in promoting a pro-inflammatory microenvironment and influencing increased epithelial cell death in the target tissues of SjS before disease onset. | 18,936,772 |
Lack of MD-2 expression in human corneal epithelial cells is an underlying mechanism of lipopolysaccharide (LPS) unresponsiveness. | In the present study we tested the responsiveness of human corneal epithelial cells (HCECs) and corneal fibroblasts to lipopolysaccharide (LPS), a Toll-like receptor (TLR) 4 ligand. Purified Pseudomonas aeruginosa LPS was used to stimulate telomerase-immortalized HCECs (HUCL) and stromal fibroblast (THK) cell lines. Exposure of cells to LPS induced a time-dependent activation of NF-kappaB in THK but not in HUCL cells, as assessed by an increase in IkappaB-alpha phosphorylation and degradation. Concomitant with NF-kappaB activation, LPS-treated THK cells, but not HUCL cells, produced a significantly larger number of cytokines than control untreated cells. A cell surface biotinylation assay revealed that HUCL cells express TLR4 intracellularly, whereas TLR5 is expressed on the cell surface. Furthermore, reverse transcriptase-PCR analysis revealed that HUCL and primary HCECs, in contrast to THK cells, do not express myeloid differentiation (MD)-2. Thus, our results demonstrate that the LPS unresponsiveness of HCECs might be due to deficient expression of MD-2, an essential component for LPS-TLR4 signaling. | 18,936,773 |
Identical-dual-bandpass sampled fiber Bragg grating and its application to ultranarrow filters. | We have theoretically proposed and experimentally demonstrated a new kind of ultranarrow identical-dual-bandpass sampled fiber Bragg gratings (SFBGs) with a pi phase shift technique. The spacing of two bandpasses of the proposed grating can be flexibly adjusted by changing the sampled period, and any desired spacing can be achieved in principle. An experimental example shows that the transmission peaks of two narrow transmission-band are near 1549.1 and 1550.1 nm. Based on the proposed SFBG, an ultranarrow identical-dual-channel filter is designed. Two channels of the proposed filter have an equal bandwidth, an even strength, and the same group delay. The bandwidth of each channel of our filter is as small as 1 pm and up to 10(-3) pm (corresponding to approximately 0.1 MHz), which is less than the bandwidth of the conventional SFBG filters by a factor of 10(2)-10(4). The proposed grating and filter can find potential applications with slow light and dual-wavelength single-longitudinal-mode fiber lasers. | 18,936,812 |
Linear basis for metallic and iridescent colors. | I have examined the correlation structure in goniochromism by principal-component analysis. Reflectance spectra were collected in synthetic samples that reproduce metallic, nacreous, and iridescent effects under different viewing angles. Although three principal components take into account 99% of the variance, between seven and eight are needed to reach 99.99%. The results were also confirmed by analyzing each viewing condition separately. It was found that although the viewing angle does not modify the first three basis functions, it affects the higher-order ones. These angle-dependent effects can be attributed to optical interference flakes. The implications for pigment identification are discussed. | 18,936,813 |
Influence of surface roughness on the polarimetric characteristics of a wire-grid grating polarizer. | The influence of surface roughness on the polarimetric performance of a wire-grid polarizer (WGP) is numerically investigated using rigorous coupled-wave analysis over 100 random surface realizations. Surface roughness is modeled with a Gaussian surface, represented by two independent parameters: surface height deviation and correlation length of a profile. The results show that WGP performance can suffer from significant degradation as well as increased deviation with surface roughness, although the extent varies with specific parameters. The influence of roughness was also examined with respect to grating period as a WGP parameter and incident light properties, such as wavelength and angle. | 18,936,821 |
Alternating current techniques in scanning electrochemical microscopy (AC-SECM). | Alternating current scanning electrochemical microscopy (AC-SECM) is a growing branch within the variety of SECM methods. This review covers publications involving AC-SECM from its beginning to date. The findings of several research groups are thematically structured along with the specific experimental procedures. This should enable researchers to rationally choose purposeful parameters for their AC-SECM experiments. | 18,936,824 |
Measurement of elastic properties of prostate cancer cells using AFM. | This communication reports that three prostate cancer cells of differing metastatic potential were discriminated based on their Young's moduli (LNCaP - 287 +/- 52 N m(-2), PC-3 - 1401 +/- 162 N m(-2) and BPH - 2797 +/- 491 N m(-2)) which were determined using AFM and the Hertz model. | 18,936,825 |
Paired emitter detector diode (PEDD)-based photometry--an alternative approach. | According to the developed model based on Shockley equation and the Lambert-Beer law, PEDD-based photometric devices generate a potentiometric analytical signal that is directly proportional to the analyte concentration. | 18,936,826 |
Fabric analysis by ambient mass spectrometry for explosives and drugs. | Desorption electrospray ionization (DESI) is applied to the rapid, in-situ, direct qualitative and quantitative analysis of mixtures of explosives and drugs from a variety of fabrics, including cotton, silk, denim, polyester, rayon, spandex, leather and their blends. The compounds analyzed were explosives: trinitrohexahydro-1,3,5-triazine (RDX), octahydro-1,3,5,7-tetranitro-1,3,5,7-tetrazocine (HMX), 2,4,6-trinitrotoluene (TNT), pentaerythritol tetranitrate (PETN) and the drugs of abuse: heroin, cocaine, and methamphetamine. Limits of detection are in the picogram range. DESI analyses were performed without sample preparation and carried out in the presence of common interfering chemical matrices, such as insect repellant, urine, and topical lotions. Spatial and depth profiling was investigated to examine the depth of penetration and lateral resolution. DESI was also used to examine cotton transfer swabs used for travel security sample collection in the screening process. High throughput quantitative analysis of fabric surfaces for targeted analytes is also reported. | 18,936,830 |
Chemical sensor based on a long-period fibre grating modified by a functionalized polydimethylsiloxane coating. | A chemical sensor based on a coated long-period grating has been prepared and characterized. Designer coatings based on polydimethylsiloxane were prepared by the incorporation of diphenylsiloxane and titanium cross-linker in order to provide enhanced sensitivity for a variety of key environmental pollutants and optimal refractive index of the coating. Upon microextraction of the analyte into the polymer matrix, an increase in the refractive index of the coating resulted in a change in the attenuation spectrum of the long-period grating. The grating was interrogated using ring-down detection as a means to amplify the optical loss and to gain stability against misalignment and power fluctuations. Chemical differentiation of cyclohexane and xylene was achieved and a detection limit of 300 ppm of xylene vapour was realized. | 18,936,831 |
Accurate calibration of mercury vapour measurements. | Almost all measurements of mercury vapour, for example those to determine mass concentration in air, are currently ultimately traceable to the vapour pressure of mercury, usually via a bell-jar calibration apparatus. This allows a saturated concentration of mercury vapour in air to develop in a confined space in equilibrium with ambient conditions, from which a known mass of mercury can be removed for calibration purposes. Setting aside the uncertainty in the vapour pressure of mercury at a given temperature, the accuracy of vapour phase mercury determinations depends critically on fully understanding the operation and sensitivities of the mercury bell-jar apparatus. This paper discusses the thermodynamic and kinetic considerations that must be taken into account when using the bell-jar apparatus, provides the theoretical basis for understanding the operation of the bell-jar, and presents experimental data demonstrating the systematic biases which may be obtained if the bell-jar is used incorrectly. These biases depend on the temperature difference between the mercury vapour in the bell-jar and the syringe used to remove the mercury vapour from the bell-jar, but they may be well in excess of 10% under some operating conditions. The results from this study have been used to propose best practice solutions for mercury vapour calibrations using the bell-jar. | 18,936,841 |
A comparison of ether- and alkyl-derivatized imidazolium-based room-temperature ionic liquids: a molecular dynamics simulation study. | Molecular dynamics simulations of ether-derivatized imidazolium-based room-temperature ionic liquids (EDI-RTILs), [C(5)O(2)mim][TFSI] and [C(5)O(2)mim][BF(4)], have been performed and compared with simulations of alkyl-derivatized analogues (ADI-RTILs). Simulations yield RTIL densities, self-diffusion coefficients and viscosity in excellent agreement with experimental data. Simulations reveal that structure in the EDI-RTILs, quantified by the extent of nanoscale segregation of tails as well as cation-ion and cation-cation correlations, is reduced compared to that observed in the ADI-RTILs. Significant correlation between ether tail oxygen atoms and imidazolium ring hydrogen atoms was observed in the EDI-RTILs. This correlation is primarily intramolecular in origin but has a significant intermolecular component. Competition of ether oxygen atoms with oxygen atoms of TFSI(-) or fluorine atoms of BF(4)(-) for coordination of the ring hydrogen atoms was found to reduce the extent of cation-anion correlation in the EDI-RTILs compared to the ADI-RTILs. The reduction in intermolecular correlation, particularly tail-tail segregation, as well as weakening of cation-anion specific interactions due to the ether tail, may account for the faster dynamics observed in the EDI-RTILs compared to ADI-RTILs. | 18,936,854 |
Effects of Macroplastique Implantation System for stress urinary incontinence and urethral hypermobility in women. | A study was carried out to evaluate efficacy of Macroplastique(R) (MPQ) Implantation System (MIS) in women with urodynamic stress urinary incontinence (SUI) and urethral hypermobility after an unsuccessful conservative treatment. This is a prospective randomized controlled trial in women without previous incontinence surgery. Twenty-four women received MPQ. Twenty-one controls underwent a pelvic floor muscle exercises home program. Follow-up was at 3 months and the MPQ group also at 12 months. At 3 months, pad usage decreased significantly more in the MPQ group than in the control group (p = 0.015). According to physician and patient self-assessment, respectively, 71% and 63% women in the MPQ group were considered cured or markedly improved. This was significantly higher compared to controls. There was a significant higher increase of Incontinence Quality-of-Life questionnaire score in the MPQ group compared to controls (p = 0.017). Improvements in MPQ group at 3 months are sustained to 12 months. Adverse events were mild and transient. MIS is an acceptable option for women with SUI and urethral hypermobility. | 18,936,867 |
Is there any evidence to advocate SUI prevention in continent women undergoing prolapse repair? An overview. | Postoperative SUI prevention at the time of prolapse surgery is still a challenging issue. Recent findings suggested that a systematic prophylactic Burch colposuspension could be performed in continent women undergoing a sacral colpopexy. The aim of this paper is to collect relevant literature in order to suggest a management strategy. A thorough PubMed research of all papers in the English language was conducted. Evidence-based medicine was analyzed and current unanswered questions were discussed. Despite evident limitations, it appears to be some benefit from preoperative screening with a stress test during prolapse reduction. In continent patient with a positive stress test, adding a preventive procedure could be fully justified. In regard to contradictory published data, when negative stress test, patient counseling is important and the ratio of risk-benefit should be rigorously discussed. Further randomized controlled studies are needed to support either a prophylactic or a second-step strategy. | 18,936,868 |
Pharmacokinetic analysis of a combined chemoendocrine treatment with paclitaxel and toremifene for metastatic breast cancer. | Multidrug resistance protein could be a target for improving the efficacy of paclitaxel (PXL). Toremifene (TOR) may moderate P-gp-related drug resistance in vitro. Some P-gp moderators may change the pharmacokinetic parameters of PXL in vivo. A pharmacokinetic (PK) study in metastatic breast cancer patients (MBC) was conducted to determine the safety and efficacy of PXL and TOR. Fifteen patients received 80 mg/m(2) PXL (i.v.) weekly and 120 mg/body TOR (p.o.) daily. For the pharmacokinetic study, PXL was administered on days 1, 8, 15, 32, and 39; TOR was given from day 18 to the end of study. On days 1, 8, 15, 18, 32, and 39, blood samples were collected from the patients who received either PXL alone or PXL + TOR, and these were analyzed by high-performance liquid chromatography. Among the 15 patients enrolled in the study, one showed a partial response, and eight had a stable disease. TOR caused no specific adverse events that were greater than grade 3, and its toxicity profile in combination with PXL was similar to that of PXL monotherapy. The PK profile of PXL was similar with or without TOR. The PK parameters of PXL indicated no inter- or intra-patient variability in previously treated patients with MBC. No increased PXL toxicity was observed. The PK profile of combined PXL and TOR was similar to that of PXL monotherapy. The addition of TOR to PXL in previously treated patients with MBC appears safe. | 18,936,884 |
Prevalence of Haemophilus influenzae with resistant genes isolated from young children with acute lower respiratory tract infections in Nha Trang, Vietnam. | Our study was undertaken to investigate the characteristics of Haemophilus influenzae in young children with acute lower respiratory tract infections in Nha Trang, Vietnam. The study population consisted of 116 children less than 5 years of age admitted to Khanh Hoa General Hospital due to acute lower respiratory tract infections between July 2004 and April 2005. Organisms could be detected from nasopharyngeal swabs (NP) in 72 (62.1%) of the 116 children. Haemophilus influenzae was the most common organism, and 39 strains were isolated from 39 children aged 2 to 60 months (mean age, 16 months). We examined 37 of these 39 H. influenzae strains. The serotypes of the 37 isolates were all nontypeable, and 22 strains (59.5%) were beta-lactamase producing. Polymerase chain reaction (PCR) analysis to identify resistance genes revealed that 17 strains had the TEM-1-type beta-lactamase gene alone, 6 strains had the ftsI gene with the same substitution as that in g low-beta-lactamase-negative ampicillin-resistant (g low-BLNAR) strains, and 6 strains had both the TEM-1-type beta-lactamase gene and the ftsI gene with the same substitution as that in g beta-lactamase-producing amoxicillin clavulanic acid-resistant (g BLPACR I) strains, although no BLNAR strains were found. Molecular typing by pulsed-field gel electrophoresis (PFGE) showed that the 6 g low-BLNAR strains had five PFGE patterns and the 6 g BLPACR I strains had four PFGE patterns. Our results indicate that BLNAR strains are still not prevalent, but that g low-BLNAR and g BLPACR I strains are potentially spreading in Nha Trang, Vietnam. | 18,936,887 |
Bacteremia caused by Desulfovibrio fairfieldensis. | Desulfovibrio species are anaerobic gram-negative, pleomorphic bacilli rarely causing infection in humans. In the present report, we describe a case of bacteremia caused by Desulfovibrio fairfieldensis. The patient, for whom biapenem was administered, rapidly improved without any sequelae. As far as we know, this is the first case report of infection by Desulfovibrio species in Japan. | 18,936,890 |
Diagnostic value of the soluble triggering receptor expressed on myeloid cells-1 in bacterial infection: a meta-analysis. | To evaluate the accuracy of the soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) as a diagnostic test for bacterial infection. Meta-analysis of 13 diagnostic studies. Medline; Embase; Web of Science (from January 1966 to January, update to August 2008); and Cochrane Controlled Clinical Trials Register Database (through first quarter 2008). A meta-analysis of all 73 studies was performed. Thirteen studies fulfilled the inclusion criteria (980 patients, 557 patients with bacterial infection, 423 with non-bacterial infection); global prevalence was 56.8%. The global sensitivity was 0.82 (95% confidence interval CI, 0.68-0.90), the specificity was 0.86 (95% CI, 0.77-0.91), the positive likelihood ratio (PLR) was 5.66 (95% CI, 3.41-9.38), the negative likelihood ratio (NLR) was 0.21 (95% CI, 0.12-0.40), and the diagnostic odds ratio (DOR) was 26.35 (95% CI, 10.32-67.28). The area under the curve of the summary receiver operator characteristic (SROC) was 0.86 (95% CI, 0.77-0.91), with a Q point value of 0.84. The sensitivity of the sTREM-1 assay for diagnosis of urinary tract infection was low (0.18, 95% CI, 0.05-0.51). sTREM-1 represents a reliable biological marker of bacterial infection, but it may be not a sufficient biological marker for infection of the urinary tract as a result of its low sensitivity. Whether sTREM-1 guidance can reduce antibiotic use as well as the measurement of sTREM-1 in different types of infection will require additional prospective studies. | 18,936,908 |
Conjugated steroids: analytical approaches and applications. | An introduction to conjugated steroids and the justification for their analysis is provided covering both environmental and biological samples. Determining conjugated steroids or indeed any organic chemical which is conjugated upon excretion from the body has relevance in diagnostic monitoring, forensic screening and environmental analysis (from the endocrine disrupter perspective). The various analytical approaches and the accompanying issues are application-dependent. There are numerous options at each stage of analysis, from extraction, hydrolysis, derivatisation, and detection, and advances can be confined to the specific application for which it was developed. Emphasis is placed on the choice of separation and how gas or liquid chromatography necessitates different preparative stages to enable conjugated steroid determination. Possible future directions and research for conjugated steroid analysis are discussed. | 18,936,918 |
Activity of an atypical Arabidopsis thaliana pectin methylesterase. | An Arabidopsis thaliana pectin methylesterase that was not predicted to contain any signaling sequence was produced in E. coli and purified using a His tag added at its N-terminus. The enzyme demethylesterified Citrus pectin with a Km of 0.86 mg/ml. The enzyme did not require salt for activity and was found to be relatively temperature-sensitive. The precipitation of enzyme-treated pectin by CaCl2 suggested that the enzyme had a blockwise mode of pectin demethylesterification. A purified kiwi (Actinidia chinensis) pectin methylesterase inhibitor had no effect on the activity of the enzyme whereas it strongly inhibited a flax pectin methylesterase. A model of the protein structure revealed that an extra amino acid sequence in this particular Arabidopsis pectin methylesterase could form a ss-strand outside the core structure, which might be preventing the inhibitor from binding the protein. | 18,936,961 |
Monitoring circulating epithelial tumour cells (CETC) to gauge therapy: in patients with disease progression after trastuzumab persisting CETC can be eliminated by combined lapatinib treatment. | In breast cancers, the gene for the growth factor receptor HER2 can be amplified leading to increased aggressiveness and metastasis formation. The monoclonal antibody trastuzumab prolongs relapse-free survival highly significantly but eventually many patients relapse. In this study, CETC were monitored using the Maintrac method during adjuvant trastuzumab treatment and during subsequent treatment with capecitabine/lapatinib. In one patient, trastuzumab led to marginal reduction in CETC with disease progress. The combination of capecitabine/lapatinib was preliminarily capable to eliminate all CETC, however, CETC reappeared. The second patient received adjuvant taxane together with trastuzumab and 1 year of further trastuzumab during which CETC increased. After stopping trastuzumab skin metastases occurred. Capecitabine/lapatinib led to complete CETC elimination with stable disease. In patients with lack of CETC reduction in spite of trastuzumab treatment correlated with disease progression the combination of capecitabine/lapatinib highly efficiently led to rapid elimination of CETC warranting further monitoring during such studies. | 18,936,973 |
Mapping the interaction sites of Aspergillus nidulans phytochrome FphA with the global regulator VeA and the White Collar protein LreB. | Aspergillus nidulans senses red and blue-light and employs a phytochrome and a Neurospora crassa White Collar (WC) homologous system for light perception and transmits this information into developmental decisions. Under light conditions it undergoes asexual development and in the dark it develops sexually. The phytochrome FphA consists of a light sensory domain and a signal output domain, consisting of a histidine kinase and a response regulator domain. Previously it was shown that the phytochrome FphA directly interacts with the WC-2 homologue, LreB and another regulator, VeA. In this paper we mapped the interaction of FphA with LreB to the histidine kinase and the response regulator domain at the C-terminus in vivo using the bimolecular fluorescence complementation assay and in vitro by co-immunoprecipitation. In comparison, VeA interacted with FphA only at the histidine kinase domain. We present evidence that VeA occurs as a phosphorylated and a non-phosphorylated form in the cell. The phosphorylation status of the protein was independent of the light receptors FphA, LreB and the WC-1 homologue LreA. | 18,936,976 |
Urinary tract infection in preterm infants: the protective role of breastfeeding. | Urinary tract infection (UTI) differs between preterm and older infants and children in terms of prevalence, clinical presentation, causative organism, and rate of underlying renal anomalies. Data on risk factors of UTI in preterm infants are limited. The aim of this study was to characterize UTI both clinically and microbiologically in premature infants and to define possible risk factors and the role of breastfeeding in its development. This case-control study was conducted in a tertiary-care neonatal intensive care unit (NICU) between 1995 and 2003. The study group included all premature infants (<37 weeks' gestation) diagnosed with UTI. Pre-, peri-, and postnatal data on demographic, clinical, laboratory, and imaging variables were collected from the medical records and microbiology laboratory log and compared with a gestational age- and birth weight-matched infants without UTI (control group). The ratio of control infants to cases was 2:1. Of the 6198 premature infants admitted to the NICU during the study period, 56 (0.9%) were included in the study group. The main causative organism was Klebsiella spp. Logistic regression analysis identified gender [odds ratio (OR) 2.96, 95% confidence interval (CI) 1.28-6.85, P < 0.0001] and the presence of a peripheral intravenous catheter on the day of infection to be significantly associated with UTI, while breast milk was associated with a lower risk of infection (OR 0.314, 95% CI 0.140-0.707, P < 0.009). | 18,936,982 |
Study of structural and electronic origin of ambergris odor of some compounds. | The correlation between structural, stereochemical as well as electronic features and ambergris odor of some tricyclic ethers is established based on quantum chemical calculation method. A definite structural fragment (a "new ambergris triangle") with certain electronic properties determining the origin of the odor is revealed. The influence of HOMO-LUMO energy gaps and total energies of some ambergris compounds on their odor intensity is investigated. | 18,936,989 |
Local friction at a sliding interface between an elastomer and a rigid spherical probe. | This paper reports on spatially resolved measurements of the shear stress distribution at a frictional interface between a flat rubber substrate and a glass lens. Silicone rubber specimens marked close to their surface by a colored pattern have been prepared in order to measure the surface displacement field induced by the steady-state friction of the spherical probe. The deconvolution of this displacement field then provides the actual shear stress distribution at the contact interface. When a smooth glass lens is used, a nearly constant shear stress is achieved within the contact. On the other hand, a bell-shaped shear stress distribution is obtained with rough lenses. These first results suggest that simple notions of real contact area and constant interface shear stress cannot account for the observed changes in local friction when roughness is varied. | 18,936,992 |
Spike synchronization of chaotic oscillators as a phase transition. | We study how a locally coupled array of spiking chaotic systems synchronizes to an external driving in a short time. Synchronization means spike separation at adjacent sites much shorter than the average inter-spike interval; a local lack of synchronization is called a defect. The system displays sudden spontaneous defect disappearance at a critical coupling strength suggesting an existence of a phase transition. Below critical coupling, the system reaches order at a definite amplitude of an external input; this order persists for a fixed time slot. Thus, the array behaves as an excitable-like system, even though the single element lacks such a property. | 18,936,995 |
"Wave" as defined by wave intensity analysis. | The propagation of waves in the arteries is generally described using Fourier analysis in terms of periodic wavetrains formed by the superposition of a mean value and sinusoidal waves at the fundamental frequency (defined by the heart rate) and its harmonics. There is, however, an alternative way to describe waves in the vasculature based upon the method-of-characteristics solution of 1-D conservation laws. This method, wave intensity analysis (WIA), can be used to describe periodic waves but can also be used to describe the propagation of non-periodic waves that cannot be practically described in terms of sinusoidal wavetrains. As a means of demonstrating how WIA defines a wave, we used data gathered in a simple bench-top experiment where a single disturbance propagated along a single elastic tube and was reflected and re-reflected between a closed and a relatively open end. Results demonstrate that forward- and backward-travelling peaks of intensity usefully define wave interactions. | 18,937,000 |
The neuroprotective role of L-cysteine towards the effects of short-term exposure to lanthanum on the adult rat brain antioxidant status and the activities of acetylcholinesterase, (Na+,K+)- and Mg2+-ATPase. | Lanthanum (La) is a rare earth element that is widely used for industrial, medical and agricultural purposes. Its neurotoxic effects are linked to its physical and chemical properties and its interaction with certain trace elements and membrane-bound enzymes. The aim of this study was to investigate the effects of short-term La-administration (as LaCl(3), 53 mg/kg) on the adult rat whole brain total antioxidant status (TAS) and the activities of acetylcholinesterase (AChE), Na(+),K(+)-ATPase and Mg(2+)-ATPase, as well as the potential effect of the co-administration of the antioxidant L: -cysteine (Cys, 7 mg/kg) on the above parameters. Twenty-eight male Wistar rats were divided into four groups: A (saline-treated control), B (La), C (Cys),and D (La and Cys). All rats were treated once daily with intraperitoneal injections of the tested compounds, for 1-week. Rats were sacrificed by decapitation and the above mentioned parameters were measured spectrophotometrically. Rats treated with La exhibited a significant reduction in brain TAS (-36%, P < 0.001, BvsA), that was partially limited by the co-administration of Cys (-13%, P < 0.01, DvsA), while Cys (group C) had no effect on TAS. The rat brain AChE activity was found significantly increased by both La (+23%, P < 0.001, BvsA) and Cys (+59%, P < 0.001, CvsA), while it was adjusted to control levels by the co-administration of La and Cys. The activity of rat brain Na(+),K(+)-ATPase was significantly decreased by La-administration (-28%, P < 0.001, BvsA), while Cys supplementation could not reverse this decrease. The activity of Mg(2+)-ATPase exhibited a slight but statistically significant reduction due to La (-8%, P < 0.01, BvsA), that was further reduced by Cys co-administration (-25%, P < 0.001, DvsA). The above findings suggest that La short-term in vivo administration causes a statistically significant decrease in the rat brain TAS and an increase in AChE activity. Both effects can be, partially or totally, reversed into control levels by Cys co-administration, which could thus be considered for future applications as a neuroprotective agent against chronic exposure to La. The activities of Na(+),K(+)- and Mg(2+)-ATPase that were inhibited by La, could not be reversed by Cys co-administration. A role for the already reported concentration-dependent interaction of La with Ca-binding sites (such as Ca(2+)-ATPase) might be considered for certain of the above phenomena. | 18,937,033 |
Quality control of photosystem II: impact of light and heat stresses. | Photosystem II is vulnerable to various abiotic stresses such as strong visible light and heat. Under both stresses, the damage seems to be triggered by reactive oxygen species, and the most critical damage occurs in the reaction center-binding D1 protein. Recent progress has been made in identifying the protease involved in the degradation of the photo- or heat-damaged D1 protein, the ATP-dependent metalloprotease FtsH. Another important result has been the discovery that the damaged D1 protein aggregates with nearby polypeptides such as the D2 protein and the antenna chlorophyll-binding protein CP43. The degradation and aggregation of the D1 protein occur simultaneously, but the relationship between the two is not known. We suggest that phosphorylation and dephosphorylation of the D1 protein, as well as the binding of the extrinsic PsbO protein to Photosystem II, play regulatory roles in directing the damaged D1 protein to the two alternative pathways. | 18,937,045 |
How parents search, interpret, and evaluate genetic information obtained from the internet. | This study describes how parents of a child referred for genetic services searched the Internet for information, summarizes how they interpreted and evaluated the information they obtained, and identifies barriers that they encountered. Audio-taped interviews were conducted with 100 ethnically diverse families referred to a pediatric genetics clinic. After transcription, coded text was entered into a software program (QSR N6) for searching and data retrieval. Matrices were created to systematically categorize and compare families' Internet use. Eighty-three percent of families obtained Internet information about the diagnosis, the clinic visit, and/or treatment and services. Those not conducting searches lacked access, Internet experience, or a diagnostic term and had lower incomes and less education, regardless of ethnicity. Families sought information in preparation for the clinic visit but barriers to obtaining and interpreting relevant information were common. Parents' Internet searching experiences illustrate common barriers to obtaining and understanding genetic information. Identifying them can help genetic counselors facilitate parents' searches for relevant information. | 18,937,062 |
Evaluation of the association between retinal binding protein 4 polymorphisms and type 2 diabetes in Chinese by DHPLC. | Serum retinal binding protein 4 (RBP4) was recently described as a new liver- and adipocyte-derived signal that may contribute to Type 2 diabetes mellitus (T2DM) and insulin resistance. The aim of this study was to test whether the RBP4 gene could be used as a genetic marker to predict the development of T2DM amongst the Chinese population of Han. For this study, a normal control group of 115 healthy subjects and an experimental group of 107 patients with T2DM were examined. A combined method of denaturing high-performance liquid chromatography (DHPLC) and sequencing was applied to the detection of the RBP4 gene variants. Two SNPs, rs17484721 and rs36035572, were analyzed. Phenotypes and biochemical indicators related to the metabolism of glucose and lipid were measured. We found that there are significant differences between the control group and the patients group in terms of their respective distributions of genotype and allele frequency. The TG levels of the TT and II genotype was significantly higher than that of the TC + CC and ID + DD, respectively, in both patient group and control group. These findings suggest that the variations in the RBP4 gene may be associated with T2DM and serum triglyeride levels in the Han Chinese. | 18,937,078 |
The predictive qualities of operator characteristics for process control performance: the influence of personality and cognitive variables. | This article examines the relationship between operator characteristics and process control performance. Thirty-nine trainee operators participated in a 4-h training session of a simulated process control task and a testing session in which various system faults had to be managed. Cognitive ability, cognitive flexibility, self-efficacy and personality traits were measured as operator characteristics. Cognitive ability related positively to system control performance but not to diagnostic performance. Participants with low cognitive flexibility performed best on system control, whereas participants with high cognitive flexibility performed best on diagnostic performance. A hierarchical regression analysis revealed that cognitive ability, cognitive flexibility and declarative knowledge accounted for about 30% of the variability of system control. The findings suggest that consideration of cognitive ability and cognitive flexibility be increased in personnel selection for complex work environments. | 18,937,088 |
Angiotensin II type 1 receptor antagonists prevent glucose-induced increases in islet blood flow in rats. | Renin-angiotensin system inhibitors are reported to be beneficial in delaying the onset of diabetes mellitus. Since islet blood hyperperfusion during hyperglycaemia may be detrimental to endothelium in pancreatic islets and eventually lead to beta-cell dysfunction, we studied acute and chronic effects of angiotensin II type 1 receptor blockers (ARB) on islet blood flow before and after glucose load. Islet blood flow was measured using the colour microsphere method in anaesthetized Sprague-Dawley rats before and 3 min after glucose injection. Olmesartan significantly reduced blood pressure, but did not affect islet blood flow 10 min after its injection. However, pretreatment with olmesartan blunted the glucose-induced increase in islet blood flow (62% of control). In rats treated with olmesartan or candesartan for 4 weeks, islet blood flow was not different from untreated control, whereas the glucose-induced increase in islet blood flow was significantly suppressed in chronically ARB-treated rats (olmesartan 59% of control, candesartan 64% of control, respectively). Acute or chronic treatment with ARB did not change insulin secretion before and in response to glucose load. Pancreatic or duodenal blood flow was not affected by ARB treatment, although acute olmesartan administration reduced pancreatic blood flow after glucose load. ARB appears to suppress the hyperglycaemia-induced islet hyperperfusion, which may ameliorate haemodynamic stress in pancreatic islets. | 18,937,099 |
Flow-mediated vasodilatation: variation and interrelationships with plasma lipids and lipoproteins. | Endothelial dysfunction is a critical, prerequisite step in atherosclerosis, and may be evaluated by flow-mediated vasodilatation (FMD). The objective of this study was to examine interrelationships between FMD and plasma lipids and lipoproteins, and to determine the between-operator and within-subject variability associated with this technique. FMD, plasma lipids and lipoproteins, including small dense LDL (sdLDL), were measured twice in 40 healthy volunteers, 4 weeks apart. Interrelationships between mean FMD responses and plasma lipids and lipoproteins were examined by correlation analysis. FMD measurements were taken by two independent operators, allowing determination of between-operator variability. Within-subject variability was determined by obtaining two measurements, 4 weeks apart, in every subject, and carried out by the same operator. FMD was inversely related to plasma triglycerides (r = -0.47, p = 0.002), total cholesterol/HDL cholesterol (r = -0.35, p = 0.03) and apolipoprotein B (r = -0.36, p = 0.02), but not to other plasma lipids and lipoproteins. When measuring variation in FMD, the following results were found: Between operators (SD = 4.0 FMD%) and within subjects (SD = 2.9 FMD%). The associations between FMD, plasma triglycerides and apoB provide evidence supporting a role for triglyceride-rich lipoproteins in endothelial dysfunction. | 18,937,098 |
The effects of interferon beta-1a on proton MR spectroscopic imaging in patients with multiple sclerosis, a controlled study, preliminary results. | To evaluate the effects of interferon beta-1a(INFbeta-1a) on brain metabolites in patients with multiple sclerosis (MS), we performed Magnetic Resonance Spectroscopy Imaging (MRSI) on five patients treated with INFbeta-1a (Rebif 44 microg), and on five untreated patients. Six healthy volunteers were used as controls. Patients were evaluated at the beginning, in the first, third, sixth, and twelfth month. There were no significant differences in normal appearing white matter (NAWM) metabolite peaks of the control group and patients with MS. However, in white matter lesions (WML) and NAWM there was significant differences between the basal and the other months' metabolic peaks (p < 0.05) in the treatment group although no differences emerged in the untreated group. These data suggest that INFbeta-1a has a favorable effect on restoration of metabolites in MS lesions. | 18,937,112 |
Endogenous glucocorticoids participate in retinal degeneration during continuous illumination. | Continuous illumination (CI) induces an oxidative stress of the retina which is involved in light-induced retinal degeneration (LIRD). As the increase of glucocorticoids (GC) could also collaborate in the damage, adrenalectomized (ADX) and sham-operated rats (control, CTL) were submitted to CI, and their eyes were studied at light and electron microscopic levels. After CI, ADX retinas were significantly thicker than CTL retinas. Retinal alterations appeared earlier and were severer in CTL than in ADX retinas. Corticosterone levels increased gradually in the sera of CTL rats along CI. These results suggest that adrenalectomy attenuates LIRD, supporting the hypothesis. | 18,937,116 |
Equipment, exposure, emission review--specification of process equipment for worker exposure control. | Worker exposure to chemical agents may occur from equipment leaks in closed processes and from open system activities and maintenance (e.g., sampling, tank gauging, line breaking, equipment flushing, and drainage). To prevent worker overexposure to chemical agents, an Equipment, Exposure, Emission Review (EEER) was developed to consistently match equipment properties to the leakage-related inhalation risk posed by each stream. For streams where gas or liquid leakage could cause worker exposure above occupational exposure limits (OEL), the EEER recommended a high performance, low leakage equipment category. Conversely, where standard engineering offered reliable containment for lower health risk streams, the EEER did not recommend over-control. The EEER matched equipment to stream health hazard as follows: (1) the composition of each stream was determined, with particular attention to chemical substances with stringent exposure limits; (2) a mixture exposure limit was calculated for each stream based on stream composition and the OEL for stream constituent chemicals; (3) each stream was classified as to its respiratory exposure hazard on the basis of the stream exposure limit; (4) equipment was recommended as a function of respiratory exposure hazard class using an Equipment Selection Matrix. Equipment options were based, in part, on the emission performance of the equipment and a near-field dispersion model that was used to relate equipment emissions to an OEL. Over a 5-yr implementation period, nearly 1700 streams of 78 refining process units were reviewed. Standard engineering practice was selected for about 70% of the streams reviewed. Benzene, hydrogen sulfide, ethanolamine, and high boiling aromatic oil streams were the primary chemical agents responsible for more stringent controls. Although the EEER criteria for stream classification and control options were arranged in order of magnitude--a form of control banding--the correct selection of control technology was based on detailed assessment of stream composition and risk, rather than on process unit name or function. The EEER and Equipment Selection Matrix provided reproducible recommendations and helped manage cost and complexity of equipment specification for health protection. | 18,937,122 |
Use of combined oral contraceptives alters metabolic determinants and genetic regulation of C-reactive protein. The Cardiovascular Risk in Young Finns Study. | Use of combined oral contraceptives (COCs) is known to increase concentrations of C-reactive protein (CRP), an important predictor of cardiovascular disease. The inflammatory nature of the disease is well acknowledged. The aim of this study was to find out whether the metabolic, lifestyle and genetic determinants of CRP differ between women who use COCs and those who do not use any hormonal contraceptives (non-users). A total of 1,257 women (24-39 years) participated in the ongoing Cardiovascular Risk in Young Finns Study, a population based cross-sectional follow-up study. Use of hormonal contraceptives was determined by questionnaire. Plasma CRP and other cardiovascular risk factors were measured; five CRP gene polymorphisms were genotyped (-717A>G, -286C>T>A, +1059G>C, +1444C>T and +1846G>A) and CRP haplotypes were constructed. Multivariate regression analysis revealed that BMI and leptin were the main determinants of CRP in non-users, whereas in COC users the main determinants were BMI, leptin and triglycerides. The median CRP and triglyceride values were significantly higher in COC users than in non-users. The correlations between triglyceride and CRP were tested separately in different COC users in accordance with progestagen content and dosage, the analysis revealing significant association only in women using a high dosage of progestagen or cyproterone. The haplotypes of CRP gene had no significant association with CRP concentration in COC users, while independent effects on CRP were found in non-users. Our study suggests that use of COCs alters the metabolic determinants and genetic regulation of CRP. | 18,937,150 |
Anaemia following initiation of androgen deprivation therapy for metastatic prostate cancer: a retrospective chart review. | Haemoglobin levels often decline into the anaemic range with androgen deprivation therapy (ADT). We conducted a chart review of patients receiving ADT for metastatic prostate cancer to assess anaemia-related symptoms. 135 stage IV prostate cancer cases were reviewed for treatment type; haemoglobin values before and after treatment; and symptoms of anaemia. Mean haemoglobin levels before and after for all treatment forms, for leuprolide alone, and for combination leuprolide/bicalutamide were calculated and evaluated for significant differences. The numbers of patients developing symptoms were recorded and the effects of specific therapies evaluated. For all ADT treated patients, mean haemoglobin declined by -1.11 g/dL (p<.0001). Leuprolide-alone treated patients had a mean decline of -1.66 g/dL (p<0.0001). Leuprolide and bicalutamide combination treatment caused a mean decline of -0.78 g/dL (p=0.0426). 16 of 43 patients had anemia symptoms. Contingency analysis with Fisher's exact test shows patients receiving leuprolide therapy alone versus other forms of ADT were significantly less likely to have symptoms (chi(2)=0.0190). The present study confirms that ADT results in a significant drop in haemoglobin levels into the anaemic range. A number of patients become symptomatic from this change. Practitioners should monitor haemoglobin levels, and treat symptomatic patients. | 18,937,151 |
[Cerebral and spinal MRI examination in patients with clinically isolated syndrome and definite multiple sclerosis]. | Magnetic resonance imaging (MRI) has become a valuable tool for diagnosing and monitoring multiple sclerosis (MS). The high sensitivity for the detection of hyperintense lesions in T 2-weighted scans contributes substantially to diagnosis. The initial lesion number or lesion volume stands for an increased probability of further accumulation of lesion burden, an earlier conversion to clinically definite MS and progression of disability in the next 5 - 15 years. This diagnostic and prognostic information gained from MRI early in the disease course lead in 2001 to a revision of the diagnostic criteria. For the first time MRI criteria were defined in addition to the clinical and paraclinical criteria using the clinical terms for dissemination with respect to space and time. In particular, the defined MRI criteria are based on lesion number and location, the appearance of new lesions and lesion enhancement using contrast agent. Reliable detection and description of older and new lesions in the disease course by MRI represents subclinical disease activity which can substitute the clinical confirmation of a relapse leading to an earlier diagnosis. This places importance on the assessment of the subclinical disease activity in sequential MR scans requiring a standardized and reproducible approach to minimize variability despite different MR scanners. This review provides an updated proposal for the approach and management of cranial and spinal MR scans in patients with MS. We describe the influence of variables which cannot be standardized (scanner, field strength, manufacturer and software) and outline potential pitfalls of clinical MR imaging in MS resulting from a non-standardized approach. This updated proposal for slice positioning, sequences and documentation is a result of a consensus process targeting systematic and standardized use in clinical MR evaluations of MS. | 18,937,154 |
Perspective on recent developments on sulfur-containing agents and hydrogen sulfide signaling. | The last couple of years have witnessed the coming together of several initially unconnected lines of investigation which now link natural sulfur products to hydrogen sulfide release and wide ranging cardiovascular protection. It has become apparent that sulfur compounds contained within garlic, onions, mushrooms and various edible beans and fruits may be transformed chemically or enzymatically in the human body with subsequent formation of hydrogen sulfide. The latter has emerged during the last decade from a shadowy existence as toxic gas to be recognized as the third gaseous transmitter besides nitric oxide ( (.)NO) and carbon monoxide (CO). Hydrogen sulfide is formed endogenously in the human body by enzymes such as cystathionine beta-synthase (CBS) in the brain and cystathionine gamma-lyase (CSE) in liver, vascular and non-vascular smooth muscle. Although its exact chemical and biochemical modes of action are still not fully understood, levels of hydrogen sulfide in the brain and vasculature have unambiguously been associated with human health and disease. Not surprisingly, agents releasing hydrogen sulfide, as well as inhibitors of hydrogen sulfide synthesis (CBS and CSE inhibitors) have been investigated. Apart from linking our daily diet to a healthy brain and cardiovasculature, these findings may also provide new leads for drug design. Future studies will therefore need to focus on how such compounds are formed and transformed in the relevant plants, how food processing affects their chemical constitution, and how they release hydrogen sulfide (or control its levels) in the human body. Such multidisciplinary research should ultimately answer the all-important question if a hearty diet is also good for the heart. | 18,937,169 |
Two cases of lymphoepithelial cyst of the pancreas: first - a cyst coexisting with a primary gastric lymphoma, second - incidentally found pancreatic cyst. | The aim of this report is to describe two cases of lymphoepithelial cysts (LEC) of the pancreas: 1. LEC coexisting with primary gastric lymphoma, 2. an incidental finding of LEC during imaging examination. 1. A 47-year old man complaining of epigastric pain showed a 2 x 1.5 cm cyst of the pancreatic head on computed tomography (CT) scan. Endoscopic biopsy revealed infiltration by a poorly differentiated neoplasm, probably carcinoma. The patient underwent gastrectomy with lymphadenectomy D 2. The pancreatic lesion was excised. Diffuse large B-cell lymphoma (pT4N1 M0BX) and LEC were diagnosed. Patient refused adjuvant therapy. No symptoms of recurrence were observed during 24-months follow-up period. 2. 50-year-old male with non-specific urinary complaints revealed a 4.2 x 3.5 cm cyst in the body of pancreas on CT scan. The cyst was excised and LEC was diagnosed. Patient had not reported any complaints during 42 months follow-up period. To the best of the authors' knowledge, the first of two presented cases is the first described case of coexistence of LEC of the pancreas and gastrointestinal lymphoma. It is difficult to ascertain if there is any causative relationship or if this coexistence is purely incidental. Incidental pancreatic cysts are more and more common finding in surgical practice. | 18,937,188 |
Resolution of refractory ascites after transcoronary septal ablation for hypertrophic obstructive cardiomyopathy in a cirrhotic patient. | This report presents the first case of complete resolution of ascites after transcoronary ablation of septal hypertrophy (TASH) in a cirrhotic patient with concomitant hypertrophic cardiomyopathy (HOCM). A 52-years-old woman with decompensated alcoholic liver cirrhosis was referred to our department for placement of a transjugular intrahepatic portosystemic stent shunt (TIPS) to treat her refractory ascites. The initial treatment with furosemide and spironolactone had to be discontinued because of severe hyponatriemia and an increase of creatinine levels. During further evaluation, HOCM was diagnosed by echocardiography and cardiac catheterization. We performed TASH in order to relieve the dynamic obstruction of the ventricular outflow tract, and the ascites completely resolved without further interventions. | 18,937,189 |
[Endothelial adrenal cyst mimicking cystic echinococcosis in a Turkish woman]. | Cystic liver lesions include hepatic echinococcosis as an important differential diagnosis, especially in patients from endemic countries. Serology might be false negative in a relevant percentage of the patients. Thus, modern clinical imaging techniques are the most important non-invasive means for making or excluding the diagnosis of hepatic echinococcosis. A 37-year-old Turkish woman was admitted to hospital because of abdominal pressure, lack of appetite and weight loss. The suspected radiological diagnosis of hepatic echinococcosis was made based on a septated, cystic liver process with calcifications seen in an already performed computered tomography. The physical examination and laboratory findings did not show any specific pathology. The serological tests for echinococcosis were negative. The MRI scan of the liver showed a 10 x 7.5 cm large, multi-segmented, cystic lesion between the right kidney and the right liver lobe. The cyst was discussed as possibly having an origin from the right adrenal gland and very unlikely from the liver or kidney. Ultrasonography (Siemens-Acuson Sequoia 512, Mountain View) showed a cystic lesion with septated structures and calcifications between the right kidney and the liver without a typical capsule. Contrast-enhanced ultrasound after fractionated injection of 4.8 mL Sonovue (Bracco, Milano) showed an intensive perfusion of the septa in the cyst. We admitted the patient for surgery. Interoperatively a right adrenalectomy and cystectomy was performed. Histology showed an epithelial adrenal cyst. The patient was asymptomatic twelve months after surgery. High-end-ultrasonography with microbubble contrast media of the second generation is the primary diagnostic tool for the differential diagnosis of cystic lesions of the liver and adrenal glands. MRI or CT scans might be additionally indicated in the case of poor ultrasound conditions in a patient or before planned surgery, but can also fail to correct determine the origin of a cyst. | 18,937,190 |
Science, marketing and wishful thinking in quantitative proteomics. | In a recent editorial (J. Proteome Res. 2007, 6, 1633) and elsewhere questions have been raised regarding the lack of attention paid to good analytical practice with respect to the reporting of quantitative results in proteomics. Using those comments as a starting point, several issues are discussed that relate to the challenges involved in achieving adequate sampling with MS-based methods in order to generate valid data for large-scale studies. The discussion touches on the relationships that connect sampling depth and the power to detect protein abundance change, conflict of interest, and strategies to overcome bureaucratic obstacles that impede the use of peer-to-peer technologies for transfer and storage of large data files generated in such experiments. | 18,937,255 |
mRNA expression profiling of phyllodes tumours of the breast: identification of genes important in the development of borderline and malignant phyllodes tumours. | The aim of this study was to identify genes involved in the development of borderline and malignant phyllodes tumours of the breast (PTs). Expression profiling of 23 PTs (12 benign, 11 borderline/malignant) was performed using Affymetrix U133A GeneChips. mRNA expression in the borderline/malignant PTs was compared to the benign PTs. A group of 162 genes was over-expressed in the borderline/malignant group with a fold change > 2 and FDR < 0.1. Four of these genes were chosen for further investigation: PAX3, SIX1, TGFB2 and HMGA2. Over-expression was validated in a separate set of formalin-fixed, paraffin-embedded (FFPE) tumours, using either in situ hybridization or immunohistochemistry. This confirmed that expression of PAX3, SIX1, TGFB2 and HMGA2 in the stromal component of PTs was associated with the borderline/malignant phenotypes (p = 8.7 x 10(-5), p = 0.05, p = 0.009, p = 0.003, respectively; Fisher's exact test). The functional consequences of down-regulating these genes were studied using siRNA in short-term cultures and cell lines established from PTs. mRNA 'knock-down' of PAX3 resulted in significantly decreased cell proliferation in both a malignant and a borderline PT cell culture. mRNA 'knock-down' of SIX1 and HMGA2 resulted in decreased cell proliferation only in the malignant PT cell line, and 'knock-down' of TGFB2 resulted in decreased cell proliferation only in the borderline PT cell culture. This study shows that these four genes are involved in the development of borderline/malignant PTs. SIX1 over-expression was most marked in the highly malignant PTs, with particularly high expression in one case of metastatic PT. PAX3, TGFB2 and HMGA2 were expressed predominantly in borderline/malignant PTs, but showed some expression in benign tumours; they may be important in the transition from the benign to borderline/malignant phenotype. | 18,937,276 |
Simultaneous quantification of a non-nucleoside reverse transcriptase inhibitor efavirenz, a nucleoside reverse transcriptase inhibitor emtricitabine and a nucleotide reverse transcriptase inhibitor tenofovir in plasma by liquid chromatography positive ion electrospray tandem mass spectrometry. | A high-performance liquid chromatography/positive ion electrospray tandem mass spectrometry method for the simultaneous quantification of efavirenz, emtricitabine and tenofovir was developed and validated with 100 microL human plasma. Following solid-phase extraction, the analytes were separated using a gradient mobile phase on a reverse-phase column and analyzed by MS/MS in the multiple reaction monitoring mode using the respective [M + H]+ ions, m/z 316 to 168 for efavirenz, m/z 248-130 for emtricitabine and m/z 288-176 for tenofovir, m/z 482-258 for rosuvastatin (IS), m/z 260-116 for propranolol (IS). The method exhibited a 100-fold linear dynamic range for all the three analytes in human plasma (20-2000, 2-200 and 20-2000 ng/mL for efavirenz, emtricitabine and tenofovir respectively). The lower limit of quantification was 2 ng/mL for emtricitabine and 20 ng/mL for both efavirenz and tenofovir with a relative standard deviation of less than 11%. Acceptable precision and accuracy were obtained for concentrations over the standard curve range. The total chromatographic run time of 4 min for each sample made it possible to analyze more than 250 human plasma samples per day. The method is precise and sensitive enough for its intended purpose. The method is also successfully applied to quantify efavirenz, emtricitabine and tenofovir concentrations in a rodent pharmacokinetic study. | 18,937,306 |
Outcome of high-risk stage 3 neuroblastoma with myeloablative therapy and 13-cis-retinoic acid: a report from the Children's Oncology Group. | The components of therapy required for patients with INSS Stage 3 neuroblastoma and high-risk features remain controversial. A retrospective cohort design was used to determine if intensive chemoradiotherapy with purged autologous bone marrow rescue (ABMT) and/or 13-cis-retinoic acid (13-cis-RA) improved outcome for patients with high-risk neuroblastoma that was not metastatic to distant sites. We identified 72 patients with INSS Stage 3 neuroblastoma enrolled between 1991 and 1996 on the Phase 3 CCG-3891 randomized trial. Patients were analyzed on an intent-to-treat basis using a log-rank test. The 5-year event-free survival (EFS) and overall survival (OS) rates for patients with Stage 3 neuroblastoma were 55 +/- 6% and 59 +/- 6%, respectively (n = 72). Patients randomized to ABMT (n = 20) had 5-year EFS of 65 +/- 11% and OS of 65 +/- 11% compared to 41 +/- 11 (P = 0.21) and 46 +/- 11% (P = 0.23) for patients randomized to CC (n = 23), respectively. Patients randomized to 13-cis-RA (n = 23) had 5-year EFS of 70 +/- 10% and OS of 78 +/- 9% compared to 63 +/- 12% (P = 0.67) and 67 +/- 12% (P = 0.55) for those receiving no further therapy (n = 16), respectively. Patients randomized to both ABMT and 13-cis-RA (n = 6) had a 5-year EFS of 80 +/- 11% and OS of 100%. Patients with high-risk Stage 3 neuroblastoma have an overall poor prognosis despite aggressive chemoradiotherapy. Further studies are warranted to determine if myeloablative consolidation followed by 13-cis-RA maintenance therapy statistically significantly improves outcome. | 18,937,318 |
Symmetry variation in the heart-descending artery system of the parthenogenetic marbled crayfish. | The internal anatomy of freshwater crayfish is strictly bilaterally symmetric, with the conspicuous exception of the vertically oriented descending artery (sternal artery), which originates from the heart and terminates in the subneural artery. Serial sectioning of 133 juveniles of the parthenogenetic marbled crayfish revealed that the descending artery was bilaterally symmetric in 4.5% of the specimens, right asymmetric in 45.1%, and left asymmetric in 50.4%. In the bilaterally symmetric variant two branches arise from the left and right chambers of the bulbus of the heart, run laterally around the hindgut, and fuse underneath it. The asymmetric variants have only one dorsal branch, which loops around the hindgut on either the left or the right side. Other structures of the heart, such as the paired antennary and hepatopancreatic arteries and the ostia or the unpaired anterior and posterior aortae, showed no symmetry variation. Because of the genetic identity of the experimental animals and their culture under identical environmental conditions, the variation in symmetry of the descending artery observed is interpreted as the result of developmental variation. We recommend that the marbled crayfish be considered for investigation of the epigenetic mechanisms responsible for the maintenance and breaking of bilateral symmetry in metazoans. | 18,937,329 |
Lanosterol metabolic product(s) is involved in primordial folliculogenesis and establishment of primordial follicle pool in mouse fetal ovary. | The primordial follicles present in neonatal ovary represent the fecundity of a female throughout her reproductive life. Germ cell meiosis and apoptosis are two important events during primordial folliculogenesis. In this study, through focusing on the cytochrome P450 lanosterol 14 alphademethylase (CYP51) and its lanosterol metabolic product(s), we explored the possible regulatory mechanism of the initiation of germ cell meiosis and primordial follicle formation. The expression of CYP51 could be detected in both oocytes and granulosa cells during primordial folliculogenesis by immunochemistry. RS21745, which leads to the reduction of lanosterol metabolic product(s) level, inhibited the primordial follicle formation in a dose-dependent manner, and thus postpone the establishment of the primordial follicle pool when the mouse fetal ovaries were cultured in serum-free medium. In contrast, the number of primordial follicle increased significantly with the accumulation of the lanosterol metabolic products caused by 0.025, 0.0625, and 0.125 microM AY9944-A-7 supplements. AY9944-A-7 also up-regulated the expression of meiotic diplotene stage marker gene msy2 and primordial follicle formation regulatory gene fig-alpha. Furthermore, AY9944-A-7 decreased the expression of apoptosis gene bax and significantly prevented oocyte apoptosis from 15.37 +/- 1.97% to 3.68 +/- 0.27% (P < 0.01) in neonatal ovary in vitro. In conclusion, our results indicate that lanosterol metabolic product(s) is involved in the primordial folliculogenesis by regulating the oocyte meiosis and apoptosis. | 18,937,335 |
Inhibition of methylation and changes in gene expression in relation to neural tube defects. | An impaired DNA methylation has been suggested to underlie the complex etiology of neural tube defects (NTDs). Previously, we have demonstrated that inhibition of methylation by periodate oxidized adenosine (Adox) results in a widening of the anterior neuropore (ANP) in our in vitro chick embryo model. Since DNA methylation is the chief regulator of gene expression, we hypothesize that inhibition of methylation by Adox in our in vitro chick embryo model will affect the expression of genes that may be involved in neurulation. In the present study, we therefore examined differential gene expression between Adox-treated and control chick embryos, using the Affymetrix Genechip Chicken Genome Array. Chick embryos of 4/5 somites were cultured in vitro with saline (control) or Adox and cranial parts were excised. Gene expression profiling was determined using the Affymetrix Genechip Chicken Genome Array on RNA isolated from two pools of Adox-treated cranial parts (n = 12) and two pools of saline-treated cranial parts (n = 12). Microarray data were validated by QPCR analysis. In the Adox-treated chick embryos, 45 probesets were up-regulated (fold > or = 2.0, p < 0.05) and 32 probesets were down-regulated (fold < or = 0.5, p < 0.05). Of the 15 genes selected for QPCR analysis, the up-regulation of phosphoserine phosphatase (PSPH), unc-51-like kinase 1 (ULK1), and chemokine (C-X-C motif) ligand 12/stromal cell-derived factor 1 (CXCL12/SDF-1) was confirmed. Inhibition of methylation by Adox affects gene expression in our in vitro chick embryo model. Further research will focus on the gene-specific methylation patterns of PSPH, ULK1, and CXCL12/SDF-1 and the role of the products of these genes in neurulation. | 18,937,356 |
Design of small-molecule peptidic and nonpeptidic Smac mimetics. | Smac/DIABLO is a protein released from mitochondria into the cytosol in response to apoptotic stimuli. Smac promotes apoptosis at least in part through antagonizing inhibitor of apoptosis proteins (IAPs), including XIAP, cIAP-1, and cIAP-2. Smac interacts with these IAPs via its N-terminal AVPI binding motif. There has been an enormous interest in academic laboratories and pharmaceutical companies in the design of small-molecule Smac mimetics as potential anticancer agents. This task is particularly challenging because it involves targeting protein-protein interactions. Nevertheless, intense research has now generated potent, specific, cell-permeable small-molecule peptidomimetics and nonpeptidic mimetics. To date, two types of Smac mimetics have been reported, namely, monovalent and bivalent Smac mimetics. The monovalent compounds are designed to mimic the binding of a single AVPI binding motif to IAP proteins, whereas the bivalent compounds contain two AVPI binding motif mimetics tethered together through a linker. Studies from several groups have clearly demonstrated that both monovalent and bivalent Smac mimetics not only enhance the antitumor activity of other anticancer agents but also can induce apoptosis as single agents in a subset of human cancer cell lines in vitro and are capable of achieving tumor regression in animal models of human cancer. In general, bivalent Smac mimetics are 100-1000 times more potent than their corresponding monovalent Smac mimetics in induction of apoptosis in tumor cells. However, properly designed monovalent Smac mimetics can achieve oral bioavailability and may have major advantages over bivalent Smac mimetics as potential drug candidates. In-depth insights on the molecular mechanism of action of Smac mimetics have been provided by several independent studies. It was shown that Smac mimetics induce apoptosis in tumor cells by targeting cIAP-1/-2 for the rapid degradation of these proteins, which leads to activation of nuclear factor kappaB (NF-kappaB) and production and secretion of tumor necrosis factor alpha (TNFalpha). TNFalpha promotes formation of a receptor-interacting serine-threonine kinase 1 (RIPK1)-dependent caspase-8-activating complex, leading to activation of caspase-8 and -3/-7 and ultimately to apoptosis. For the most efficient apoptosis induction, Smac mimetics also need to remove the inhibition of XIAP to caspase-3/-7. Hence, Smac mimetics induce apoptosis in tumor cells by targeting not only cIAP-1/-2 but also XIAP. The employment of potent, cell-permeable, small-molecule Smac mimetics has yielded important insights into the regulation of apoptosis by IAP proteins. To date, at least one Smac mimetic has been advanced into clinical development. Several other Smac mimetics are in an advanced preclinical development stage and are expected to enter human clinical testing for the treatment of cancer in the near future. | 18,937,395 |
pH-sensitivity of the E3/K3 heterodimeric coiled coil. | This manuscript reports on the self-assembly properties of two complementary peptide sequences, E3 and K3, which are derived from the known IAAL E3/K3 heterodimeric coiled coil motif. Circular dichroism spectroscopy, analytical ultracentrifugation, and fluorescence resonance energy transfer experiments indicated that a stoichiometric mixture of these two peptides forms a stable heterodimeric coiled coil at pH 7. At pH 5, in contrast, the E3/K3 heterodimeric coiled coil is unstable and unfolds to generate E3 homotrimers that coexist with K3 unimers and a small fraction of K3 homodimers. This pH-induced unfolding transition was unprecedented for this coiled coil motif but is of interest as it occurs within a physiologically relevant pH range, as it is encountered, for example, during cellular uptake via the endosomal pathway. This feature, in combination with the relatively short length of the E3 and K3 peptides and the high stability of the E3/K3 coiled coil at pH 7 makes this folding motif very attractive for the development of noncovalent polymer therapeutics and self-assembled biohybrid hydrogels. | 18,937,405 |
Synthesis of alpha-keto-imides via oxidation of ynamides. | A de novo preparation of alpha-keto-imides via ynamide oxidation is described. With a number of alkyne oxidation conditions screened, a highly efficient RuO2-NaIO4 mediated oxidation and a DMDO oxidation have been identified to tolerate a wide range of ynamide types. In addition to accessing a wide variety of alpha-keto-imides, the RuO2-NaIO4 protocol provides a novel entry to the vicinal tricarbonyl motif via oxidation of push-pull ynamides, and imido acylsilanes from silyl-substituted ynamides. Chemoselective oxidation of ynamides containing olefins can be achieved by using DMDO, while the RuO2-NaIO4 protocol is not effective. These studies provide further support for the synthetic utility of ynamides. | 18,937,407 |
Efficient iron/copper cocatalyzed alkynylation of aryl iodides with terminal alkynes. | We developed a highly efficient and practical protocol for the coupling of terminal alkynes with aryl iodides that is catalyzed by inexpensive and environmentally benign Fe/Cu. A broad spectrum of substrates can participate in the process effectively to produce desired products in good yields. The versatility, generality, low cost, and environmental friendliness, in combination with exceptionally high reaction rates, render this method particularly attractive for industrial applications. | 18,937,417 |
One-step label-free optical genosensing system for sequence-specific DNA related to the human immunodeficiency virus based on the measurements of light scattering signals of gold nanorods. | A one-step label-free optical genosensing method has been developed in this contribution by taking short DNA target with its sequence related to the human immunodeficiency virus type 1 (HIV-1) as an example. By employing anisotropic nonspherical and positively charged gold nanorods (Au-NRs) as the recognition platform, which show high stability against aggregation under high ionic strength conditions without any additional stable reagent, we found that the addition of target DNA to the mixture of nonmodified Au-NRs suspension and label-free probe DNA in high ionic strength buffer leads to a color change from red to light purple in less than 5 min, displaying strong plasmon resonance light scattering (PRLS) signals. Mechanism investigations showed that the strong PRLS signals should be ascribed to the aggregation of Au-NRs induced by the formed double-stranded oligonucleotides (dsDNA) from the hybridization of target DNA with probe DNA. With the PRLS signals, we monitored the hybridization process of a 21-mer single-stranded oligonucleotide (ssDNA) from the HIV-1 U5 long terminal repeat (LTR) sequence with its complementary oligonucleotide and detected the effect of single-base-pair mismatches. Two polymerase chain reaction (PCR) amplicon artificial samples derived from Mycobacterium tuberculosis glmS and genes encoding for Bacillus glucanase and an HIV-1 LTR sample isolated from HIV-1-positive blood were detected with satisfactory results, showing that the present method has simplicity, sensitivity, specificity, and reliability for sequence-specific DNA detection related to the HIV gene. | 18,937,420 |
Quantitation of steroid hormones in thin fresh frozen tissue sections. | As analytical technologies in proteomics and metabolomics continue to mature, there is an increasing need to apply these to clinically relevant biologic samples. In this study, a liquid chromatography-tandem mass spectrometry method that utilizes selected reaction monitoring was used to measure the absolute quantity of estrogens and estrogen metabolites and testosterone in 8-microm tissue sections obtained from a fresh frozen lymph node tumor infiltrated by metastatic breast carcinoma. Total (conjugated plus unconjugated) and unconjugated levels of these steroid hormones were measured using two cohorts, each containing five adjacent serial sections cut from this tumor. The results were highly reproducible across replicate samples, showing that typical histological tissue sections represent an important sample type for the measurement of these specific metabolites. | 18,937,426 |
Evaluation of flexible linear tricationic salts as gas-phase ion-pairing reagents for the detection of divalent anions in positive mode ESI-MS. | Anion analysis is of great importance to many scientific areas of interest. Problems with negative mode ESI-MS prevent researchers from achieving sensitive detection for anions. Recently, we have shown that cationic reagents can be paired with anions, such that detection can be done in the positive mode, allowing for low limits of detections for anions using ESI-MS. In this analysis, we present the use of 16 newly synthesized flexible linear tricationic ion-paring reagents for the detection of 11 divalent anions. These reagents greatly differ in structure from previously reported trigonal tricationic ion-pairing agents, such that they are far more flexible. Here we present the structural features of these linear trications that make for good ion-pairing agents as well as show the advantage of using these more flexible ion-pairing reagents. In fact, the limit of detection for sulfate using the best linear trication was found to be 25 times lower than when the best rigid trication was used. Also, MS/MS experiments were performed on the trication-dianion complex to significantly reduce the detection limit for many dianions. Limits of detection in this analysis were as low as 50 fg. | 18,937,427 |
Interaction model based on local protein substructures generalizes to the entire structural enzyme-ligand space. | Chemogenomics is a new strategy in in silico drug discovery, where the ultimate goal is to understand molecular recognition for all molecules interacting with all proteins in the proteome. To study such cross interactions, methods that can generalize over proteins that vary greatly in sequence, structure, and function are needed. We present a general quantitative approach to protein-ligand binding affinity prediction that spans the entire structural enzyme-ligand space. The model was trained on a data set composed of all available enzymes cocrystallized with druglike ligands, taken from four publicly available interaction databases, for which a crystal structure is available. Each enzyme was characterized by a set of local descriptors of protein structure that describe the binding site of the cocrystallized ligand. The ligands in the training set were described by traditional QSAR descriptors. To evaluate the model, a comprehensive test set consisting of enzyme structures and ligands was manually curated. The test set contained enzyme-ligand complexes for which no crystal structures were available, and thus the binding modes were unknown. The test set enzymes were therefore characterized by matching their entire structures to the local descriptor library constructed from the training set. Both the training and the test set contained enzyme-ligand complexes from all major enzyme classes, and the enzymes spanned a large range of sequences and folds. The experimental binding affinities (p K i) ranged from 0.5 to 11.9 (0.7-11.0 in the test set). The induced model predicted the binding affinities of the external test set enzyme-ligand complexes with an r (2) of 0.53 and an RMSEP of 1.5. This demonstrates that the use of local descriptors makes it possible to create rough predictive models that can generalize over a wide range of protein targets. | 18,937,438 |
Chiral anion-mediated asymmetric ring opening of meso-aziridinium and episulfonium ions. | Reactions proceeding through cationic intermediates that lack a Lewis or Brønsted basic site present a challenge for traditional asymmetric catalysis based on chiral metals or organocatalysts. We present an enantioselective ring opening of tetrasubstituted meso-aziridinium ions with alcohol nucleophiles proceeding through a chiral ion pair with a binaphthol-phosphate anion. The reaction is initiated by silver-induced ring closure of beta-chloroamines using the Ag salt of the chiral anion as in situ generated catalyst. Use of insoluble Ag2CO3 as silver source is essential to obtain high enantioselectivity; we believe the chiral phosphate acts as a "chiral anion phase transfer catalyst" to bring silver ion into the organic phase. The chiral anion concept can also be extended to the related asymmetric opening of meso-episulfonium ions generated by protonation of trichloroacetimidates vicinal to sulfides. | 18,937,464 |
Structural analysis of the Mn(IV)/Fe(III) cofactor of Chlamydia trachomatis ribonucleotide reductase by extended X-ray absorption fine structure spectroscopy and density functional theory calculations. | The class Ic ribonucleotide reductase from Chlamydia trachomatis ( Ct) uses a stable Mn(IV)/Fe(III) cofactor to initiate nucleotide reduction by a free-radical mechanism. Extended X-ray absorption fine structure (EXAFS) spectroscopy and density functional theory (DFT) calculations are used to postulate a structure for this cofactor. Fe and Mn K-edge EXAFS data yield an intermetallic distance of approximately 2.92 A. The Mn data also suggest the presence of a short 1.74 A Mn-O bond. These metrics are compared to the results of DFT calculations on 12 cofactor models derived from the crystal structure of the inactive Fe 2(III/III) form of the protein. Models are differentiated by the protonation states of their bridging and terminal OH X ligands as well as the location of the Mn(IV) ion (site 1 or 2). The models that agree best with experimental observation feature a mu-1,3-carboxylate bridge (E120), terminal solvent (H 2O/OH) to site 1, one mu-O bridge, and one mu-OH bridge. The site-placement of the metal ions cannot be discerned from the available data. | 18,937,466 |
Binding of flavor compounds and whey protein isolate as affected by heat and high pressure treatments. | The interactions of whey protein isolate (WPI) and flavor compounds (2-nonanone, 1-nonanal, and trans-2-nonenal) were investigated, and the influence of flavor compound structure and heat and high pressure denaturation on the interactions were determined by using headspace solid-phase microextraction (SPME) and gas chromatography (GC). The binding of WPI and the flavor compounds decreased in the order trans-2-nonenal > 1-nonanal > 2-nonanone. The differences in binding can be explained with hydrophobic interactions only in the case of 2-nonanone, whereas the aldehydes, in particular trans-2-nonenal, can also react covalently. Heat and high pressure treatment affected protein-flavor interactions depending on the structure of the flavor compound. Upon both heat and high pressure denaturation, the binding of 2-nonanone to WPI decreased, while the binding of 1-nonanal remained unchanged, and the affinity for trans-2-nonenal increased rapidly. The results suggest that hydrophobic interactions are weakened upon heat or high pressure denaturation, whereas covalent interactions are enhanced. | 18,937,489 |
Phytochemical diversity in tubers of potato cultivars and landraces using a GC-MS metabolomics approach. | Phytochemical diversity with respect to a range of polar (including amino acids, organic acids, sugars, and sugar alcohols) and nonpolar (including fatty acids, alkanols, and sterols) metabolites was examined within tubers from a total of 29 genetically diverse potato cultivars and Chilean landraces using a metabolomics approach by gas chromatography-mass spectrometry. From principal component analysis of the polar and nonpolar metabolite data there was insufficient variation to differentiate the majority of cultivars and landraces. Analysis of all polar metabolite profiles revealed separation of two cultivars (Glenna and Morag) from the other cultivars and landraces and a separate cluster of one landrace line, largely due to higher levels of sugars. Pentland Javelin was distinct in containing high levels of many amino acids. The two Solanum tuberosum group phureja cultivars (Inca Sun and Mayan Gold) were not particularly similar and were not separated from the S. tuberosum group tuberosum cultivars. Analysis of the nonpolar metabolite data revealed partial separation of two landrace lines and, on the basis of some minor fatty acids, Mayan Gold was distinct. The differences in metabolite profiles are considered in terms of the taxonomy and breeding history of the cultivars and possible influences from other factors such as developmental stage of the tuber. With a view to exploring biosynthetic links between metabolites, a pairwise correlation analysis was performed on all metabolites. The significance of high correlations between many amino acids and between several nonpolar metabolites is discussed. | 18,937,493 |
Location of subunit d in the peripheral stalk of the ATP synthase from Saccharomyces cerevisiae. | ATP synthase from Saccharomyces cerevisiae is an approximately 600 kDa membrane protein complex. The enzyme couples the proton motive force across the mitochondrial inner membrane to the synthesis of ATP from ADP and inorganic phosphate. The peripheral stalk subcomplex acts as a stator, preventing the rotation of the soluble F 1 region relative to the membrane-bound F O region during ATP synthesis. Component subunits of the peripheral stalk are Atp5p (OSCP), Atp4p (subunit b), Atp7p (subunit d), and Atp14p (subunit h). X-ray crystallography has defined the structure of a large fragment of the bovine peripheral stalk, including 75% of subunit d (residues 3-123). Docking the peripheral stalk structure into a cryo-EM map of intact yeast ATP synthase showed that residue 123 of subunit d lies close to the bottom edge of F 1. The 37 missing C-terminal residues are predicted to either fold back toward the apex of F 1 or extend toward the membrane. To locate the C terminus of subunit d within the peripheral stalk of ATP synthase from S. cerevisiae, a biotinylation signal was fused to the protein. The biotin acceptor domain became biotinylated in vivo and was subsequently labeled with avidin in vitro. Electron microscopy of the avidin-labeled complex showed the label tethered close to the membrane surface. We propose that the C-terminal region of subunit d spans the gap from F 1 to F O, reinforcing this section of the peripheral stalk. | 18,937,496 |
Soluble oligomers of the intramembrane serine protease YqgP are catalytically active in the absence of detergents. | Rhomboid, a polytopic membrane serine protease, represents a unique class of proteases that cleave substrates within the transmembrane domain. Elucidating the mechanism of this extraordinary catalysis comes with inherent challenges related to membrane-associated peptide hydrolysis. Here we established a system that allows expression and isolation of YqgP, a rhomboid homologue from Bacillus subtilis, as a soluble protein. Intriguingly, soluble YqgP is able to specifically cleave a peptide substrate that contains the transmembrane domain of Spitz. Mutation of the catalytic dyad abolished protease activity, and substitution of another highly conserved residue, Asn241, with Ala or Asp significantly reduced the catalytic efficiency of YqgP. We have identified the cleavage site that resides in the middle of the transmembrane domain of Spitz. Replacement of two residues that contribute to the scissile bond by Ala did not eliminate cleavage, but rather led to additional or alternative cleavages. Moreover, we have demonstrated that soluble YqgP exists as oligomers that are required for catalytic activity. These results suggest that soluble oligomers of maltose binding protein-YqgP complexes form micellelike structures that are able to retain the active conformation of the protease for catalysis. Therefore, this work not only provides a unique system for elucidating the reaction mechanism of rhomboid but also will facilitate the characterization of other intramembrane proteases as well as non-protease membrane proteins. | 18,937,501 |
The I260Q variant of DNA polymerase beta extends mispaired primer termini due to its increased affinity for deoxynucleotide triphosphate substrates. | DNA polymerase beta plays a key role in base excision repair. We have previously shown that the hydrophobic hinge region of polymerase beta, which is distant from its active site, plays a critical role in the fidelity of DNA synthesis by this enzyme. The I260Q hinge variant of polymerase beta misincorporates nucleotides with a significantly higher catalytic efficiency than the wild-type enzyme. In the study described here, we show that I260Q extends mispaired primer termini. The kinetic basis for extension of mispairs is defective discrimination by I260Q at the level of ground-state binding of the dNTP substrate. Our results suggest that the hydrophobic hinge region influences the geometry of the dNTP binding pocket exclusively. Because the DNA forms part of the binding pocket, our data are also consistent with the interpretation that the mispaired primer terminus affects the geometry of the dNTP binding pocket such that the I260Q variant has a higher affinity for the incoming dNTP than wild-type polymerase beta. | 18,937,502 |
Skeletal muscle group VIA phospholipase A2 (iPLA2beta): expression and role in fatty acid oxidation. | Among the phospholipases A 2 (PLA 2s) are the group VI Ca (2+)-independent PLA 2s (iPLA 2s), and expression of multiple transcripts of iPLA 2 in skeletal muscle has been reported. In the present study, phospholipase activity and sequential ATP and calmodulin affinity column chromatography analyses reveal that skeletal muscle iPLA 2 exhibits properties characteristic of the iPLA 2beta isoform. The phospholipase activity of iPLA 2beta has been demonstrated to participate in signal transduction, cell proliferation, and apoptosis. We report here that skeletal muscle from iPLA 2beta-null mice, relative to wild-type muscle, exhibits a reduced capacity to oxidize palmitate but not palmitoyl-CoA or acetyl-CoA in the absence of changes in fatty acid transporters CD36 and CPT1 or beta-hydroxyacyl-CoA dehydrogenase activity. Recently, purified iPLA 2beta was demonstrated to manifest a thioesterase activity which catalyzes hydrolysis of fatty acyl-CoAs. The liberated CoA-SH facilitates fatty acid transport into the mitochondria. In this regard, we find that fractions eluted from the ATP column and containing iPLA 2beta phospholipase activity also contained acyl-CoA thioesterase activity that was inhibited by the bromoenol lactone (BEL) suicide inhibitor of iPLA 2beta. We further find that acyl-CoA thioesterase activity in skeletal muscle preparations from iPLA 2beta-null mice is significantly reduced, relative to WT activity. These findings suggest that the absence of acyl-CoA thioesterase activity of iPLA 2beta can lead to reduced fatty acyl-CoA generation and impair fatty acid oxidation in iPLA 2beta-null mice. Our findings therefore reveal a novel function of iPLA 2beta, related not to its phospholipase activity but to its thioesterase activity, which contributes to optimal fatty acid oxidation in skeletal muscle. | 18,937,505 |
Laser fabrication and spectroscopy of organic nanoparticles. | In working with nanoparticles, researchers still face two fundamental challenges: how to fabricate the nanoparticles with controlled size and shape and how to characterize them. In this Account, we describe recent advances in laser technology both for the synthesis of organic nanoparticles and for their analysis by single nanoparticle spectroscopy. Laser ablation of organic microcrystalline powders in a poor solvent has opened new horizons for the synthesis of nanoparticles because the powder sample is converted directly into a stable colloidal solution without additives and chemicals. By tuning laser wavelength, pulse width, laser fluence, and total shot number, we could control the size and phase of the nanoparticles. For example, we describe nanoparticle formation of quinacridone, a well-known red pigment, in water. By modifying the length of time that the sample is excited by the laser, we could control the particle size (30-120 nm) for nanosecond excitation down to 13 nm for femtosecond irradiation. We prepared beta- and gamma-phase nanoparticles from the microcrystal with beta-phase by changing laser wavelength and fluence. We present further results from nanoparticles produced from several dyes, C(60), and an anticancer drug. All the prepared colloidal solutions were transparent and highly dispersive. Such materials could be used for nanoscale device development and for biomedical and environmental applications. We also demonstrated the utility of single nanoparticle spectroscopic analysis in the characterization of organic nanoparticles. The optical properties of these organic nanoparticles depend on their size within the range from a few tens to a few hundred nanometers. We observed perylene nanoscrystals using single-particle spectroscopy coupled with atomic force microscopy. Based on these experiments, we proposed empirical equations explaining their size-dependent fluorescence spectra. We attribute the size effect to the change in elastic properties of the nanocrystal. Based on the results for nanoparticles of polymers and other molecules with flexible conformations, we assert that size-dependent optical properties are common for organic nanoparticles. While "electronic confinement" explains the size-dependent properties of inorganic nanoparticles, we propose "structural confinement" as an analogous paradigm for organic nanoparticles. | 18,937,507 |
The importance of sensory-motor control in providing core stability: implications for measurement and training. | Although the hip musculature is found to be very important in connecting the core to the lower extremities and in transferring forces from and to the core, it is proposed to leave the hip musculature out of consideration when talking about the concept of core stability. A low level of co-contraction of the trunk muscles is important for core stability. It provides a level of stiffness, which gives sufficient stability against minor perturbations. Next to this stiffness, direction-specific muscle reflex responses are also important in providing core stability, particularly when encountering sudden perturbations. It appears that most trunk muscles, both the local and global stabilization system, must work coherently to achieve core stability. The contributions of the various trunk muscles depend on the task being performed. In the search for a precise balance between the amount of stability and mobility, the role of sensory-motor control is much more important than the role of strength or endurance of the trunk muscles. The CNS creates a stable foundation for movement of the extremities through co-contraction of particular muscles. Appropriate muscle recruitment and timing is extremely important in providing core stability. No clear evidence has been found for a positive relationship between core stability and physical performance and more research in this area is needed. On the other hand, with respect to the relationship between core stability and injury, several studies have found an association between a decreased stability and a higher risk of sustaining a low back or knee injury. Subjects with such injuries have been shown to demonstrate impaired postural control, delayed muscle reflex responses following sudden trunk unloading and abnormal trunk muscle recruitment patterns. In addition, various relationships have been demonstrated between core stability, balance performance and activation characteristics of the trunk muscles. Most importantly, a significant correlation was found between poor balance performance in a sitting balance task and delayed firing of the trunk muscles during sudden perturbation. It was suggested that both phenomena are caused by proprioceptive deficits. The importance of sensory-motor control has implications for the development of measurement and training protocols. It has been shown that challenging propriocepsis during training activities, for example, by making use of unstable surfaces, leads to increased demands on trunk muscles, thereby improving core stability and balance. Various tests to directly or indirectly measure neuromuscular control and coordination have been developed and are discussed in the present article. Sitting balance performance and trunk muscle response times may be good indicators of core stability. In light of this, it would be interesting to quantify core stability using a sitting balance task, for example by making use of accelerometry. Further research is required to develop training programmes and evaluation methods that are suitable for various target groups. | 18,937,521 |
Mucocele: a human model for lymphangiogenesis. | The mechanism of lymphangiogenesis is poorly understood, and controversy exists whether it is part of the inflammatory response to tissue injury. Utilizing markers specific to lymphatics, we aimed to study if lymphangiogenesis plays a role in the tissue response of mucoceles. Twenty-three extravasated mucoceles were selected. They were grouped by using widely accepted histologic criteria of wound healing into early-, intermediate-, and late-phase lesions. To identify lymphatic vessels we used lymphatic endothelium-specific antibodies (VEGFR3, Prospero-related homeobox gene-1 [Prox-1], and D2-40). To assess the proportion of lymphatic channels to all lesional vessels we used the panendothelial marker CD31. The presence, distribution, and proportion of lymphatic channels were assessed and compared among the groups. To investigate the involvement of lymphangiogenic signals, the expression of VEGFC was determined. To assess for proliferative activity of lymphatic endothelial cells we utilized Ki-67 antibody. Early-phase lesions (n = 6) were characterized by the presence of centrally located mucicarmine-positive material (mucin pools) with numerous inflammatory cells dominated by mucin-laden CD163-positive macrophages. Only scattered peripheral thin-walled large and small vessels were seen in the stroma surrounding the central mucin pool. Less than half of these vessels were of lymphatic nature as determined by Prox-1, VEGFR3, and D2-40 positivity. The histology of the intermediate-phase lesions (n = 6) was dominated by numerous lymphatics of varying size, not seen in the early phase. The histology of late-phase lesions (n = 11) resembled a "pseudo-cyst," with dense granulation tissue containing rare macrophages and rare lymphatic vessels. Although VEGFC was present in all phases, the highest expression was in the early phase. Low-grade proliferative lymphatic endothelium was noted in the intermediate lesions with a Ki-67 index of 4%. Early lymphangiogenesis and late lymphatic vessel regression were observed during mucocele evolution. The abundant newly formed ectatic lymphatic vessels seen in the intermediate phase may play a role in the clearance of extravasated material (mucin, edema, and lymph fluid) and in the initiation of the young fibroblast-rich granulation tissue. Mucocele appears to be an excellent human model for studying the factors that play a role in new lymphangiogenesis and regression. | 18,937,525 |
Enantioselectivity in the immunotoxicity of the insecticide acetofenate in an in vitro model. | Chiral pesticides with an asymmetrical center in their molecular structures possess enantioselectivity, not only in their pesticidal activities toward targeted organisms but also in toxicities to nontargeted organisms. Despite the fact that chiral pesticides deserve particular attention because of their ubiquitous presence in living and working environments, there has been limited research into their enantioselectivity in chronic toxicity. The immunotoxicity of chiral pesticides with respect to enantioselectivity has not been studied before. In this study, the role of enantioselectivity in the immunotoxicity of acetofenate (AF), an organochlorine insecticide, was investigated in an in vitro macrophage cell line model. Results of the cytotoxicity assay showed a clear dose-dependent growth inhibition effect of AF with enantioselectivity on RAW264.7 cells. S-(+)-AF was clearly more toxic to macrophages than R-(-)-AF and rac-AF. This work also demonstrated that S-(+)-AF possesses the strongest effects in induction of intracellular reactive oxygen species, DNA damage, and upregulation of p53 gene expression. These results, for the first time, show stark selectivity between enantiomers in their ability to induce macrophage-involved immunotoxicity of AF. These results suggest that assessment of the environmental safety and health risk of chiral contaminants should consider the role of enantioselectivity in immunotoxicity. In addition, our study will improve the knowledge of the role of enantioselectivity in immunotoxicity of chiral contaminants. | 18,937,538 |
Rigid interferon-alpha subtype responses of human plasmacytoid dendritic cells. | The large family of human type I interferon (IFN) includes 13 distinct subtypes of IFN-alpha, all utilizing a single type I IFN receptor. Many viruses have created evasion strategies to disable this cytokine family, highlighting their importance in antiviral defense. It is unclear what advantage the presence of so many different IFN-alpha subtypes provides, but functional differences observed among individual IFN-alpha subtypes suggested that they might play distinct regulatory roles during an immune response. To determine whether IFN-alpha subtype responses differ depending on a particular type of insult and thus whether IFN-alpha subtype responses are flexible to adapt to distinct pathogen challenges, we developed a novel nested multiplex reverse transcriptase polymerase chain reaction assay with which we measured expression of all IFN-alpha subtypes by freshly isolated human plasmacytoid dendritic cells (pDCs), a main source of IFN-alpha following pathogen challenge. Collectively our data show a remarkable stability in the relative magnitude and the kinetics of induction for each IFN-alpha subtype produced by pDC. Although various stimuli used, A-, B- and C-class CpGs, live and heat-inactivated influenza viruses and the TLR7 agonist R837 affected the overall magnitude of the response, each IFN-alpha subtype was induced at statistically similar relative levels and with similar kinetics, thereby revealing a great degree of rigidity in the IFN-alpha response pattern of pDC. These data are most consistent with the induction of optimized ratios of IFN-alpha subtypes, each of which may have differing signaling properties or alternatively, a great degree of redundancy in the IFN-alpha response. | 18,937,549 |
Multistate outbreak of Pseudomonas fluorescens bloodstream infection after exposure to contaminated heparinized saline flush prepared by a compounding pharmacy. | Pharmaceutical compounding, the manipulation of ingredients to create a customized medication, is a widespread practice. In January 2005, the Centers for Disease Control and Prevention was notified of 4 cases of Pseudomonas fluorescens bacteremia that were traced to contaminated heparinized saline intravenous flush syringes prepared as a compounded medical product. We reviewed medical records of symptomatic patients with P. fluorescens-positive cultures of blood specimens or sections of explanted catheters, reviewed the production process of syringes, performed syringe cultures, compared isolates by pulsed-field gel electrophoresis (PFGE), and examined catheters by scanning electron microscopy. We identified 80 patients in 6 states with P. fluorescens-positive cultures during December 2004-March 2006. Sixty-four patients (80%) had received a diagnosis of cancer. Seventy-four (99%) of 75 patients for whom information about catheter type was available had long-term indwelling catheters. Thirty-three (41%) of 80 cases were diagnosed 84-421 days after the patient's last potential exposure to a contaminated flush (delayed-onset cases). Compared with patients with early infection onset, more patients with delayed infection onset had venous ports (100% versus 50%; P <.001). By PFGE, clinical isolates from 50 (98%) of 51 patients were related to isolates cultured from unopened syringes. Scanning electron microscopy of explanted catheters revealed biofilms containing organisms morphologically consistent with P. fluorescens. This outbreak underscores important challenges in ensuring the safety of compounded pharmaceuticals and demonstrates the potential for substantially delayed infections after exposures to contaminated infusates. Exposures to compounded products should be considered when investigating outbreaks. Patients exposed to contaminated infusates require careful follow-up, because infections can occur long after exposure. | 18,937,575 |
Twenty years of single center experience in ESWL 1987-2007: an evaluation of 3079 patients. | Since 1987 we have consecutively operated five different Dornier lithotriptors in the management of lithiasis at all levels of the urinary tract. At the time of usage of each machine we periodically evaluated the treatment results in order to eventually adapt treatment strategies to improve results. None of these evaluations comprised the totality of patients treated on a certain machine during the entire period it was in use. This overview retrospectively compares the results over the entire period in order to gauge the impact of the different machines and SW-sources on clinical results. A total of 3079 patients, treated from september 1987 till september 2006 with two electrohydraulic machines, HM4 (1987-1988) and MPL9000 (1988-1994), and three electromagnetic machines, Compact (1991-1999), DoLi U/50 (1996-1999) and DoLi S (1999-2006) were thus evaluated. Parameters reviewed were stone location and size, retreatment rate, auxiliary procedures, stone free rate and Effectiveness Quotient (EQ). There is no significant difference in stone size or stone free rate (p=0.4715) for the different groups. There is a significant difference for auxiliary procedure rate and retreatment rate for the different machines. The DoLiS with EMSE 220F-XXP scores significantly better than any of the other systems for auxiliary procedure rate pre-ESWL (p<0.05) and total auxiliary procedure rate (p<0.05), and retreatment rate (p=0.0024). There is a gradual increase in EQ with the consecutive machines. Although stone free rates (85%-88.8%) remained constant, Effectiveness Quotients improved. This is largely due to reduced auxiliary procedure rates and reduced retreatment rates. The first effect is a consequence of improvement in treatment strategies and experience, the latter no doubt also of improvement in SW-sources. | 18,937,585 |
Extracorporeal shock wave lithotripsy in an elderly population: how to prevent complications and make the treatment safe and effective. | The aim of our study is to consider the feasibility and the results of shock wave lithotripsy (SWL) in an elderly cohort of patients, considering different diseases and concomitant morbidity. From January 2003 up to July 2006, a total of 1100 SWL treatments were performed in our Stone Centre with Dornier Lithotripter S device. We retrospectively analyzed all the treatments carried out in patients older than 70 years of age, collecting a total of 130 patients. The average age was 75.1 years (range: 70-89). Stone location was renal in 95 and ureteral in 45 patients. Information about SWL outcomes and complications were collected as well as patient's characteristics and treatment modalities. Average stone size was 10.2+/-3.4 and 8.7+/-3.1 for the renal and ureteral location, respectively. 73 out of 140 patients (52.1%) were stone free after a single treatment; 49 patients (35%) required an adjunctive session, whereas SWL was unsuccessful in 18 (12.8%) patients. We observed 64, 24, 21, 10, 31 cases of concomitant arterial hypertension, diabetes mellitus, chronic renal failure, solitary kidney condition and previous neoplastic pathologies. A total of 8 and 6 subjects had previous cardiac surgery and atrial fibrillation respectively, thus requiring a warfarin scheduled conversion to low molecular weight heparin. Five patients had a pace maker implant and three patients an abdominal aortic aneurism. No SWL-related complications were found in this series considering both urological and systemic features. SWL represents the treatment of choice for urolithiasis, and it has to be recommended especially to geriatric patients. In those subjects, SWL complications can be avoided with a proper and personalized preparation, together with an ECG and ultrasound continuously monitored procedure. | 18,937,586 |
Long-term outcome of laparoscopic retroperitoneal nephropexy. | Laparoscopy has been reported recently as a minimally invasive approach for nephropexy. We evaluated our long-term outcomes and quality of life (QoL) after laparoscopic retroperitoneal nephropexy (LRNP). Forty-eight patients with symptomatic nephroptosis with a mean age of 36.2 years underwent LRNP between February 1993 and October 2004 in two German centers. Preoperatively, intravenous urography (IVU) and a renal scan were performed in supine and upright positions. Postoperatively, the IVU and renal scan were repeated. The patients were asked after a median follow-up of 8.16 years for long-term postoperative outcome with a mailed questionnaire about their QoL, symptoms, and whether they would undergo the operation again. No major intraoperative complications were observed. The mean operative time was 95 minutes (range 50-200 min). The median blood loss was less than 50 mL. Postoperatively, 94.1% of the kidneys radiographically showed no ptosis or ptosis less than one vertebral body. We were able to contact 41 of 48 (85.4%) patients, of whom 95% had no objective symptoms after the operation and 91% had an improvement of their pain symptoms. Of the contacted patients, 70.7% reported an improvement in their QoL and 87% would undergo the operation again. LRNP is a minimally invasive, suitable, established method for managing symptomatic nephroptosis with good long-term clinical outcomes and patient satisfaction. This approach also improves patients' perceived QoL. | 18,937,591 |
Diagnostic yield of renal biopsy immediately prior to laparoscopic radiofrequency ablation: a multicenter study. | Ablative therapy is increasing for the management of small renal masses. Laparoscopic as well as percutaneous cryotherapy and radiofrequency ablation (RFA) have been utilized. Herein we review our experience with renal biopsy immediately prior to laparoscopic RFA. A prospectively collected database containing all patients who underwent laparoscopic RFA by three different surgeons at two different institutions was reviewed. Renal biopsies were performed in each patient during transperitoneal laparoscopy after mobilization of the kidney and prior to RFA. The biopsy needle was passed percutaneously via a sheath through the abdominal wall. Multiple core biopsies (3-5) were taken under visual and ultrasonic guidance. All were submitted for permanent pathologic sectioning. 138 patients underwent renal biopsy prior to RFA. Mean tumor size was 3.0 cm (range 1.0-6.9). The mean age was 72 years (range 39-90). There were 42 females and 96 males. Mean blood loss was 28 ml (0-400 ml). Only 5 patients lost more than 50 ml, and in each case the bleeding was associated with complicated renal mobilization and dissection prior to biopsy. Final pathology revealed renal cell carcinoma in 95, oncocytic neoplasm in 26, and angiomyolipoma in 9.8 patients were considered to have nondiagnostic biopsies. In this group, final pathology revealed benign cysts in 3, inconclusive specimens in 3, fibrosis in 1, and normal tissue in 1. Hence, a clear diagnosis was possible in 130 of 138 patients, which is 94.2%. RCC was diagnosed in 68.8% of the patients, and in 73.1% of the conclusive biopsies. Eight patients had perioperative complications, including low-grade fevers (2) perirenal/retroperitonal hematoma (2), pleural tear/pneumothorax (2), CHF exacerbation, and wound infection. In our multicenter experience, renal biopsy of 138 renal lesions at the time of laparoscopic RFA had a diagnostic yield of 94.2%. RCC was diagnosed in 68.8% of the patients, and in 73.1% of the conclusive biopsies. | 18,937,593 |
Effect of rimonabant, micronised fenofibrate and their combination on cardiometabolic risk factors in overweight/obese patients: a pilot study. | To assess the effect of rimonabant, micronised fenofibrate and their combination on anthropometric and metabolic parameters in overweight/obese patients with dyslipidaemia. All patients (n = 30) received a hypocaloric diet ( approximately 600 kcal/day deficit) and were randomly allocated to receive open-label rimonabant (R) 20 mg/day (n = 10), micronised fenofibrate (F) 200 mg/day (n = 10) or rimonabant 20 mg/day plus fenofibrate 200 mg/day (RF) (n = 10). Anthropometric and metabolic parameters were assessed at baseline and 3 months after treatment initiation. Compared with baseline similar significant reductions in body weight, body mass index and waist circumference were observed in the R (-6, -5 and -5%, respectively; p < 0.01) and RF group (-5% for all, p < 0.05), while improvements in these parameters were smaller in the F group (-2, -2.5 and -2%, respectively; p < 0.05). Triglycerides were reduced by 18% in the R group (p = NS), by 39% in the F group (p < 0.001) and by 46% in the RF group (p < 0.05). Importantly, combination treatment resulted in a 42% increase in high-density lipoprotein cholesterol (HDL-C) levels (p < 0.05), while HDL-C was not significantly altered in the two monotherapy groups. Subsequently, a more pronounced increase in apolipoprotein A-I (ApoA-I) levels (+25%) was observed in the RF group compared with changes in both monotherapy groups (p < 0.0001 vs R and p < 0.005 vs F group). Low-density lipoprotein cholesterol (LDL-C) levels were not significantly altered in any group. Apolipoprotein B (apoB) levels were reduced in all groups and this reduction was significantly more pronounced in the RF group (p < 0.05 vs baseline as well as p < 0.005 and p < 0.01 for RF vs R and F groups, respectively). ApoB/apoA-I ratio decreased by 3% with R (p = NS), by 18% with F (p < 0.05) and by 40% with RF treatment (p < 0.01). Total cholesterol to HDL-C ratio decreased by 20% with F (p < 0.0001) and by 33% with RF therapy (p < 0.005), while it was not significantly altered in R group. The combination of rimonabant and fenofibrate may further improve metabolic parameters in overweight/obese patients with dyslipidaemia compared with each monotherapy. This improvement is particularly pronounced for HDL-C levels. | 18,937,609 |
Antibiotic management of sepsis: current concepts. | The development of guidelines for sepsis management has improved disease survival and reduced treatment costs. Adequate antibiotic therapy is the cornerstone of sepsis treatment. Specific rules should be established in every institution according to its profiles. To review the current knowledge about the best drugs to be used as empiric treatment for sepsis based on their clinical efficacy and costs. Medline 1950 - 2008 was searched using the following terms: sepsis, organ failure, system failure, SIRS, septic shock, antibiotic, pneumonia, urinary tract infection, urosepsis, catheter-related infection, bloodstream, abdominal infection, and surgical wound. For most septic shock patients, monotherapy is adequate and treatment should be initiated in the first hour after first sepsis-induced organ dysfunction. The drug of choice varies in different situations and choosing the right antibiotic enables better survival, fewer complications and shorter stays in intensive care. | 18,937,614 |
Niacin: a lipid polypill? | Niacin is one of the oldest yet also most diverse lipid lowering agents. As it not only lowers low-density-lipoprotein (LDL) cholesterol, triglycerides (TG) and lipoprotein(a) [Lp(a)] but also increases high-density-lipoprotein (HDL) cholesterol, it is useful for treating a wide variety of lipid disorders including mixed hyperlipidaemia, hypertriglyceridaemia and isolated low HDL cholesterol, as well as elevated Lp(a). Niacin, which exists in several different formulations, such as immediate release (IR), extended release (ER) and slow release (SR) niacin, has several modes of action: it modulates liver TG synthesis, which leads to increased intracellular apolipoprotein (apo) B degradation and increases TG lipolysis in adipose tissue. Recently, a specific niacin receptor has also been discovered. Several clinical outcome trials have demonstrated that niacin reduces coronary artery disease risk in combination with statins and two large mortality trials are currently underway looking at hard end-point reduction with niacin and statin compared to statin alone. Niacin's major adverse event (AE) is flushing, and this prevents many patients from either taking it or reaching target doses of this drug. Flushing incidence and intensity is reduced with ER-niacin and by co-administration of aspirin and a selective or non-selective prostaglandin inhibitor. | 18,937,622 |
Premature atherosclerotic cardiovascular disease and systemic lupus erythematosus from bedside to bench. | Cardiovascular morbidity and mortality in SLE is increased in patient with established disease, and SLE itself has been determined to be an independent risk factor for cardiovascular events. Autopsy studies have demonstrated that the coronary vessels of SLE patients have atherosclerotic plaque, and most cardiovascular events are not attributable to active vasculitis. It is believed that patients with inflammatory disease, including SLE, are more likely to have vulnerable plaque rupture, accounting for more frequent events. Elevated homocysteine levels have been associated with the presence and progression of atherosclerotic plaque. Enzyme polymorphisms involved in the folatehomocysteine pathway do not seem to contribute to differences in homocysteine concentration or atherosclerotic plaque. Recently, endothelial dysfunction has been identified as an early abnormality in ASCVD, and has been demonstrated in the vessels of SLE patients. Premature cardiovascular disease in SLE patients is likely attributable to the consequences of inflammation. There is preliminary evidence that type I interferons maybe the initial stimulation of the cascade of atherosclerotic development, starting with endothelial damage, and abnormal vascular repair. | 18,937,629 |
Emerging therapeutics for rheumatoid arthritis. | Therapeutics options for rheumatoid arthritis (RA) have increased tremendously in the past decade with the introduction of biological agents in 1999. Several different cellular and cytokine targets have been identified, with specific inhibitors now approved to treat RA, including the tumor necrosis factor (TNF) antagonists (adalimumab, etanercept, infliximab), an interleukin 1 (IL1) antagonist (anakinra), an inhibitor of T cell co-stimulation (abatacept), and a selective depleter of B cells (rituximab). As research has progressed, additional promising targets have been identified. Results from RA studies using several new agents have been reported in the last year. Some of these compounds are similar to agents already available, with additional TNF inhibitors (certolizumab pegol, golimumab) and agents targeting CD20 (ocrelizumab, ofatumumab, TRU-015) in development. Other agents are directed toward new cytokine targets, including IL-6 (tocilizumab), and lymphotoxin pathways (briobacept), as well as other B-cell targets, to include BLyS and APRIL (belimumab, atacicept). Additional small molecule therapies have been studied that are directed against intracellular kinases, including JAK-3 and Syk. This article provides a brief update of data from selected clinical trials in RA, highlighting efficacy, and mechanism-based safety concerns. | 18,937,634 |
Update on the management of hyperuricemia and gout. | Gout is the most common inflammatory arthritis in the United States, with more than three million sufferers. Management of gout has changed relatively little in the past 50 years, despite the fact that many gout patients have contraindications to one or more currently available gout therapies. However, recent insights into gout pathophysiology suggest that time is ripe for a change. This article reviews recent updates in the management of gout, including new insights into dietary management that may permit better control of hyuperuricemia. Also reviewed are the biological and clinical data behind newly-developed drugs for gout that are likely to receive serious consideration for FDA approval, and clinical use, in the foreseeable future. | 18,937,638 |
Osteoarthritis: a tale of three tissues. | While research in osteoarthritis has focused on the events that lead to the destruction of articular cartilage, recent evidence suggests that two other components of the joints-bone and synovium-also play key roles in pathogenesis. All three tissues undergo alterations in concert at the structural levels in response to mechanical stress and joint malalignment. Advanced imaging studies such as MRI support this interdependence, revealing the classical changes of joint space narrowing and cartilage degeneration as well as the more recently appreciated bone marrow lesions and synovitis that may correlate with clinical symptoms. Molecular evidence also points to a coordinated release of cytokines and other inflammatory mediators from each of the three tissues together in progression of disease, although we are still in search of biochemical signatures that will predict the subset of patients who progress more quickly-and who will provide key clues to successful molecular targets in future therapies. At this time we lack definitive evidence pointing to which, if any, of the three tissues should serve as the main target for disease modification or structure protection, although most efforts have focused on cartilage. Thus current therapies focus on controlling symptoms, while research efforts search for reliable imaging and molecular biomarkers to help guide future trials of potential disease-modifying agents. | 18,937,640 |
Advanced imaging in osteoarthritis. | Historically plain radiography has been the primary investigative tool by which structure in osteoarthritis is measured. Magnetic resonance imaging (MRI) is widely used in medical diagnosis for its various advantageous features, such as high-resolution capability, the ability to produce an arbitrary anatomic cross-sectional image, and wide range of available tissue contrast. Its ability to image features such as the subchondral bone, cartilage and soft tissue structures means that its application in knee osteoarthritis (OA) raises hope of improving our understanding of structural associations of pain and function in OA joints, previously based on conventional radiography. Additionally, MRI has the potential for assessing the effect of risk factors for epidemiologic investigation and the effectiveness of therapeutic interventions in OA clinical trials. | 18,937,641 |
Tissue estimation of protein gene product 9.5 (PGP 9.5) expression and apoptosis in vitiligo. | Vitiligo is probably the end result of different interacting processes. To determine the possible roles of neural and apoptotic mechanisms in the pathogenesis of vitiligo. Fifty-six biopsies from 28 patients with generalized vitiligo (28 from depigmented lesional areas and 28 from clinically nondepigmented skin at the periphery of the same areas) were examined; the panaxonal marker neuropeptide protein gene product 9.5 (PGP 9.5) and apoptosis were investigated using immunohistochemistry. Statistically significant differences were detected in the numbers of PGP 9.5-positive nerve fibers/axons in the papillary dermis between the center and periphery of the lesions (i.e. increased at the center in comparison with the periphery). A statistically significant inverse association was found between PGP 9.5 immunostaining in the dermis at the lesion center and the duration of the disease. When apoptosis and PGP 9.5 expression were compared, there was an identical distribution of PGP 9.5-positive nerve fibers/axons and apoptotic cells in the epidermis (i.e. basal in the lesion center; diffuse at the lesion periphery). There is a possible connection between the neural and apoptotic pathogenetic theories of vitiligo. | 18,937,653 |
Subsets and Splits
No community queries yet
The top public SQL queries from the community will appear here once available.