title stringlengths 0 1.13k | abstract stringlengths 1 15.7k | PMID int64 22 36.5M |
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Effect of endothelium-specific insulin resistance on endothelial function in vivo. | Insulin resistance is an independent risk factor for the development of cardiovascular atherosclerosis. A key step in the development of atherosclerosis is endothelial dysfunction, manifest by a reduction in bioactivity of nitric oxide (NO). Insulin resistance is associated with endothelial dysfunction; however, the mechanistic relationship between these abnormalities and the role of impaired endothelial insulin signaling versus global insulin resistance remains unclear. To examine the effects of insulin resistance specific to the endothelium, we generated a transgenic mouse with endothelium-targeted overexpression of a dominant-negative mutant human insulin receptor (ESMIRO). This receptor has a mutation (Ala-Thr(1134)) in its tyrosine kinase domain that disrupts insulin signaling. Humans with the Thr(1134) mutation are insulin resistant. We performed metabolic and vascular characterization of this model. ESMIRO mice had preserved glucose homeostasis and were normotensive. They had significant endothelial dysfunction as evidenced by blunted aortic vasorelaxant responses to acetylcholine (ACh) and calcium ionophore. Furthermore, the vascular action of insulin was lost in ESMIRO mice, and insulin-induced endothelial NO synthase (eNOS) phosphorylation was blunted. Despite this phenotype, ESMIRO mice demonstrate similar levels of eNOS mRNA and protein expression to wild type. ACh-induced relaxation was normalized by the superoxide dismutase mimetic, Mn(III)tetrakis(1-methyl-4-pyridyl) porphyrin pentachloride. Endothelial cells of ESMIRO mice showed increased superoxide generation and increased mRNA expression of the NADPH oxidase isoforms Nox2 and Nox4. Selective endothelial insulin resistance is sufficient to induce a reduction in NO bioavailability and endothelial dysfunction that is secondary to increased generation of reactive oxygen species. This arises independent of a significant metabolic phenotype. | 18,835,939 |
First experience with real-time three-dimensional transoesophageal echocardiography-guided transseptal in patients undergoing atrial fibrillation ablation. | Transseptal (TS) puncture during atrial fibrillation (AF) ablation is a relatively safe procedure in experienced hands. However, major and minor complications cannot be completely ruled out. Real-time three-dimensional transeosophageal echocardiography (RT 3D TEE) is a novel imaging technology that permits direct visualization of the fossa ovalis in a 3D perspective, thereby sensibly lowering the likelihood of potential adverse effects during TS. In our study, we describe the technique and assess the feasibility, advantages, and safety of this novel imaging method in guiding TS puncture in a series of consecutive patients undergoing AF ablation. We performed TS puncture guided by RT 3D TEE under general anaesthesia in 24 consecutive patients (16 male, 55.4 +/- 8.1 years) undergoing ablation for drug refractory AF. The fossa ovalis could clearly be seen and easily be distinguished from surrounding anatomical structures in all 24 patients. All punctures required a single attempt to access left atrium. Mean orientation of the needle hub when puncturing was 4.30 o'clock (ranging from 3 o'clock to 6.30 o'clock), and mean distances from the needle tip to the aortic and to the posterior wall were, respectively, 13.5 +/- 7 and 35 +/- 7.3 mm. Total fluoroscopic time was 120.6 +/- 34 s. No major or minor complications were experienced. Real-time three-dimensional transeosophageal is a very useful tool in guiding TS puncture in patients undergoing AF ablation with the invaluable advantage of the 3D direct visualization of the fossa ovalis. This permits fast and safe transatrial access with a single puncture attempt. | 18,835,940 |
International tables of glycemic index and glycemic load values: 2008. | To systematically tabulate published and unpublished sources of reliable glycemic index (GI) values. A literature search identified 205 articles published between 1981 and 2007. Unpublished data were also included where the data quality could be verified. The data were separated into two lists: the first representing more precise data derived from testing healthy subjects and the second primarily from individuals with impaired glucose metabolism. The tables, which are available in the online-only appendix, list the GI of over 2,480 individual food items. Dairy products, legumes, and fruits were found to have a low GI. Breads, breakfast cereals, and rice, including whole grain, were available in both high and low GI versions. The correlation coefficient for 20 staple foods tested in both healthy and diabetic subjects was r = 0.94 (P < 0.001). These tables improve the quality and quantity of GI data available for research and clinical practice. | 18,835,944 |
Metabolic syndrome predicts new onset of chronic kidney disease in 5,829 patients with type 2 diabetes: a 5-year prospective analysis of the Hong Kong Diabetes Registry. | Type 2 diabetes is the leading cause of end-stage renal disease worldwide. Aside from hyperglycemia and hypertension, other metabolic factors may determine renal outcome. We examined risk associations of metabolic syndrome with new onset of chronic kidney disease (CKD) in 5,829 Chinese patients with type 2 diabetes enrolled between 1995 and 2005. Metabolic syndrome was defined by National Cholesterol Education Program Adult Treatment Panel III criteria with the Asian definition of obesity. Estimated glomerular filtration rate (eGFR) was calculated using the abbreviated Modification of Diet in Renal Disease formula modified for the Chinese population. New onset of CKD was defined as eGFR <60 ml/min per 1.73 m(2) at the time of censor. Subjects with CKD at baseline were excluded from the analysis. After a median follow-up duration of 4.6 years (interquartile range: 1.9-7.3 years), 741 patients developed CKD. The multivariable-adjusted hazard ratio (HR) of CKD was 1.31 (95% CI 1.12-1.54, P = 0.001) for subjects with metabolic syndrome compared with those without metabolic syndrome. Relative to subjects with no other components of metabolic syndrome except for diabetes, those with two, three, four, and five metabolic syndrome components had HRs of an increased risk of CKD of 1.15 (0.83-1.60, P = 0.407) 1.32 (0.94-1.86, P = 0.112), 1.64 (1.17-2.32, P = 0.004), and 2.34 (1.54-3.54, P < 0.001), respectively. The metabolic syndrome traits of central obesity, hypertriglyceridemia, hypertension, and low BMI were independent predictors for CKD. The presence of metabolic syndrome independently predicts the development of CKD in subjects with type 2 diabetes. | 18,835,954 |
Prediabetic and diabetic in vivo modification of circulating low-density lipoprotein attenuates its stimulatory effect on adrenal aldosterone and cortisol secretion. | Modification of low-density lipoprotein (LDL) and abnormal aldosterone and cortisol metabolism have been implicated in the pathogenesis of type 2 diabetes (DM2) and diabetic vascular disease. Since LDL serves as a major cholesterol source for adrenal steroidogenesis, we investigated whether LDL modification in prediabetic and diabetic subjects influences adrenocortical aldosterone and cortisol release. LDL was isolated from 30 subjects with normal glucose tolerance (NGT-LDL), 30 subjects with impaired glucose tolerance (IGT-LDL), and 26 patients with DM2 (DM2-LDL). Oxidation and glycoxidation characteristics of LDL apolipoprotein B100 of each individual was assessed by gas chromatography-mass spectrometry analysis. Human adrenocortical cells (NCI-H295R) were incubated for 24 h with 100 microg/ml LDL and after removal of supernatants stimulated for a further 24 h with angiotensin II (AngII). In supernatants, aldosterone and cortisol secretion was measured. IGT-LDL and DM2-LDL were substantially more modified than NGT-LDL. Each of the five measured oxidation/glycoxidation markers was significantly positively associated with glycemic control, measured as HbA(1c). LDL from all subjects stimulated both the basal and AngII-induced aldosterone and cortisol release from adrenocortical cells. However, hormone secretion was significantly inversely related to the degree of LDL oxidation/glycoxidation. We conclude that LDL modifications in IGT and DM2 subjects may have significant clinical benefits by counteracting prediabetic and diabetic overactivity of the renin-angiotensin-aldosterone system and enhanced cortisol generation. | 18,835,979 |
A unique combination of genetic systems for the synthesis of trehalose in Rubrobacter xylanophilus: properties of a rare actinobacterial TreT. | Trehalose is the primary organic solute in Rubrobacter xylanophilus under all conditions tested, including those for optimal growth. We detected genes of four different pathways for trehalose synthesis in the genome of this organism, namely, the trehalose-6-phosphate synthase (Tps)/trehalose-6-phosphate phosphatase (Tpp), TreS, TreY/TreZ, and TreT pathways. Moreover, R. xylanophilus is the only known member of the phylum Actinobacteria to harbor TreT. The Tps sequence is typically bacterial, but the Tpp sequence is closely related to eukaryotic counterparts. Both the Tps/Tpp and the TreT pathways were active in vivo, while the TreS and the TreY/TreZ pathways were not active under the growth conditions tested and appear not to contribute to the levels of trehalose observed. The genes from the active pathways were functionally expressed in Escherichia coli, and Tps was found to be highly specific for GDP-glucose, a rare feature among these enzymes. The trehalose-6-phosphate formed was specifically dephosphorylated to trehalose by Tpp. The recombinant TreT synthesized trehalose from different nucleoside diphosphate-glucose donors and glucose, but the activity in R. xylanophilus cell extracts was specific for ADP-glucose. The TreT could also catalyze trehalose hydrolysis in the presence of ADP, but with a very high K(m). Here, we functionally characterize two systems for the synthesis of trehalose in R. xylanophilus, a representative of an ancient lineage of the actinobacteria, and discuss a possible scenario for the exceptional occurrence of treT in this extremophilic bacterium. | 18,835,983 |
Genetic analysis of the Enterococcus vancomycin resistance conjugative plasmid pHTbeta: identification of the region involved in cell aggregation and traB, a key regulator gene for plasmid transfer and cell aggregation. | The Enterococcus plasmid pHTbeta (63.7 kbp) is a pheromone-independent, highly conjugative pMG1-like plasmid that carries a Tn1546-like transposon encoding vancomycin resistance. The transfer-related regions (Tra I, Tra II, and Tra III) containing oriT and a putative nickase gene (traI) have previously been identified in pHTbeta, and in this study, we found that the plasmid conferred the ability to self-aggregate on the host strain Enterococcus faecalis FA2-2. A region where mutation resulted in the impairment of aggregation was identified and mapped to a point upstream of the transfer-related Tra I region. This region consisted of an approximately 6-kbp segment that contained the five open reading frames (ORFs) ORF9 to ORF13. These ORFs are considered to encode the aggregation function, although the precise mode of action of each ORF has not yet been elucidated. An in-frame deletion mutant of ORF10 resulted in reduced aggregation and decreased transfer frequency in broth mating. Transcription analysis of the aggregation region showed that the five ORFs from ORF9 to ORF13 form an operon structure, and a long transcript that started from a promoter region located upstream of ORF9 was identified. Tra II spans a 1.7-kbp region containing ORF56 and ORF57. Tn917-lac insertions into or an in-frame deletion mutant of ORF56 (187 amino acids) resulted in impaired transfer and aggregation. The cloned ORF56 complemented these functions in trans. The transcription levels of ORF10 and ORF13 were reduced in the in-frame mutants of ORF56, but this reduction was complemented by a cloned ORF56 in trans. The results indicated that ORF56 positively regulated the aggregation and plasmid transfer in the host strain, and ORF56 was designated traB. | 18,835,991 |
Evidence for growth of enterococci in municipal oxidation ponds, obtained using antibiotic resistance analysis. | The Christchurch wastewater treatment plant uses a series of six oxidation ponds to reduce the bacterial load of treated effluent before it is discharged into the local estuary. To ensure that this discharge does not adversely affect water quality in the receiving environment, local regulations specify maximum levels in the discharge for a number of parameters, including enterococci. Between 2001 and 2006, regulations required fewer than 300 enterococci per 100 ml in summer. During this period, the discharge intermittently exceeded this limit, with unexplained levels of enterococci of up to 180,000/100 ml. Characterization of these enterococci by antibiotic resistance analysis showed that enterococci sampled over 4 months had almost identical resistance profiles. In contrast, enterococci from raw sewage and wildfowl from around the oxidation ponds had a diverse range of antibiotic resistance profiles that could be distinguished from each other and also from those of enterococci from the discharge. The hypothesis of a clonal nature of the enterococci in the discharge was supported by molecular genotype analysis, suggesting that these bacteria may have replicated in the pond environment rather than being reflective of breakthrough in the sewage treatment process or the result of recent wildfowl inputs to the ponds. This study highlights the usefulness of antibiotic resistance analysis in identifying this phenomenon and is the first report of apparent replication of a specific type of enterococci in an oxidation pond environment. | 18,836,001 |
Quantification and genotyping of torque teno virus at a wastewater treatment plant in Japan. | Torque teno virus (TTV) DNA was quantitatively detected in influent and effluent samples collected from a wastewater treatment plant in Japan, with the highest concentration being 4.8 x 10(4) copies/liter. Genogroup-specific nested PCR demonstrated that TTV of genogroup 3 was the most abundant in wastewater among the five genogroups tested. | 18,836,012 |
HtrA is essential for efficient secretion of recombinant proteins by Lactococcus lactis. | HtrA is a unique protease on the extracellular surface of Lactococcus lactis. It is known to take part in the proteolysis of many secreted recombinant proteins, and the mutation of htrA can lead to the complete stabilization of recombinant proteins. In this work, we have shown that htrA mutation also leads to significant reduction of the efficiency of recombinant-protein secretion. We also show that the level of HtrA can be lowered by the suppression of the acid tolerance response (ATR) in L. lactis. Instead of using an L. lactis htrA mutant, the reduction of the HtrA level in wild-type recombinant cultures of L. lactis by ATR suppression may serve as a better strategy for the production of secreted recombinant proteins. | 18,836,019 |
Haplotype sorting using human fosmid clone end-sequence pairs. | An important goal of human genetics and genomics is to understand the complete spectrum of genetic variation across a specific human haplotype. By combining information from a dense SNP map with fosmid end-sequence pairs (ESPs) aligned to the human genome reference sequence, we have developed a simple method to resolve human haplotypes using a previously developed clone resource. By partitioning ESPs into either haplotype, we have generated a haplotype-specific clone map for eight diploid genomes (four Yoruba African and four non-African samples). On average, 59% of each haploid genome is covered by haplotype-assigned clones with an N50 length of 110 kbp. By comparing this clone-based haplotype map against HapMap phased data sets, we estimate an error rate of 0.71% when trio information is available and 6.6% in its absence. We present these data in the form of an interactive browser that allows clones corresponding to specific haplotypes to be recovered and sequenced within these eight human genomes. As an example, we sequenced 165 fosmid clone inserts to generate 6.8 Mbp of sequenced haplotypes, and demonstrate its utility in uncovering phase-switching errors and for the discovery of novel SNPs especially in Asian and African samples. We discuss the potential application of this resource in understanding the pattern of genetic variation in complex regions of the genome that may not be adequately resolved by next-generation sequencing technology or SNP haplotype imputation. | 18,836,033 |
Disability and risk of non-fatal residential injuries among adults. | Many unintentional injuries occur in the home, but little research has considered the specific vulnerability of people with disabilities. Cross-sectional study examining nationally representative data from the 2004-2006 National Health Interview Surveys. Adults aged 18 and older who reported having an unintentional, non-motor vehicle-related injury in the home (n = 2189) or outside the home (n = 2072) and those who reported no injuries (n = 81,919) 3 months before their interview. Non-fatal, unintentional, non-motor vehicle-related injuries. Among respondents experiencing a residential injury, 21.2% reported one type of disability, 11.2% reported two disabilities, and 9.1% reported three or more disabilities. As the number of disabilities increased, the odds of reporting a residential injury increased. Adults with three or more disabilities had three times the odds of reporting a residential injury (adjusted odds ratio = 3.2, 95% CI 2.7 to 3.9), compared with adults reporting no injury. The risk of injury in the residential environment among adults with disabilities increases with increasing numbers of disabilities. Attention to home safety issues for residents with disabilities is needed. | 18,836,046 |
Syntaxin 5 regulates the endoplasmic reticulum channel-release properties of polycystin-2. | Polycystin-2 (PC2), the gene product of one of two genes mutated in dominant polycystic kidney disease, is a member of the transient receptor potential cation channel family and can function as intracellular calcium (Ca(2+)) release channel. We performed a yeast two-hybrid screen by using the NH(2) terminus of PC2 and identified syntaxin-5 (Stx5) as a putative interacting partner. Coimmunoprecipitation studies in cell lines and kidney tissues confirmed interaction of PC2 with Stx5 in vivo. In vitro binding assays showed that the interaction between Stx5 and PC2 is direct and defined the respective interaction domains as the t-SNARE region of Stx5 and amino acids 5 to 72 of PC2. Single channel studies showed that interaction with Stx5 specifically reduces PC2 channel activity. Epithelial cells overexpressing mutant PC2 that does not bind Stx5 had increased baseline cytosolic Ca(2+) levels, decreased endoplasmic reticulum (ER) Ca(2+) stores, and reduced Ca(2+) release from ER stores in response to vasopressin stimulation. Cells lacking PC2 altogether had reduced cytosolic Ca(2+) levels. Our data suggest that PC2 in the ER plays a role in cellular Ca(2+) homeostasis and that Stx5 functions to inactivate PC2 and prevent leaking of Ca(2+) from ER stores. Modulation of the PC2/Stx5 interaction may be a useful target for impacting dysregulated intracellular Ca(2+) signaling associated with polycystic kidney disease. | 18,836,075 |
Rituximab monotherapy for primary cutaneous B-cell lymphoma: response and follow-up in 16 patients. | We have carried out a retrospective analysis to evaluate the therapeutic value of the anti-CD20 antibody rituximab in 16 consecutive patients with primary cutaneous CD20+ B-cell lymphomas. Sixteen patients (4 females, 12 males) with a median age of 54 years received systemic therapy with rituximab 375 mg/m(2) once weekly for four or six consecutive weeks. Eleven patients had primary cutaneous follicle center cell lymphoma and five patients had a primary cutaneous marginal zone B-cell lymphoma. Of the 16 patients with PCBCL, 14 patients (87.5%) achieved complete remission (CR). In two patients, partial remission was obtained and additional focal radiotherapy was applied, which resulted in final CR. Five to 14 (35%) patients with CR relapsed, in an interval between 6 and 37 months. There were no severe side-effects. On the basis of our results, single-agent treatment with i.v. rituximab appears to be feasible and safe and results in a high rate of durable remissions. Judging from our data, it appears to be an attractive treatment option and should be directly compared with local radiotherapy. | 18,836,086 |
A multifactorial strategy of pain management is associated with less pain in scheduled vaccination of children. A study realized by family practitioners in 239 children aged 4-12 years old. | The multiplicity of vaccine injections during childhood leads to iterative painful and stressful experiences which may lead in turn to anticipated pain and then possibly to a true needle phobia. We aimed at evaluating a multifactorial strategy of pain management combining pharmacological and non-pharmacological approaches during vaccination, as compared to usual care, in 4- to 12-year-old children. In all, 239 children were enrolled by 25 family practitioners in an open-label study. After a pseudo-randomization, usual pain management (n = 132) was compared to a multifactorial strategy (n = 107) associating preliminary application of an anesthesic patch, preferential use of specified vaccines, child education by the parents and the doctor, parental accompaniment and child distraction with soap bubbles during the procedure. The primary outcome (i.e. child pain) was assessed with a self-report scale named visual analog scale (VAS) of pain. A significant decrease in pain was obtained using the multifactorial strategy, as assessed by self-reported VAS (P < 0.0001). This was confirmed by another self-report scale (the facial pain scale revised: P = 0.005), as well as with hetero-evaluations by GPs and parents [Children's Hospital of Eastern Ontario Pain Scale: P = 0.0007; GPs VAS (P < 0.0001), parents VAS (P < 0.0001)], which were secondary outcome criteria. This multifactorial method significantly decreases vaccination pain in 4- to 12-year-old children. This strategy could make vaccines more acceptable to children and may improve child-doctor relationships and contribute to a decrease in child fear about health care. | 18,836,092 |
UV-inducible base excision repair of oxidative damaged DNA in human cells. | Methylene blue (MB) acts as a photosensitizer and after excitation by visible light (VL) produces reactive oxygen species that result in oxidatively damaged DNA. (MB + VL) produces predominantly 8-hydroxyguanine as well as other single base modifications in DNA that are repaired by base excision repair (BER). We have used a recombinant non-replicating human adenovirus, Ad5HCMVlacZ, which expresses the beta-galactosidase (beta-gal) reporter gene, to examine the role of the p53 tumor suppressor in constitutive and inducible BER of MB + VL-damaged DNA in human cells. Host cell reactivation (HCR) of beta-gal activity for MB + VL-treated Ad5HCMVlacZ was examined in normal human fibroblasts and several transformed and tumor cell lines with compromised p53 function using both non-treated cells and cells pretreated with ultraviolet light of 200-280 nm wavelength (UVC). Constitutive HCR of the MB + VL-treated reporter gene in untreated cells did not correlate with wild-type p53 expression levels, suggesting that factors other than p53 expression levels can influence constitutive BER of the reporter gene. UVC pre-treatment of the normal fibroblast strains resulted in an enhanced HCR of the MB + VL-treated reporter gene and a concomitant increase in the expression of p53, suggesting that p53 may be involved in UV-inducible BER in normal human fibroblasts. In contrast, p53 expression did not correlate with HCR values for the p53-compromised cells in UVC-pre-treated cells. In particular, the SKOV-3, LFS 087 and NF-E6 cells showed no up-regulation of p53 expression following UVC, and yet these cells showed significant enhancement of HCR following UVC pre-treatment. These results indicate that BER of MB + VL-damaged DNA is inducible in human cells by pre-UVC treatment and that the enhancement in BER may result from both p53-dependent and p53-independent mechanisms. | 18,836,099 |
A 'Regularly Irregular' tachycardia: what is the diagnosis? | We report the case of a 46-year-old female presented to the emergency room with sustained palpitations. Her ECG showed a narrow QRS regularly irregular tachycardia. This tachycardia was immediately terminated by a single dose of adenosine, and sinus rhythm was restored. Diagnosis of atrial tachycardia, orthodromic reciprocating tachycardia, and atrial nodal reentrant tachycardia (AVNRT) are discussed. An electrophysiological study was performed for further evaluation, and our final hypothesis was AVNRT with triple nodal pathways. A single application of radiofrequency energy in the posterior septum near the coronary sinus ostium effectively eliminated the tachycardia. | 18,836,153 |
Regulation of biomechanical signals by NF-kappaB transcription factors in chondrocytes. | Physical therapies and exercise are beneficial not only for physiological recovery in inflamed or injured joints, but also for promoting a homeostatic equilibrium in healthy joints. Human joints provide the pivot points and physiological hinges essential for ambulation and movement to the body, and it is this mobility that in return promotes the health of the joints. But how mobilization regulates the joint microenvironment at the molecular level has remained enigmatic for many years. Recent advances in joint biomechanics and molecular approaches have facilitated an enriched understanding of how joints operate. Consequently, the mechanisms active during joint inflammation that lead to arthritic conditions, both in vivo in animal models, and in vitro at cell and tissue levels, have become increasingly detailed and defined. These efforts have produced mounting evidences supporting the premise that biomechanical signals play a fundamental role in both the etiopathogenesis of arthritic diseases and in the physiological restoration of joints. This report aims to summarize current peer-reviewed literature and available experimental data to explain how the signals generated by mechanical forces/joint mobilization generate beneficial effects on inflamed articular cartilage, and to propose the basis for using appropriate physical therapies for the optimal benefit to the patient suffering from joint associated injuries. | 18,836,228 |
Mechanical regulation of proteoglycan synthesis in normal and osteoarthritic human articular chondrocytes--roles for alpha5 and alphaVbeta5 integrins. | The importance of biomechanical forces in regulating normal chondrocyte metabolism is well established and the mechanisms whereby mechanical forces are transduced into biochemical responses by chondrocytes are beginning to be understood. Previous studies have indicated that cyclical mechanical stimulation induces increased aggrecan gene expression in normal but not osteoarthritic chondrocytes in monolayer. It remains unclear, however, whether these effects on gene expression are associated with changes in proteoglycan production and whether any changes in proteoglycan expression is dependent on integrins or integrin associated proteins. Normal and osteoarthritic articular chondrocytes in monolayer were exposed to 0.33 Hz mechanical stimulation for 20 min in the absence or presence of function modifying anti-integrin antibodies. Following stimulation GAG and proteoglycan (PG) synthesis was assessed by DMMB assay and western blotting. Mechanical stimulation of normal chondrocytes resulted in increased GAG synthesis that was blocked by the presence of antibodies to alpha5 and alphaVbeta5 integrins and CD47. Electrophoretic patterns of PGs released from normal chondrocytes following mechanical stimulation showed an increase in newly-synthesized aggrecan that was not fragmented or degraded. Chondrocytes from osteoarthritic cartilage showed lower levels of GAG production when compared to normal chondrocytes and synthesis was not influenced by mechanical stimulation. These studies show that chondrocytes derived from normal and OA cartilage have different matrix production responses to mechanical stimulation and suggest previously unrecognised roles for alphaVbeta5 integrin in regulation of chondrocyte responses to biomechanical stimulation. | 18,836,230 |
Why is obesity associated with osteoarthritis? Insights from mouse models of obesity. | Obesity is one of the most significant, and potentially most preventable, risk factors for the development of osteoarthritis, and numerous studies have shown a strong association between body mass index and osteoarthritis of the hip, knee, foot and hand. However, the mechanism(s) by which obesity contributes to the onset and progression of osteoarthritis are not fully understood. The strong association between body mass index, altered limb alignment, and osteoarthritis of the knee--and the protective effects of weight loss--support the classic hypothesis that the effects of obesity on the joint are due to increased biomechanical loading and associated alterations in gait. However, obesity is now considered to be a low-grade systemic inflammatory disease, and recent studies suggest that metabolic factors associated with obesity alter systemic levels of pro-inflammatory cytokines that are also associated with osteoarthritis. Thus, the ultimate influence of obesity on osteoarthritis may involve a complex interaction of genetic, metabolic, and biomechanical factors. In this respect, mouse models of obesity can provide excellent systems in which to examine causal relationships among these factors. In recent years, there have been surprisingly few reports examining the effects of obesity on osteoarthritis using mouse models. In this paper, we review studies on mice and other animal models that provide both direct and indirect evidence on the role of obesity and altered diet in the development of osteoarthritis. We also examine the use of different body mass indices for characterizing "obesity" in mice by comparing these indices to typical adiposity levels observed in obese humans. Taken together, evidence from studies using mice suggest that a complex interaction of environmental and genetic factors associated with obesity contribute to the incidence and severity of osteoarthritis. The ability to control these factors, together with the development of methods to conduct more intricate measures of local biomechanical factors, make mouse models an excellent system to study obesity and osteoarthritis. | 18,836,239 |
Modulatory effect of rhein on IL-1alpha-induced responses in human chondrocytes: a comparative study between antibody microarrays and specific ELISAs. | The present work aimed to take advantage of the screening capacity of protein arrays to search for additional targets of rhein in interleukin (IL)-1-stimulated chondrocytes. Primary cultures of chondrocytes from osteoarthritic (OA) patients were stimulated for 24 and 48 h with 1 ng/ml of IL-1alpha, in the presence or absence of 10(-5) M of rhein. Culture supernatants were analyzed with arrays membranes consisting of 120 antibodies directed against cytokines, chemokines, and angiogenic or growth factors and were controlled for 8 proteins by specific immuno-enzymatic assays (ELISA). Protein arrays showed that several CC or CXC chemokines, the growth factor GM-CSF, the cytokines IL-6, IL-7 and IL-10 (but unexpectedly not IL-1beta or TNFalpha) and the adhesion molecule ICAM-1 were induced maximally by IL-1alpha. In IL-1-stimulated chondrocytes, rhein reduced slightly the production of MCP-1 and increased those of IL-1Ra, of the cytokine receptors sgp130, IL-6R, sTNFR I and R II, but also of some chemokines or ICAM-1. Specific ELISAs confirmed the effect of rhein on MCP-1, IL-1Ra, sgp130, IL-6R and sTNFR II but was discrepant for GROalpha and were always more sensitive than protein arrays to detect IL-1 effects such as IL-1Ra and TNFalpha release. The present data show that rhein modulated some IL-1-induced responses contributing possibly to its chondroprotective (IL-1Ra, MCP-1) or cytokine modifying (sTNFR II, sgp130) properties, but that protein arrays were poorly sensitive to check for IL-1- and/or rhein-induced changes. | 18,836,244 |
Chondroitin sulphate-mediated fusion of brain neural folds in rat embryos. | Previous studies have demonstrated that during neural fold fusion in different species, an apical extracellular material rich in glycoconjugates is involved. However, the composition and the biological role of this material remain undetermined. In this paper, we show that this extracellular matrix in rat increases notably prior to contact between the neural folds, suggesting the dynamic behaviour of the secretory process. Immunostaining has allowed us to demonstrate that this extracellular matrix contains chondroitin sulphate proteoglycan (CSPG), with a spatio-temporal distribution pattern, suggesting a direct relationship with the process of adhesion. The degree of CSPG involvement in cephalic neural fold fusion in rat embryos was determined by treatment with specific glycosidases.In vitro rat embryo culture and microinjection techniques were employed to carry out selective digestion, with chondroitinase AC, of the CSPG on the apical surface of the neural folds; this was done immediately prior to the bonding of the cephalic neural folds. In all the treated embryos, cephalic defects of neural fold fusion could be detected. These results show that CSPG plays an important role in the fusion of the cephalic neural folds in rat embryos, which implies that this proteoglycan could be involved in cellular recognition and adhesion. | 18,836,253 |
Functional tradeoffs in axonal scaling: implications for brain function. | Like electrical wires, axons carry signals from place to place. However, unlike wires, because of the electrochemical mechanisms for generating and propagating action potentials, the performance of an axon is strongly linked to the costs of its construction and operation. As a consequence, the architecture of brain wiring is biophysically constrained to trade off speed and energetic efficiency against volume. Because the biophysics of axonal conduction is well studied, this tradeoff is amenable to quantitative analysis. In this framework, an examination of axon tract composition can yield insights into neural circuit function in regard to energetics, processing speed, spike timing precision, and average rates of neural activity. | 18,836,261 |
Oxaliplatin/5-fluorouracil/leucovorin (FOLFOX4) regimen as an adjuvant chemotherapy in the treatment of advanced jejunal adenocarcinoma: a report of 2 cases. | To present our clinical experience of 5-fluorouracil/leucovorin/oxaliplatin (FOLFOX4) regimen administered as an adjuvant chemotherapy to 2 patients with advanced jejunal adenocarcinoma. A 55-year-old woman presented with recurrent upper abdominal pain, nausea and vomiting. A small bowel series as well as the abdominal computed tomography scan revealed an irregular narrowing lesion at the proximal jejunum. The patient then underwent an exploratory laparotomy and the jejunal adenocarcinoma with localized peritoneal metastasis was found (R0 resection, T3N1M1, stage IV). Chemotherapy with FOLFOX4 regimen of 12 cycles was initiated after the curative resection. No adverse event was observed during the period of chemotherapy. She has been well without evidence of recurrence for over 20 months postoperatively. The second case was a 77-year-old female presenting with mechanical ileus. Surgical exploration revealed a proximal jejunal adenocarcinoma with regional lymph node involvement (R0 resection, T3N1M0, stage III). She also received the FOLFOX4 chemotherapy of 12 cycles with an uneventful course. No obvious toxicity developed except for temporary grade I peripheral neuropathy and skin eruption. This patient has survived well and has been free of this disease for over 12 months since the operation. This report showed that adjuvant chemotherapy with FOLFOX4 regimen seems effective and well tolerated in these 2 patients with advanced jejunal adenocarcinoma. Further investigation of a large number of patients with long-term follow-up is needed to confirm these findings. | 18,836,281 |
PTEN signaling pathways in glioblastoma. | Malignant gliomas are the most common primary brain tumor in adults, but the prognosis for patients with these tumors remains poor despite advances in diagnosis and standard therapies such as surgery, radiation therapy, and chemotherapy. Progress in the treatment of gliomas now depends to a great extent on an increased understanding of the biology of these tumors. Recent insights into the biology of gliomas include the finding that tyrosine kinase receptors and signal transduction pathways play a role in tumor initiation and maintenance. Deregulation of phosphatidylinositol 3-kinase (PI3K) signaling pathways resulting from genetic alterations in the PTEN tumor suppressor gene on 10q23 at the level of LOH, mutation and methylation have been identified in at least 60% of glioblastoma. Loss of PTEN function by mutation or LOH correlates with poor survival in anaplastic astrocytoma and glioblastoma, suggesting that PTEN plays a role in patient outcome. Interestingly, amplification of Epidermal growth factor receptor (EGFR) in the background of heterozygous PTEN knockout mice develop invasive glioma very similar to human glioblastoma, demonstrating the importance of PTEN in glioma progression and providing a model system to evaluate the efficacy of targeting PTEN in glioblastoma. | 18,836,294 |
Immunotherapy of metastatic renal cell carcinoma. | In 1992, high-dose bolus interleukin (IL)-2 was granted Food and Drug Administration approval based on its ability to produce durable complete responses in a small number of patients with metastatic renal cell carcinoma (RCC). However, the substantial toxicity and limited efficacy that is associated with IL-2 has narrowed its application to highly selected patients treated at specialized centers. In recent years, the relative merits of low- and high-dose cytokine regimens have been clarified by the results of 4 randomized trials. Taken together, these studies suggest that high-dose IV bolus IL-2 is superior in terms of response rate and possibly response quality to regimens that involve either low-dose IL-2 and interferon-alpha, intermediate- or low-dose IL-2 alone, or low-dose interferon-alpha alone. More significantly, investigations associated with these trials suggest that the potential exists for identifying predictors of response (or resistance) and limiting IL-2 therapy to those most likely to benefit. The Cytokine Working Group has launched the high-dose IL-2 "select" trial to determine, in a prospective fashion, if the predictive model proposed by Atkins et al. can identify a group of patients with advanced RCC who are significantly more likely to respond to high dose IL-2-based therapy ("good" risk) than a historical, unselected patient population. For patients unlikely to benefit from IL-2, are unable to receive it or who progress after IL-2, the emergence of molecularly targeted therapies offers hope for improved clinical outcome. As the list of effective therapies for metastatic RCC grows, improvements in patient selection and more "targeted" approaches will be required to optimize the benefits of cytokine therapy in metastatic RCC. | 18,836,337 |
Minocycline as adjunctive therapy for schizophrenia: an open-label study. | Minocycline is a caspase inhibitor, decreases inducible nitric oxide synthase, and has been shown to delay disease in a mouse model of neuropsychiatric disorders. Recently, we reported the antipsychotic effects of minocycline in patients with schizophrenia. In a pilot investigation, we administered minocycline (150 mg/d) for 4 weeks as an open-label adjunct to antipsychotic medication to 22 patients with schizophrenia. The Positive and Negative Syndrome Scale for schizophrenia showed statistically significant and robust clinical improvements with minocycline treatment, which were maintained at follow-up evaluation 4 weeks after the end of minocycline treatment. There were no adverse events. These results suggest that minocycline may be a safe and effective adjunct to antipsychotic medications, and that augmentation with minocycline may prove to be a viable strategy for "boosting" antipsychotic efficacy and for treating schizophrenia. | 18,836,347 |
Minimally invasive multilevel percutaneous correction and fusion for adult lumbar degenerative scoliosis: a technique and feasibility study. | Prospective evaluation of 12 patients undergoing surgery for lumbar degenerative scoliosis. To assess the feasibility of minimally invasive spine surgery (MIS) techniques in the correction of lumbar degenerative deformity. Patient age, comorbidities, and blood loss may be limiting factors when considering surgical correction of lumbar degenerative scoliosis. MIS may allow for significantly less blood loss and tissue disruption than open surgery. Twelve patients underwent circumferential fusion. The age range of these patients was 50 to 85 years (mean of 72.8 y). Of the 12 patients, 7 were men and 5 were women. All patients underwent direct lateral transpsoas approach for discectomy and fusion with polyetheretherketone cage and rh-BMP2. All fusions to the sacrum included L5-S1 fusion with the Trans1 Axial Lumbar Interbody Fusion technique. Posteriorly, multilevel percutaneous screws were inserted using the CD Horizon Longitude system. Radiographs, visual analog scores (VAS), and treatment intensity scores (TIS) were assessed preoperatively and at last postoperative visit. Operative times and estimated blood loss were recorded. Mean number of segments operated on was 3.64 (range: 2 to 8 segments). Mean blood loss for anterior procedures (transpsoas discectomy/fusion and in some cases L5-S1 interbody fusion) was 163.89 mL (SD 105.41) and for posterior percutaneous pedicle screw fixation (and in some cases L5-S1 interbody fusion) was 93.33 mL (SD 101.43). Mean surgical time for anterior procedures was 4.01 hours (SD 1.88) and for posterior procedures was 3.99 hours (SD 1.19). Mean Cobb angle preoperatively was 18.93 degrees (SD 10.48) and postoperatively was 6.19 degrees (SD 7.20). Mean preoperative VAS score was 7.1; mean preoperative TIS score was 56.0. At mean follow-up of 75.5 days, mean VAS was 4.8; TIS was 28.0. A combination of 3 MIS techniques allows for correction of lumbar degenerative scoliosis. Multisegment correction can be performed with less blood loss and morbidity than for open correction. | 18,836,355 |
The actin regulator coronin 1A is mutant in a thymic egress-deficient mouse strain and in a patient with severe combined immunodeficiency. | Mice carrying the recessive locus for peripheral T cell deficiency (Ptcd) have a block in thymic egress, but the mechanism responsible is undefined. Here we found that Ptcd T cells had an intrinsic migration defect, impaired lymphoid tissue trafficking and irregularly shaped protrusions. Characterization of the Ptcd locus showed a point substitution of lysine for glutamic acid at position 26 in the actin regulator coronin 1A that enhanced its inhibition of the actin regulator Arp2/3 and resulted in its mislocalization from the leading edge of migrating T cells. The discovery of another coronin 1A mutant during an N-ethyl-N-nitrosourea-mutagenesis screen for T cell-lymphopenic mice prompted us to evaluate a T cell-deficient, B cell-sufficient and natural killer cell-sufficient patient with severe combined immunodeficiency, whom we found had mutations in both CORO1A alleles. Our findings establish a function for coronin 1A in T cell egress, identify a surface of coronin involved in Arp2/3 regulation and demonstrate that actin regulation is a biological process defective in human and mouse severe combined immunodeficiency. | 18,836,449 |
CCR9 expression defines tolerogenic plasmacytoid dendritic cells able to suppress acute graft-versus-host disease. | Dendritic cells (DCs) are 'professional' antigen-presenting cells that are key in the regulation of immune responses. Here we characterize a unique subset of tolerogenic DCs that expressed the chemokine receptor CCR9 and migrated to the CCR9 ligand CCL25, a chemokine linked to the homing of T cells and DCs to the gut. CCR9(+) DCs were of the plasmacytoid DC (pDC) lineage, had an immature phenotype and rapidly downregulated CCR9 in response to maturation-inducing pDC-restricted Toll-like receptor ligands. CCR9(+) pDCs were potent inducers of regulatory T cell function and suppressed antigen-specific immune responses both in vitro and in vivo, including inhibiting acute graft-versus-host disease induced by allogeneic CD4(+) donor T cells in irradiated recipients. Our results identify a highly immunosuppressive population of pDCs present in lymphoid tissues. | 18,836,452 |
The H3K36 demethylase Jhdm1b/Kdm2b regulates cell proliferation and senescence through p15(Ink4b). | The Ink4a-Arf-Ink4b locus has a crucial role in both cellular senescence and tumorigenesis. JmjC domain-containing histone demethylase 1b (Jhdm1b, also known as Kdm2b and Fbxl10), the mammalian paralog of the histone demethylase Jhdm1a (also known as Kdm2a and Fbxl11), has been implicated in cell-cycle regulation and tumorigenesis. In this report, we show that Jhdm1b is a histone H3 lysine 36 (H3K36) demethylase. Knockdown of Jhdm1b in primary mouse embryonic fibroblasts inhibits cell proliferation and induces cellular senescence in a pRb- and p53 pathway-dependent manner. Notably, the effect of Jhdm1b on cell proliferation and cellular senescence is mediated through derepression of p15(Ink4b), as loss of p15(Ink4b) function rescues cell-proliferation defects in Jhdm1b-knockdown cells. Chromatin immunoprecipitation on ectopically expressed Jhdm1b demonstrates that Jhdm1b targets the p15(Ink4b) locus and regulates its expression in an enzymatic activity-dependent manner. Alteration of Jhdm1b level affects Ras-induced neoplastic transformation. Collectively, our results indicate that Jhdm1b is an H3K36 demethylase that regulates cell proliferation and senescence through p15(Ink4b). | 18,836,456 |
Chemical control of protein stability and function in living mice. | Conditional control of protein function in vivo offers great potential for deconvoluting the roles of individual proteins in complicated systems. We recently developed a method in which a small protein domain, termed a destabilizing domain, confers instability to fusion protein partners in cultured cells. Instability is reversed when a cell-permeable small molecule binds this domain. Here we describe the use of this system to regulate protein function in living mammals. We show regulation of secreted proteins and their biological activity with conditional secretion of an immunomodulatory cytokine, resulting in tumor burden reduction in mouse models. Additionally, we use this approach to control the function of a specific protein after systemic delivery of the gene that encodes it to a tumor, suggesting uses for enhancing the specificity and efficacy of targeted gene-based therapies. This method represents a new strategy to regulate protein function in living organisms with a high level of control. | 18,836,461 |
Management of Wilms tumor: current standard of care. | Wilms tumor is the most common renal malignancy in children. In the 1930s, overall survival for children with Wilms tumor was approximately 30%. Use of multidisciplinary therapy, guided by results from multi-institutional, randomized trials, has substantially improved overall survival to about 90%. Management of Wilms tumor differs substantially between Europe and the US. In Europe, the International Society of Pediatric Oncology protocols call for management of patients with presumptive Wilms tumor with neoadjuvant chemotherapy followed by nephrectomy and further chemotherapy. In the US, protocols developed by the National Wilms Tumor Study Group advise primary nephrectomy followed by a chemotherapy regimen tailored to the pathologic tumor stage. Despite these disparate strategies, overall survival is similar in patients managed according to European and US protocols. Patients with Wilms tumor now have excellent survival. Therefore, current goals aim to reduce the morbidity associated with therapy. Important complications of treatment for Wilms tumor include cardiomyopathy, renal failure, and increased risk of a secondary malignancy. Currently, the role of laparoscopic surgery in management of Wilms tumor remains extremely limited. | 18,836,464 |
The Janus face of dendritic cells in cancer. | On the basis of experimental models and some human data, we can assume that tumor outgrowth results from the balance between immunosurveillance (the extrinsic tumor suppressor mechanisms) and immunosubversion dictated by transformed cells and/or the corrupted surrounding microenvironment. Cancer immunosurveillance relies mainly upon conventional lymphocytes exerting either lytic or secretory functions, whereas immunosubversion results from the activity of regulatory T or suppressor myeloid cells and soluble mediators. Although specific tools to target or ablate dendritic cells (DCs) became only recently available, accumulating evidence points to the critical role of the specialized DC system in dictating most of the conventional and regulatory functions of tumor-specific T lymphocytes. Although DC can be harnessed to silence tumor development, tumors in turn can exploit DC to evade immunity. Indeed, DCs harbor defects in their differentiation and stimulatory functions in cancer-bearing hosts and can actively promote T-cell tolerance to self-tumor antigens. In this review, we will focus on the dual role of DC during tumor progression and discuss pharmacoimmunological strategies to harness DC against cancer. | 18,836,473 |
NKG2D ligands in tumor immunity. | The activating receptor NKG2D (natural-killer group 2, member D) and its ligands play an important role in the NK, gammadelta(+) and CD8(+) T-cell-mediated immune response to tumors. Ligands for NKG2D are rarely detectable on the surface of healthy cells and tissues, but are frequently expressed by tumor cell lines and in tumor tissues. It is evident that the expression levels of these ligands on target cells have to be tightly regulated to allow immune cell activation against tumors, but at the same time avoid destruction of healthy tissues. Importantly, it was recently discovered that another safeguard mechanism controlling activation via the receptor NKG2D exists. It was shown that NKG2D signaling is coupled to the IL-15 receptor pathway in a cell-specific manner suggesting that priming of NKG2D-mediated activation depends on the cellular microenvironment and the distinct cellular context. This review will provide a broad overview of our up-to-date knowledge of the NKG2D receptor and its ligands in the context of tumor immunology. Strategies to amplify NKG2D-mediated antitumor responses and counteract tumor immune escape mechanisms will be discussed. | 18,836,475 |
Akt phosphorylation of La regulates specific mRNA translation in glial progenitors. | The Akt signaling pathway activity increases as normal tissue progresses to malignant transformation, and regulates the translation of specific messenger RNAs (mRNAs) through multiple mechanisms. We have identified one such mechanism of Akt-dependent translation control as involving the lupus autoantigen La. La is an RNA-associated protein that contains multiple trafficking elements to support the interaction with RNAs in different subcellular locations. We show here that the La protein is a direct target of the serine/threonine protein kinase Akt on threonine 301, and La nuclear export in mouse glial progenitors, as well as its association with polysomes is modulated by Akt activity. Using a functional approach to determine the network of genes affected by La in the cytoplasm by microarray analysis of polysome-bound mRNAs, we found that La binds 34% of the polysome bound mRNAs and regulates the expression of a specific pool of mRNAs under KRas/Akt activation. Therefore, La appears to be an important contributor to Akt-mediated translational regulation of these transcripts in murine glial cells. | 18,836,485 |
Poor outcome in post transplant lymphoproliferative disorder with pulmonary involvement after allogeneic hematopoietic SCT: 13 years' experience in a single institute. | EBV-induced post transplant lymphoproliferative disorder (PTLD) continues to be a major complication after transplantation. Between January 1993 and April 2006, 12 cases of B-cell lymphoproliferative disorder were identified among 577 patients after allogeneic hematopoietic SCT (HSCT) with an overall incidence of 2.51% at 1 year. Grades II-IV acute GVHD, CMV antigenemia and the use of antithymocyte globulin (ATG) were independent risk factors for PTLD. At diagnosis, all of the tumors were CD20-positive and 11 (92%) were EBV-encoded RNA (EBER)-positive. Of the 12 patients with B-cell lymphoproliferative disorder, 8 had pulmonary involvement and 10 had extranodal involvement. Eleven patients received weekly rituximab therapy at a dose of 375 mg/m(2); the median interval between the onset of symptoms and rituximab therapy was 6 days. The overall mortality rate was 92% and seven (64%) of the deaths were directly attributable to disseminated PTLD within days or weeks of presentation. In our series, pulmonary PTLD followed an extremely aggressive course and poor response to current therapy, even though rituximab was included in the therapeutic regimens. | 18,836,488 |
Recent Advances and Future Advances in Time-of-Flight PET. | Simple theory predicts that the statistical noise variance in PET can be reduced by an order of magnitude by using time-of-flight (TOF) information. This reduction can be obtained by improving the coincidence timing resolution, and so would be achievable in clinical, whole body studies using with PET systems that differ little from existing cameras. The potential impact of this development is large, especially for oncology studies in large patients, where it is sorely needed. TOF PET was extensively studied in the 1980's but died away in the 1990's, as it was impossible to reliably achieve sufficient timing resolution without sacrificing other important PET performance aspects, such as spatial resolution and efficiency. Recent advances in technology (scintillators, photodetectors, and high speed electronics) have renewed interest in TOF PET, which is experiencing a rebirth. However, there is still much to be done, both in instrumentation development and evaluating the true benefits of TOF in modern clinical PET. This paper looks at what has been accomplished and what needs to be done before time-of-flight PET can reach its full potential. | 18,836,513 |
Gender Differences in Patterns of Association Between Prosocial Behavior, Personality, and Externalizing Problems. | This study examines whether prosocial behavior and personality have independent or overlapping associations with adolescent externalizing problems. A total of 128 female and 103 male early adolescents (M = 13.6 years old) completed personality inventories. Prosocial behavior was assessed by peer nominations (N = 663). Composite aggression and delinquency scores were derived from maternal and self-reports. Path analyses indicated gender differences in patterns of association. For girls, links between prosocial behavior and both aggression and delinquency were fully mediated by agreeableness and partially mediated by conscientiousness. For boys, prosocial behavior, agreeableness, and conscientiousness were independently and negatively associated with aggression and delinquency. The findings suggest that personality and prosocial behavior are uniquely related to boys' behavior problems but cannot be readily disentangled when it comes to girls' behavior problems. | 18,836,524 |
A novel role for the SMG-1 kinase in lifespan and oxidative stress resistance in Caenorhabditis elegans. | The PTEN tumour suppressor encodes a phosphatase, and its daf-18 orthologue in Caenorhabditis elegans negatively regulates the insulin/IGF-1 DAF-2 receptor pathway that influences lifespan in worms and other species. In order to identify new DAF-18 regulated pathways involved in aging, we initiated a candidate RNAi feeding screen for clones that lengthen lifespan. Here, we report that smg-1 inactivation increases average lifespan in a daf-18 dependent manner. Genetic analysis is consistent with SMG-1 acting at least in part in parallel to the canonical DAF-2 receptor pathway, but converging on the transcription factor DAF-16/FOXO. SMG-1 is a serine-threonine kinase which plays a conserved role in nonsense-mediated mRNA decay (NMD) in worms and mammals. In addition, human SMG-1 has also been implicated in the p53-mediated response to genotoxic stress. The effect of smg-1 inactivation on lifespan appears to be unrelated to its NMD function, but requires the p53 tumour suppressor orthologue cep-1. Furthermore, smg-1 inactivation confers a resistance to oxidative stress in a daf-18-, daf-16- and cep-1-dependent manner. We propose that the role of SMG-1 in lifespan regulation is at least partly dependent on its function in oxidative stress resistance. Taken together, our results unveil a novel role for SMG-1 in lifespan regulation. | 18,836,529 |
The impact of work environment on mood disorders and suicide: Evidence and implications. | The purpose of this paper is to review the evidence estimating an impact of occupational factors on mood disorders and suicide, and the efficacy of interventions. This review is based on literature searches using Medline and Psych INFO from 1966 to 2007 (keywords: work stress, job insecurity, job strain, shift work, violence, occupational health, mood disorders, depression, and suicide). To establish the relationship between occupational variables and mood disorders, we focused on clinically significant disorders rather than depressive symptoms. During the last decade, prospective epidemiological studies have suggested a predictive association between the work environment and mood disorders. Recently, increasing numbers of clinical trials have shown favorable effect size of intervention and suggested preferable return-on-investment results. However, low awareness and social stigma still decrease workers access to treatment. Mental health professionals in conjunction with employers have to devise a creative system to make the quality care being offered more accessible to employees. In addition, further outcome data is needed to evaluate the benefit of managing mood disorders in the workplace, and to foster awareness of positive implications for employees, employers, their families, and the society at large. In addition, the work environment, with its chemical (e.g. chemosensory factors, pollutants), physical (e.g. lighting, noise, temperature, outdoor views and activities), biological (e.g., chronobiological factors, allergens, infectious agents), psychological (e.g. demand-control, effort-reward balance), social (e.g. cohesiveness, support), and organizational (e.g. leadership styles) component should meet minimal standards, and may improve with striving towards the optimum. | 18,836,547 |
The Relationship Between Gray Matter Morphometry and Neuropsychological Performance in a Large Sample of Cognitively Healthy Adults. | Voxel-based morphometry (VBM) was used to examine the relationship between gray matter (GM) volume and performance on two commonly used clinical neuropsychological measures of frontal lobe or executive function, the Trail Making Test part B (TrailsB) and the Controlled Oral Word Association Test (COWAT) in 221 cognitively healthy adults between the ages of 18 and 84. We hypothesized that these measures would be associated with GM volume in the dorsolateral frontal lobes. Voxel-based multiple regression was used to correlate cognitive function with modulated GM probability maps while controlling for age, education, gender, and total intracranial volume. A relationship with TrailsB was found in bilateral lateral inferior frontal gyri and left basal ganglia. A relationship with COWAT was found in the left lateral inferior and middle frontal gyri. Lesion studies have long implicated the importance of these regions for executive function. The present results confirm and extend those prior findings to healthy adults. | 18,836,573 |
Diagnosing and treating attention-deficit/hyperactivity disorder in adults. | Adult attention deficit/hyperactivity disorder (ADHD) is a valid and impairing psychiatric disorder. In this article, we review the diagnosis of ADHD in adults, focusing on symptom presentation differences between pediatric and adult ADHD as well as the importance of assessing functional impairments. Differentiating ADHD from other clinical disorders is often the most difficult part of making an ADHD diagnosis in adults. Psychiatric comorbidities are also described and discussed as potential impact factors upon not only diagnosing ADHD but also treatment of adult ADHD. Especially in those adults with psychiatric comorbidities, treatments need to be multimodal and include both pharmacotherapy and psychosocial interventions. | 18,836,579 |
Deficit schizophrenia: an update. | The criteria for deficit schizophrenia were designed to define a group of patients with enduring, primary (or idiopathic) negative symptoms. In 2001, a review of the literature suggested that deficit schizophrenia constitutes a disease separate from nondeficit forms of schizophrenia. Here we provide a review of new studies, not included in that paper, in which patients with deficit schizophrenia and those with nondeficit schizophrenia were compared on dimensions typically used to distinguish diseases: signs and symptoms, course of illness, pathophysiological correlates, risk and etiological factors, and treatment response. Replicated findings and new evidence of double dissociation supporting the separate disease hypothesis are highlighted. Weaknesses in research and treatment options for these patients are also emphasized. | 18,836,581 |
Humeral shaft fractures and radial nerve palsy: to explore or not to explore...That is the question. | Humeral shaft fracture with radial nerve palsy has been a subject of debate since this entity was originally described by Holstein and Lewis in 1963. As the literature provides support for almost any approach in treating patients with this injury, surgeons have no definitive literary guidance. To clarify how physicians are actually treating these patients, we surveyed practice tendencies in observation versus exploration of the radial nerve. In addition, we have integrated our survey results with the current literature to propose an algorithm directing treatment of these patients. | 18,836,600 |
Total wrist arthroplasty. | In the article, I review the history of total wrist arthroplasty designs; give an overview of and design rationale for the ReMotion (Small Bone Innovations, Morrisville, PA) total wrist arthroplasty; describe the indications, technique, and postoperative care for this implant; and present some early, very encouraging results. | 18,836,607 |
Radial endoscopic ultrasonography in the preoperative staging of pancreatic cancer. | Endoscopic ultrasonography (EUS) is a diagnostic method that aims to detect and stage tumors of the pancreas more accurately. It has a high predictive role regarding tumor resectability. The present paper aims to assess the diagnostic accuracy of radial EUS in the staging of pancreatic cancer as well as the role of EUS to predict tumor resectability. 30 patients (22 males, 8 females, mean age 61 +/- 12 years) with pancreatic masses staged by both radial EUS and surgery (17 patients with intraoperative exploration and 13 with pathological examination of surgical specimens) and with histologically proved adenocarcinoma were included in the study. Surgical examination was indicated in patients with pancreatic masses evidenced by imaging methods other than EUS, without distant metastases proved preoperatively, and without taking into consideration the staging obtained by EUS. Resectability criteria for pancreatic tumors as assessed by EUS were invasion of superior mesenteric artery or invasion of celiac trunk. The accuracy of EUS T staging was 86.6%, that of N staging was 93.3% while that of the vascular invasion was 80%. The accuracy of EUS for predicting tumor stage had a direct impact on the assessment of tumor resectability (83.3%, CI 95%: 81.5- 85.2). It had a sensitivity of 100%, specificity of 75%, PPV of 91.6% and NPV of 100%. The radial EUS of the pancreas is an accurate method for tumor staging. For establishing tumor resectability, association with other imaging methods is advisable for arterial assessment. | 18,836,619 |
Prospective study on warfarin and regional chemotherapy in patients with pancreatic carcinoma. | The aim is to prospectively examine the effect of regional gemcitabine and mitomycin-C with systemic gemcitabine together with warfarin in patients with inoperable pancreatic carcinoma, and compare the effect to systemic gemcitabine alone. Seventeen patients received 1.25 mg of warfarin daily, gemcitabine 800 mg/m2 on day 1 and mitomycin-C 8 mg/m2 on day 2 regionally and gemcitabine 800 mg/m2 on day 14 peripherally. The cycle was repeated every 4 weeks. Median survival since presentation was 6.8 months, while median total survival was 9.6 months. Excluding the 3 patients who died before receiving any therapy, the median survival since presentation resulted in 10.7 months and the median total survival, 12.7 months. One patient developed bleeding that required transfusion and 2 patients developed anemia (Grades III/IV). Comparing these data to historical controls of large cohorts supports the notion that this regimen offers a viable alternative to systemic gemcitabine alone. A regimen consisting of regional gemcitabine and mitomycin-C with systemic gemcitabine and low-dose warfarin compares favorably to the gold standard of systemic gemcitabine. These data suggest the feasibility of a large prospective study on the use of warfarin and combined regional and systemic chemotherapy in patients with pancreatic carcinoma. | 18,836,621 |
[Cytokine-eluting stents as new drug-delivery devices for angiogenic therapy]. | The stimulation of the endogenous adaptive vessel growth (angiogenesis, arteriogenesis) provides a promising therapeutic approach for the large number of patients with vascular occlusive disease that is not eligible for current interventional treatments. Despite the proven efficacy of various factors in pre-clinical experimental studies, the successful translation of angiogenic therapies into clinical practice yet remains to be made. Most authors identified the mode of administrations as culprit for the neutral effects observed in the majority of clinical trials. Although experimental studies have proven the superiority of continuous intra-arterial application above other routes (iv, im, sc), clinical trials focused on either bolus therapy, iv or sc application respectively, due to the lack of technical solutions to fulfill the requirements of intra-arterial delivery. The recent developments in the field of drug eluting stents may offer new possibilities for local drug delivery. Local release of cytokines, such as TGF-beta, has been shown to induce collateral growth in an experimental model of PAD. Other factors might eventually render useful to stabilize atherosclerotic plaques downstream of the site of stent implantation. | 18,836,644 |
Understanding fetal alcohol spectrum disorders (FASDs): toward identification of a behavioral phenotype. | Fetal alcohol spectrum disorders (FASDs) currently represent the leading cause of mental retardation in North America, ahead of Down syndrome and cerebral palsy. The damaging effects of alcohol on the developing brain have a cascading impact on the social and neurocognitive profiles of affected individuals. Researchers investigating the profiles of children with FASDs have found impairments in learning and memory, executive functioning, and language, as well as hyperactivity, impulsivity, poor communication skills, difficulties with social and moral reasoning, and psychopathology. The primary goal of this review paper is to examine current issues pertaining to the identification of a behavioral phenotype in FASDs, as well as to address related screening and diagnostic concerns. We conclude that future research initiatives comparing children with FASDs to nonalcohol-exposed children with similar cognitive and socioemotional profiles should aid in uncovering the unique behavioral phenotype for FASDs. | 18,836,653 |
Ruptured jejunal diverticulum due to a single-band small bowel obstruction. | Jejunal diverticulosis is rare and often goes unnoticed until complications occur. The diverticula are true, acquired diverticula and often asymptomatic. Jejunal diverticulosis can be associated with diverticulosis of the duodenum, ileum, and colon. Here we describe a patient with known severe diverticular disease of the large bowel, who presented acutely with abdominal pain and signs of generalised peritonitis. Laparotomy showed ruptured jejunal diverticulosis with a single band over the terminal ileum, causing small bowel obstruction. Spontaneous perforation of a jejunal diverticulum is rare and is usually an intraoperative finding. One should exclude a precipitating cause, such as coexisting distal obstruction, stricture, or a foreign body. | 18,836,661 |
Benign hepatic portal venous gas in a critically ill patient. | Hepatic portal venous gas (HPVG) formation is regarded as a sign of serious intra-abdominal process. This report presents an abdominal CT scan of a patient with incidental but rare finding of HPVG after nasogastric intubation. The presence of HPVG should prompt a thorough diagnostic evaluation to immediately rule out a catastrophic intra-abdominal condition. | 18,836,664 |
[Steady-state responses of the auditory system: a comparison of different methods]. | Determining the hearing threshold in children is one of the most important topics in audiology. Because the existing methods-brainstem evoked response audiometry (BERA) and cortical evoked response audiometry (CERA)-show some severe insufficiencies, it is necessary to look for improved methods. A promising approach may be amplitude modulation following responses (AMFR). In contrast to the conventional transient auditory evoked potentials, these responses show a high-frequency specificity, and they possibly allow statements about the hearing threshold in the low-frequency range. The purpose of our study was to objectively detect the hearing threshold in normal-hearing persons of various ages. Pure-tone audiometry served as a subjective control test. For objective tests, we used the measurement of AMFR (two different systems with distinct parameters) and CERA. We compared the different methods with regard to accuracy of the determination of the hearing threshold and investigated the practicability. The results showed some large deviations between the subjective hearing threshold and the objectively determined responses. The lowest deviations appeared at low frequencies. With respect to the variability of results, CERA was clearly superior to AMFR. Despite large deviations in the responses objectively determined by AMFR, we think AMFR is suitable to close some gaps in determining objective hearing thresholds, at least at low frequencies. | 18,836,669 |
Effects of atorvastatin on calcium-regulating proteins: a possible mechanism to repair cardiac dysfunction in spontaneously hypertensive rats. | Previous clinical and experimental studies have demonstrated that statins, the inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, can improve left ventricular function in damaged hearts. Also, the normal expression of Ca(2+) regulatory proteins is critical for efficient myocardial function. However, it is still unclear whether the beneficial effect of statins on cardiac function is associated with alterations of Ca(2+) regulatory proteins. In this study, we investigated the effect of atorvastatin on cardiac function in spontaneously hypertensive rats (SHRs), focusing in particular on its impact on the expression of sarcoplasmic reticulum Ca(2+)-adenosine triphosphatase (SERCA2a), phospholamban (PLB) and its phosphorylated form (phosphorylated PLB), all of which are Ca(2+) regulatory proteins in myocardium. SHRs showed decreases in gene expression of SERCA2a and phosphorylated PLB, and reduction in SERCA activity in the left ventricular myocardium, as well as reduced cardiac function, compared to age-matched Wistar Kyoto rats (WKYs). Furthermore, we showed that in SHRs atorvastatin preserved cardiac dysfunction accompanied by positive alterations in calcium regulatory proteins, with up-regulation in expression of SERCA2a and phosphorylated PLB, and with improvement of SERCA activity. Thus, atorvastatin has positive effects on calcium regulatory proteins, which may be one of the mechanisms of the beneficial effect of statins on cardiac function in spontaneously hypertensive rats. | 18,836,677 |
Modeling the effects of resection, radiation and chemotherapy in glioblastoma. | The standard treatment for newly diagnosed glioblastoma multiforme is surgical resection followed by radiotherapy and chemotherapy. Most studies on these treatments are retrospective clinical data analysis. To integrate these studies, a mathematical model is developed. The model predicts the survival time of patients who undergo resection, radiation, and chemotherapy with different protocols. | 18,836,688 |
Hesitation behaviour of hoverflies Sphaerophoria spp. to avoid ambush by crab spiders. | Pollinators possess several antipredator adaptations that minimise predation risk during foraging. In addition to morphological adaptations, hoverflies might have behavioural antipredator adaptations. We conducted three field experiments to investigate whether the "hesitation behaviour" of hoverflies Sphaerophoria spp., moving backwards and forwards in front of a flower, is effective in avoiding ambush predators on flowers. First, we compared the behaviour of different flower visitors, including several bees and other hoverflies, with Sphaerophoria spp. behaviour. Only Sphaerophoria spp. exhibited the hesitation behaviour in front of flowers. The flight behaviour was observed more frequently before landing on flowers than on leaves. Second, we investigated rejection by Sphaerophoria spp. to artificially placed corpses of the crab spider Thomisus labefactus. The rejection rate of flowers with a crab spider placed on or under it was significantly higher than that of non-treated flowers. Moreover, the presence of a spider on the flower decreased the number of hesitation displays, compared with non-treated flowers. Finally, to determine whether hesitation behaviour could be a consequence of floral assessment, we investigated hoverfly rejection of previously foraged flowers. Sphaerophoria spp. did not reject flowers that had been visited by the same individual or conspecifics within 3 min. We suggest that hesitation behaviour may be adaptive, enabling assessment of predation risk and hence avoiding ambush predators on flowers. | 18,836,694 |
Characterization of new oxidation products of 9H-carbazole and structure related compounds by biphenyl-utilizing bacteria. | 9H-Carbazole and its derivatives are useful for versatile pharmacological applications. To obtain different derivatives of 9H-carbazole, 24 isolates of biphenyl-utilizing bacteria have been investigated regarding their ability to produce hydroxylated 9H-carbazole metabolites. Our analyses showed that 9H-carbazole was primarily converted into 9H-carbazol-1-ol (15 strains) and 9H-carbazol-3-ol (9 strains), while carbazol-9-ol was formed as a minor product (12 strains). The formation of 9H-carbazol-3-ol by the spontaneous release from the corresponding dihydrodiols was provided by the first-time detection of 3-hydroxy-1,2,3,9-tetrahydrocarbazol-4-one. The dependence of product yields on different parameters was exemplarily analyzed for Ralstonia sp. SBUG 290. Biphenyl-grown cells showed higher oxidation activities than cells cultivated with organic acids or nutrient broth, while co-cultivation of Ralstonia sp. SBUG 290 with biphenyl and 9H-carbazole led to an enhanced yield of 9H-carbazol-1-ol. The tested bacterial strains were also studied regarding their biotransformation of the two structure-related compounds 9H-fluorene and dibenzothiophene. Twenty-one strains primarily transformed 9H-fluorene into 9H-fluoren-9-ol and fluoren-9-one. Three strains accumulated benzo[c]chromen-6-one as a novel dead-end product during the incubation with 9H-fluorene, 9H-fluoren-9-ol, and fluoren-9-one. Dibenzothiophene has been mainly transformed into the dead-end product dibenzothiophene-5-oxide, while additional metabolites indicated that the transformation followed the so called Kodama pathway. | 18,836,714 |
Her-2 DNA versus cell vaccine: immunogenicity and anti-tumor activity. | Direct comparison and ranking of vaccine formulations in pre-clinical studies will expedite the identification of cancer vaccines for clinical trials. Two human ErbB-2 (Her-2) vaccines, naked DNA and whole cell vaccine, were tested side-by-side in wild type and Her-2 transgenic mice. Both vaccines can induce humoral and cellular immunity to the entire repertoire of Her-2 epitopes. Mice were electro-vaccinated i.m. with a mixture of pGM-CSF and pE2TM, the latter encodes Her-2 extracellular and transmembrane domains. Alternatively, mice were injected i.p. with human ovarian cancer SKOV3 cells that have amplified Her-2. In wild type mice, comparable levels of Her-2 antibodies (Ab) were induced by these two vaccines. However, T cell immunity and protection against Her-2(+) tumors were superior in DNA vaccinated mice. In BALB Her-2 transgenic (Tg) mice, which were tolerant to Her-2, DNA and cell vaccines were administered after regulatory T cells (Treg) were removed by anti-CD25 mAb. Again, comparable levels of Her-2 Ab were induced, but DNA vaccines rendered greater anti-tumor activity. In B6xDR3 Her-2 Tg mice that expressed the autoimmune prone HLA-DR3 allele, higher levels of Her-2 Ab were induced by SKOV3 cell than by Her-2 DNA. But anti-tumor activity was still more profound in DNA vaccinated mice. Therefore, Her-2 DNA vaccine induced greater anti-tumor immunity than cell vaccine, whether mice were tolerant to Her-2 or susceptible to autoimmunity. Through such side-by-side comparisons in appropriate pre-clinical test systems, the more effective vaccine formulations will emerge as candidates for clinical trials. | 18,836,716 |
Apical hypertrophic cardiomyopathy in childhood: a long-term follow-up report of two cases. | We present two children with apical hypertrophic cardiomyopathy (APH), both of whom remained asymptomatic for more than 15 years. The inverted T-wave on electrocardiograms and myocardial hypertrophy mostly confined to the apical region on echocardiograms showed no significant changes during follow-up. Magnetic resonance imaging revealed a cavitylike portion at the apex in one case, but the diagnosis of noncompacted myocardium was unlikely because there was no blood communication with the true left ventricular cavity. The other case had typically thick and solid myocardium at the apex. The findings in these patients demonstrate that APH might present in childhood and suggest that the prognosis might be good. | 18,836,757 |
An auxiliary method to reduce potential adverse impacts of projected land developments: subwatershed prioritization. | An index based method is developed that ranks the subwatersheds of a watershed based on their relative impacts on watershed response to anticipated land developments, and then applied to an urbanizing watershed in Eastern Pennsylvania. Simulations with a semi-distributed hydrologic model show that computed low- and high-flow frequencies at the main outlet increase significantly with the projected landscape changes in the watershed. The developed index is utilized to prioritize areas in the urbanizing watershed based on their contributions to alterations in the magnitude of selected flow characteristics at two spatial resolutions. The low-flow measure, 7Q10, rankings are shown to mimic the spatial trend of groundwater recharge rates, whereas average annual maximum daily flow, QAMAX, and average monthly median of daily flows, QMMED, rankings are influenced by both recharge and proximity to watershed outlet. Results indicate that, especially with the higher resolution, areas having quicker responses are not necessarily the more critical areas for high-flow scenarios. Subwatershed rankings are shown to vary slightly with the location of water quality/quantity criteria enforcement. It is also found that rankings of subwatersheds upstream from the site of interest, which could be the main outlet or any interior point in the watershed, may be influenced by the time scale of the hydrologic processes. | 18,836,760 |
Transcatheter closure of a chronic iatrogenic arteriovenous fistula between the carotid artery and the brachiocephalic vein with an Amplatzer duct occluder in combination with a carotid stent. | We report an original method of transcatheter closure of an arteriovenous fistula using the combination of an Amplatzer PDA occluder and a carotid stent. The fistula was between the left carotid artery and the brachiocephalic vein. The patient had significant left-to-right shunt and was highly symptomatic. Due to the large orifice and pseudoaneurysmatic enlargement of the fistula, we had to use a large Amplatzer PDA occluder and the protruding part of the PDA device disk had to be covered with a carotid stent. The fistula was completely closed. The patient stopped having symptoms and, 2 years after the procedure, the effect persists. | 18,836,769 |
Methods for assessing leg length discrepancy. | The use of accurate and reliable clinical and imaging modalities for quantifying leg-length discrepancy (LLD) is vital for planning appropriate treatment. While there are several methods for assessing LLD, we questioned how these compared. We therefore evaluated the reliability and accuracy of the different methods and explored the advantages and limitations of each method. Based on a systematic literature search, we identified 42 articles dealing with various assessment tools for measuring LLD. Clinical methods such as use of a tape measure and standing blocks were noted as useful screening tools, but not as accurate as imaging modalities. While several studies noted that the scanogram provided reliable measurements with minimal magnification, a full-length standing AP computed radiograph (teleoroentgenogram) is a more comprehensive assessment technique, with similar costs at less radiation exposure. We recommend use of a CT scanogram, especially the lateral scout view in patients with flexion deformities at the knee. Newer modalities such as MRI are promising but need further investigation before being routinely employed for assessment of LLD. Level IV, diagnostic study. See the Guidelines for Authors for a complete description of levels of evidence. | 18,836,788 |
Adjuvant treatments for resectable pancreatic cancer. | Pancreatic cancer remains one of the most challenging malignancies to treat successfully. The majority of patients present with unresectable advanced-stage cancer, and only 20% of patients can undergo resection. Even if surgical resection is performed, the recurrence rate is high and the survival rate after surgery is poor. Therefore, effective adjuvant therapy is needed to improve the prognosis of patients with pancreatic cancer. Until now, no universally accepted standard adjuvant therapy for this disease has been available: chemoradiotherapy followed by chemotherapy is considered the optimal therapy in the United States, while chemotherapy alone is the current standard in Europe. However, recent randomized controlled trials (RTOG [Radiation Therapy Oncology Group] 9704; CONKO [Charité Onkologie]-001; and a Japanese study) have suggested a benefit of adjuvant chemotherapy with gemcitabine for patients with resectable pancreatic cancer. This article will review the clinical trials of adjuvant therapy for this disease, including the results of recent trials. | 18,836,798 |
Efficacy of vessel sealing system for major Glisson bundles and major bile ducts. | The efficacies of vessel sealing system (VSS) devices for major Glisson bundles and major bile ducts have not yet been determined. Male pigs (n = 6) and a LigaSure V device and an Atlas 20 (Valleylab, Boulder, CO, USA) device were used in this study. After laparotomy, the common bile duct and the right and left first-degree Glisson bundles were sealed by the VSS. The lower and upper parts of the common bile ducts were also sealed. Macro-and microscopic examinations were performed for the analysis of specimens taken just after VSS application. In an analysis of bile duct specimens taken 1 week after the VSS application, both burst pressure tests and histological examinations were performed. (1) In the analysis of the specimens (Glisson bundles and bile ducts) obtained just after the VSS application, the macroscopic changes included permanent, flattened changes of the Glisson bundles and bile ducts, without showing any blood or bile leakage. Histological examination of the transverse sections of the Glisson bundle after VSS application revealed that not only the blood vessels but also the bile ducts were fused together. (2) In the analysis of the specimens (bile ducts) obtained 1 week after the VSS application, second-look laparotomy showed extrahepatic bile duct obstruction. The mean burst pressure of the sealed bile ducts was 74.4 +/- 20.1 mmHg. Histological examination revealed that the lumen of the bile duct was completely sealed and the duct was surrounded by dense connective tissues. The VSS is useful for the safe sealing of not only the major Glisson bundles but also the major bile ducts. | 18,836,807 |
Alterations in Event Related Potentials (ERP) associated with tinnitus distress and attention. | Tinnitus related distress corresponds to different degrees of attention paid to the tinnitus. Shifting attention to a signal other than the tinnitus is therefore particularly difficult for patients with high tinnitus related distress. As attention effects on Event Related Potentials (ERP) have been shown this should be reflected in ERP measurements (N100, phase locking). In order to prove this hypothesis single sweep ERP recordings were obtained in 41 tinnitus patients as well as 10 control subjects during a period of time when attention was shifted to a tone (attended) and during a second phase (unattended) when they did not focus attention to the tone. Whereas tinnitus patients with low distress showed a significant reduction in both N100 amplitude and phase locking when comparing the attended and unattended measurement condition a group of patients with high tinnitus related distress did not show such ERP alterations. Using single sweep ERP measurements the results of our study show, that attention in high tinnitus related distress patients is captured by their tinnitus significantly more than in low distress patients. Furthermore our results provide the basis for future neurofeedback based tinnitus therapies aiming at maximizing the ability to shift attention away from the tinnitus. | 18,836,827 |
Bayesian variable selection for the Cox regression model with missing covariates. | In this paper, we develop Bayesian methodology and computational algorithms for variable subset selection in Cox proportional hazards models with missing covariate data. A new joint semi-conjugate prior for the piecewise exponential model is proposed in the presence of missing covariates and its properties are examined. The covariates are assumed to be missing at random (MAR). Under this new prior, a version of the Deviance Information Criterion (DIC) is proposed for Bayesian variable subset selection in the presence of missing covariates. Monte Carlo methods are developed for computing the DICs for all possible subset models in the model space. A Bone Marrow Transplant (BMT) dataset is used to illustrate the proposed methodology. | 18,836,829 |
The targeting of endothelial progenitor cells to a specific location within a microfluidic channel using magnetic nanoparticles. | A common problem with the in vivo therapeutic applications of cells is that cells can rapidly disappear into the circulatory system after an injection. Magnetic nanoparticles can be used to solve this problem. Bacterial magnetic nanoparticles were used in this study for targeting stem cells at a specific location within a microfluidic channel. Magnetic nanoparticles were isolated from Magnetospirillum sp. AMB-1 and delivered to endothelial progenitor cells (EPCs). Cellular uptake of magnetic nanoparticles and their functional feasibility was characterized in vitro. The environment of a human blood vessel was simulated using a microfluidic channel. Magnetic nanoparticle-incorporated EPCs were injected into a microchannel and the flow rate of cells was uniformly controlled by use of a syringe pump. EPCs were effectively targeted to a specific location within the microchannel by an external magnetic field (about 400 mT). About 40% of EPCs were efficiently targeted with a flow rate of 5 microl min(-1) when 10 microg of magnetic nanoparticles were used per 10(4) cells. This microfluidic system provides a useful tool towards a better understanding of the behavior of magnetic nanoparticle-incorporated cells within the human circulatory system for clinical use. | 18,836,835 |
Development of a fully implantable wireless pressure monitoring system. | A fully implantable wireless pressure sensor system was developed to monitor bladder pressures in vivo. The system comprises a small commercial pressure die connected via catheter to amplifying electronics, a microcontroller, wireless transmitter, battery, and a personal digital assistant (PDA) or computer to receive the wireless data. The sensor is fully implantable and transmits pressure data once every second with a pressure detection range of 1.5 psi gauge and a resolution of 0.02 psi. In vitro calibration measurements of the device showed a high degree of linearity and excellent temporal response. The implanted device performed continuously in vivo in several porcine studies lasting over 3 days. This system can be adapted for other pressure readings, as well as other vital sign measurements; it represents the first step in developing a ubiquitous sensing platform for telemedicine and remote patient monitoring. | 18,836,836 |
Patient reported outcome measures: a model-based classification system for research and clinical practice. | The umbrella term Patient Reported Outcomes (PRO) has been successfully proposed for instruments measuring perceived health outcomes, but its relationship to current conceptual models remains to be established. Our aim was to develop a classification system for PRO measures based on a valid conceptual model. We reviewed models and classification schemes of health outcomes and integrated them in a common conceptual framework, based on the models by Wilson and Cleary and the International Classification of Functioning (ICF). We developed a cross-classification system based on the minimum common set of consistent concepts identified in previous classifications, and specified categories based on the WHO International Classifications (ICD-10, and ICF). We exemplified the use of the classification system with selected PRO instruments. We identified three guiding concepts: (1) construct (the measurement object); (2) population (based on age, gender, condition, and culture); and (3) measurement model (dimensionality, metric, and adaptability). The application of the system to selected PRO measures demonstrated the feasibility of its use, and showed that most of them actually assess more than one construct. This classification system of PRO measures, based on a valid integrated conceptual model, should allow the classification of most currently used instruments and may facilitate a more adequate selection and application of these instruments. | 18,836,850 |
Discoidin domain receptor 1, a tyrosine kinase receptor, is upregulated in an experimental model of remyelination and during oligodendrocyte differentiation in vitro. | The discoidin domain receptor (DDR1) is highly expressed in oligodendrocytes during the neurodevelopmental myelination process and is genetically associated to schizophrenia. In this study, we aimed to further assess the involvement of DDR1 in both remyelination and oligodendrocyte differentiation. In the mouse model of demyelination-remyelination induced by oral administration of cuprizone, in situ hybridization showed an upregulation of the DDR1 gene in three different white matter areas (corpus callosum, dorsal fornix, and external capsule) during the remyelination period. Moreover, real time reverse transcriptase polymerase chain reaction showed that the increase in DDR1 messenger RNA (mRNA) was strongly correlated with the number of DDR1-positive cells in the corpus callosum (Spearman coefficient = 0.987, P = 0.013). Cells positive for DDR1 mRNA were also positive for oligodendrocyte markers (OLIG2, carnosine, and APC) but not for markers of oligodendrocyte precursors (NG2), myelin markers (CNPase), microglia (CD11b), or reactive glia (GFAP). Differentiation of a human oligodendroglial cell line, HOG16, was associated with an increase in mRNA expression of DDR1 and several myelin proteins (MBP and MOBP) but not other proteins (APC and CNPase). Here, we demonstrate that DDR1 is upregulated in vitro and in vivo when oligodendrocyte myelinating machinery is activated. Further studies are needed to identify the specific molecular pathway. | 18,836,851 |
Metallic biomaterials. | Ti alloys composed of nontoxic and allergy-free elements and Ni-free stainless steels and Co-Cr alloys are currently being developed. Ni-free Ti alloys exhibiting superelastic behavior, or the shape memory effect, are also being developed. beta-type Ti alloy with a low elastic modulus has proved to be effective for inhibiting bone absorption and enhancing bone remodeling. Simple bioactive surface modifications such as alkali-treatment processes and the calcium phosphate glass-ceramic dip-coating method are applicable to newly developed beta-type Ti alloys such as lowmodulus Ti-29Nb-13Ta-4.6Zr. Blood-compatible polymers such as poly(ethylene glycol) have been successfully fixed on the surface of Ti via chemical bonding by an electrodeposition method. Ti alloys for dental applications have also been recently developed. | 18,836,869 |
Simulation of the fluid dynamics in artificial aortic roots: comparison of two different types of prostheses. | As a consequence of the growing number of elderly people, the incidence of degenerative aortic diseases continues to increase. Often, artificial aortic roots are needed to replace the native tissue. Some physical characteristics of the artificial aortic root, however, are quite different from native aorta and need to be optimized. The supposed benefit of a prosthesis with artificial sinuses of Valsalva could first be checked by numerical calculations. Two simplified base geometries were used for simulating the flow and pressure distributions, especially in the coronary arteries. One model approximates the ascending aorta as a tube, and the other uses a design with toroidal dilation of the aortic root to approximate the native geometry of the sinuses of Valsalva. The flow and pressure distributions in both models were compared in the ascending aorta as well as in the right and the left coronary arteries. Both the pressure and the velocity distribution in the coronary artery region were not significantly higher in the model with the sinus design compared to the tube model. The sinus design only slightly increased the mean pressures and the velocities in both the ascending aorta and in the coronary arteries. Higher pressure in the coronary arteries should improve the blood circulation and decrease the risk of a surgery-related coronary incident. The sinus design did not show the hoped-for benefits, and therefore it is only a minor factor in optimizing future aortic root prostheses. | 18,836,872 |
Suicidality in Chinese adolescents in Hong Kong: the role of family and cultural influences. | Adolescent suicidal ideation has found to predict suicidal behaviors and psychopathology in adulthood. Previous studies focused solely on the medical and environmental risk factors, which were insufficient to give a holistic picture of adolescent suicidality. To assess the role of affective and cognitive attributes in the identification and prevention of adolescent suicidal ideation. A community sample of 511 participants (age 15-19 years) were asked to indicate their suicidality in the 12 months and in their lifetime. Generalized estimating equation regression models were used to examine the effect of psychosocial and socio-environmental correlates in relation to adolescent suicidal ideation. The data show that perceived responsibilities for family was the only protective factor, while a coping mechanism by behavioral disengagement, severity of depressive symptoms, a history of deliberate self-harm, chronic physical illness or pain, media reporting of suicide news, and low household income were the risk factors for adolescent suicidal ideation. The results suggest that a multilayer effort for preventing adolescent suicide is needed by providing support for children in deprived families; enhancing life skills in the teens; strengthening family relationship; improving mental and health services; and promoting responsible media reporting on suicide. | 18,836,885 |
Electromagnetic navigation bronchoscopy in combination with PET-CT and rapid on-site cytopathologic examination for diagnosis of peripheral lung lesions. | The combination of electromagnetic navigation bronchoscopy (ENB), PET-CT, and rapid on-site cytopathologic examination (ROSE) for the routine diagnostic work-up of peripheral lung lesions has not been evaluated previously. The aim of this study was to determine the accuracy and safety of ENB in combination with PET-CT and ROSE in subjects with endobronchially invisible peripheral lung lesions. ENB was performed in 13 subjects with radiologically suspected lung cancer who were referred to our tertiary-care hospital between October 2005 and November 2006. ENB was performed using the superDimension/Bronchus System. FDG-PET-CT scans were part of the diagnostic workup. Bronchoscopy was done under general anesthesia and ROSE was available in this setting. The final diagnosis was based on the histopathologic results of specimens obtained either by ENB or, if ENB was not diagnostic, by surgery or CT-guided fine-needle aspiration (FNA). The mean diameter of peripheral lesions ranged from 1.4 to 5.3 cm (average = 3.0 +/- 1.2 cm). In 76.9% of the patients, ENB resulted in obtaining a correct diagnosis, as defined by the definite histopathologic result. Sensitivity and specificity of ROSE was 84.6 and 100%, respectively. In malignant lesions the SUV ranged from 2.0 to 17.0 and was independent of lesion size. The positive predictive value of a positive PET-CT scan for a diagnosis of malignancy was 90%. No ENB-related adverse events were seen during and up to 24 h after bronchoscopy. ENB in combination with PET-CT and ROSE is safe and effective in the diagnostic workup of peripheral lung lesions. | 18,836,886 |
Mitochondrial fatty acid oxidation defects--remaining challenges. | Mitochondrial fatty acid oxidation defects have been recognized since the early 1970s. The discovery rate has been rather constant, with 3-4 'new' disorders identified every decade and with the most recent example, ACAD9 deficiency, reported in 2007. In this presentation we will focus on three of the 'old' defects: medium-chain acyl-CoA dehydrogenase (MCAD) deficiency, riboflavin responsive multiple acyl-CoA dehydrogenation (RR-MAD) deficiency, and short-chain acyl-CoA dehydrogenase (SCAD) deficiency. These disorders have been discussed in many publications and at countless conference presentations, and many questions relating to them have been answered. However, continuing clinical and pathophysiological research has raised many further questions, and new ideas and methodologies may be required to answer these. We will discuss these challenges. For MCAD deficiency the key question is why 80% of symptomatic patients are homozygous for the prevalent ACADM gene variation c.985A > G whereas this is found in only approximately 50% of newborns with a positive screen. For RR-MAD deficiency, the challenge is to find the connection between variations in the ETFDH gene and the observed deficiency of a number of different mitochondrial dehydrogenases as well as deficiency of FAD and coenzyme Q(10). With SCAD deficiency, the challenge is to elucidate whether ACADS gene variations are disease-associated, especially when combined with other genetic/cellular/environmental factors, which may act synergistically. | 18,836,889 |
Analysis of the free range behaviour of laying hens and the genetic and phenotypic relationships with laying performance. | 1. Over twelve 28-d laying periods (almost one year), 272 laying hens of the Lohmann Silver strain, individually tagged with transponders, were monitored on their ranging behaviour and laying performance in an aviary system with an adjacent winter garden. 2. From laying periods 1 to 12, the daily frequency of passages between the barn and the winter garden of individual hens, showed an antagonistic trend compared to the average duration of single visits. While the frequency of passages decreased until the end of the recording period to 8 passages per hen and day, the average duration of single visits increased to a maximum of 32 min per hen. 3. The heritability estimates for the traits, length of stay in the winter garden and frequency of passages were higher for the last 5 laying periods than at the beginning of the recording period. For the last 5 laying periods, the estimates for the duration of stay in the winter garden varied between h(2) = 0.21 and 0.32 and for the frequency of passages, between h(2) = 0.30 and 0.49. 4. Most of the estimated heritabilities for the rate of lay were on an expected medium level (h(2) = 0.09 to 0.45). Deviant h(2)-values to a few laying periods were based on low additive genetic variances or high environmental variance. 5. Genetic correlations between both free range traits and the laying performance were negative (r(g length of stay) = -0.34 and r(g passage frequency) = -0.08). 6. Generally, there seems to be a possibility to influence the ranging behaviour through selection. Further investigations with different genotypes and varying dates of exposure to the laying environment, should be carried out to clarify possible influences on other traits and the negative correlation with laying performance. | 18,836,899 |
Effect of egg turning and incubation time on carbonic anhydrase gene expression in the blastoderm of the Japanese quail (Coturnix c. japonica). | 1. The gene expression of carbonic anhydrase, a key enzyme for the production of sub-embryonic fluid (SEF), was assessed in turned and unturned eggs of the Japanese quail. The plasma membrane-associated isoforms CA IV, CA IX, CA XII, CA XIV, and the cytoplasmic isoform CA II, were investigated in the extra-embryonic tissue of the blastoderm and in embryonic blood. 2. Eggs were incubated at 37.6 degrees C, c.60% RH, and turned hourly (90 degrees ) or left unturned. From 48 to 96 h of incubation mRNA was extracted from blastoderm tissue, reverse-transcribed to cDNA and quantified by real-time qPCR using gene-specific primers. Blood collected at 96 h was processed identically. 3. Blastoderm CA IV gene expression increased with the period of incubation only in turned eggs, with maxima at 84 and 96 h of incubation. Only very low levels were found in blood. 4. Blastoderm CA II gene expression was greatest at 48 and 54 h of incubation, subsequently declining to much lower levels and unaffected by turning. Blood CA II gene expression was about 25-fold greater than in the blastoderm. 5. The expression of CA IX in the blastoderm was the highest of all isoforms, yet unaffected by turning. CA XII did not amplify and CA XIV was present at unquantifiable low levels. 6. It is concluded that only gene expression for CA IV is sensitive to egg turning, and that increased CA IV gene expression could account for the additional SEF mass found at 84 to 96 h of incubation in embryos of turned eggs. | 18,836,903 |
Selenium requirement of growing male turkeys. | 1. The aim of the experiment was to estimate the selenium requirement of growing male turkeys using the selenium concentrations in different organs and blood plasma and by fitting a continuous broken line to the activity of glutathione peroxidase in liver and plasma. 2. Newly hatched male BUT BIG 6 turkeys were fed either on the selenium deficient basal soybean-maize diets (selenium <0.010 mg/kg diet) adapted to the NRC (1994) and GfE (2004) recommendations for growing turkeys from 0 to 2 weeks (prestarter diet) and 3 to 5 weeks (starter diet) or the basal diets supplemented with 0.10, 0.15, 0.20, 0.25, 0.30, 0.35 or 0.40 mg selenium/kg diet as sodium selenate. Vitamin E was supplemented adequately in all diets. 3. After 5 weeks the weight in all groups (mean 2568 g) exceeded the expectations for the genotype investigated. Feed consumption and weight gain were however significantly reduced in the group receiving the selenium-deficient diet. 4. After 2 and 5 weeks selenium concentration and activity of glutathione peroxidase in the plasma and the organs examined were greatly influenced by selenium supplementation. 5. Under the conditions investigated, 0.30 mg Se/kg diet was necessary for fast-growing male turkeys to ensure maximum selenium accumulation in the organs examined and maximum glutathione peroxidase activity in plasma and liver. | 18,836,905 |
Circadian serum concentrations of tylosin in broilers after feed or water medication. | 1. Because tylosin is a time-dependent antibacterial agent, and because feeding and drinking of broilers decreases in late afternoon and ceases in the dark, it was hypothesised that serum concentrations of this drug are greatly reduced during the dark period. 2. The trial was carried out in a commercial poultry house, under standard broiler husbandry conditions, with food and water withdrawn from 22:00 until 07:00 h next morning and exposed to a natural light cycle of 13L:11D. 3. Broilers were given tylosin tartrate, in either feed or water, for 5 d as follows: 100, 200 and 300 ppm in feed, equivalent to 12.6, 25.2 and 37.8 mg/kg/d, respectively; and 200 and 400 mg/l in drinking water, equivalent to 51 to 102 mg/kg/d, respectively. 4. At 07:00 h on d 4, and for the next 40 h, hourly serum samples were obtained and analysed for tylosin by means of a microbiological assay. 5. Day vs night concentrations of tylosin expressed as area under the curve (AUC) in all groups revealed greater values during the day. The highest AUC and AUC(24)/minimal inhibitory concentration (MIC) ratio were obtained in the group medicated with 400 mg/l and the corresponding lowest values were found in the group medicated with 100 ppm in feed. 6. In conclusion, tylosin did not reach therapeutic serum concentrations during the dark period, at all dose rates tested when administered in feed or water. A sustained release form of this drug is needed to solve this inadequacy of tylosin medication in broilers. | 18,836,909 |
Clinico-pathomorphological, serum biochemical and histological studies in broilers fed ochratoxin A and a toxin deactivator (Mycofix Plus). | 1. Toxic effects of two concentrations (0.5 and 1 mg/kg) of ochratoxin A (OTA) and attenuating effects of a toxin deactivator (Mycofix Plus(MTV INSIDE)) containing the yeast Trichosporon mycotoxinivorans on the performance (feed conversion ratio; body weight gain), serum enzymes (lactate dehydrogenase, gamma-glutamyltranspeptidase and aspartate aminotransferase) and clinico-pathomorphology of internal organs were studied in 270 one-day-old broiler chicks divided into 9 groups over a 42-d period. 2. Feed conversion ratios (FCR) in groups fed toxin deactivator were improved compared with groups receiving OTA only. An increase in the relative weight of kidney and liver was observed in groups fed 0.5 and 1 mg/kg OTA on day 42 of the experiment as compared with the control group. In contrast, relative weights of bursa of Fabricius and spleen were not significantly affected in experimental groups exposed to OTA as compared to control groups determined on days 28 and 42 of age. 3. Serum enzymes (LDH, GGT and AST) values in OTA treated groups determined on days 28 and 42 were higher than those of the control group. 4. Histopathological examination of kidney on day 42 revealed degenerative changes in the epithelial cells of the proximal convoluted tubules and massive necrosis of the proximal tubular epithelial cells. These changes were less marked in birds receiving 0.5 mg/kg OTA than in those receiving 1 mg/kg. In general, histological changes in kidneys, liver, bursa and spleen were less pronounced in birds receiving OTA and toxin deactivator concomitantly. 5. Dietary OTA at 0.5 and 1 mg/kg adversely affects FCR, increases the serum liver enzymes and induces pronounced pathomorphological and histological changes in internal organs of broiler chicks. Co-administration of OTA with deactivator attenuated the harmful effects. | 18,836,911 |
Functional and ultrastructural analysis of endothelial-like cells derived from bone marrow stromal cells. | Recent studies have suggested that bone marrow stromal cells (BMSC) have the potential to differentiate into endothelial cells. However, the physiologic functions of the endothelial-like cells derived from BMSC have not been well studied. Human BMSC were induced to differentiate into endothelial-like cells with a combination of cytokines. Morphologic, phenotypic, ultrastructural and functional characterizations of the endothelial-like cells were made. Human BMSC were successfully differentiated into cells with endothelial-like morphology and phenotype in vitro. These cells expressed various endothelial cell functions in vitro, such as release of von Willebrand factor (vWF) mediated by histamine, acetylated low-density lipoprotein (acLDL) uptake, binding of Ulex europaeus agglutinin-1 (UEA-1) and in vitro capillary formation. The cells also acquired important ultrastructural and physiologic properties of endothelial cells as they contained Weibel-Palade bodies, abundant mitochondria with a homogeneous mitochondrial matrix, diluted rough endoplasmic reticula, enlarged Golgi complexes, a regular arrangement of microfilaments and many surface cytoplasmic processes and plasmalemmal vesicles, as well as intercellular tight junctions and desmosome-like structures. Subcutaneous implantation of the endothelial-like cells in Matrigel plugs in immunodeficient mice resulted in the formation of functional blood vessels that contained erythrocytes. Moreover, these cells contributed to in vivo neovascularization during wound healing in rabbit ischemic hindlimb models. Physiologic features of the endothelial-like cells derived from BMSC suggest the potential use of these cells as a functional cell source for therapeutic applications. | 18,836,916 |
Identification of genes associated with paraquat-induced toxicity in SH-SY5Y cells by PCR array focused on apoptotic pathways. | Paraquat (PQ) (1,1-dimethyl-4,4'-bipyridinium dichloride), a widely used herbicide, has been suggested as a potential etiologic factor for the development of Parkinson's disease (PD). In this sense, understanding of the molecular mechanism underlying PQ-induced toxicity to neural cells is important for optimal use as well as for the development of new drugs. To gain insights into PQ-induced neurotoxicity, polymerase chain reaction (PCR) array analysis focused on a panel of apoptosis-related genes was performed using neuroblastoma SH-SY5Y cells. Up to 65 apoptosis-related genes were monitored. Our analysis of apoptotic process through microarray technology showed that in PQ-induced neuroblastoma SH-SY5Y cells, there is a different expression of BIK, CASP3, CASP7, CRADD, DAPK, FAS, and other related genes, in comparison to unstimulated cells. Evaluation of genes regulated differentially is essential for the development of therapeutic approaches in multifactorial diseases as PD. Our data provide a useful basis for screening candidate targets for early diagnosis and further intervention in PQ-mediated toxicity of neural cells. | 18,836,921 |
Physicochemical characteristics of aerosol particles generated during the milling of beryllium silicate ores: implications for risk assessment. | Inhalation of beryllium dusts generated during milling of ores and cutting of beryl-containing gemstones is associated with development of beryllium sensitization and low prevalence of chronic beryllium disease (CBD). Inhalation of beryllium aerosols generated during primary beryllium production and machining of the metal, alloys, and ceramics are associated with sensitization and high rates of CBD, despite similar airborne beryllium mass concentrations among these industries. Understanding the physicochemical properties of exposure aerosols may help to understand the differential immunopathologic mechanisms of sensitization and CBD and lead to more biologically relevant exposure standards. Properties of aerosols generated during the industrial milling of bertrandite and beryl ores were evaluated. Airborne beryllium mass concentrations among work areas ranged from 0.001 microg/m(3) (beryl ore grinding) to 2.1 microg/m(3) (beryl ore crushing). Respirable mass fractions of airborne beryllium-containing particles were < 20% in low-energy input operation areas (ore crushing, hydroxide product drumming) and > 80% in high-energy input areas (beryl melting, beryl grinding). Particle specific surface area decreased with processing from feedstock ores to drumming final product beryllium hydroxide. Among work areas, beryllium was identified in three crystalline forms: beryl, poorly crystalline beryllium oxide, and beryllium hydroxide. In comparison to aerosols generated by high-CBD risk primary production processes, aerosol particles encountered during milling had similar mass concentrations, generally lower number concentrations and surface area, and contained no identifiable highly crystalline beryllium oxide. One possible explanation for the apparent low prevalence of CBD among workers exposed to beryllium mineral dusts may be that characteristics of the exposure material do not contribute to the development of lung burdens sufficient for progression from sensitization to CBD. In comparison to high-CBD risk exposures where the chemical nature of aerosol particles may confer higher bioavailability, respirable ore dusts likely confer considerably less. While finished product beryllium hydroxide particles may confer bioavailability similar to that of high-CBD risk aerosols, physical exposure factors (i.e., large particle sizes) may limit development of alveolar lung burdens. | 18,836,922 |
Partial remission indicates poor functioning and a high level of psychiatric symptoms: a 3-phase 6-year follow-up study on major depression. | Patients with depression in partial remission are at high risk of relapse, but factors associated with being in this outcome group are not well known. We conducted a clinical survey to examine the course of major depression in 87 patients during a follow-up period of 6 years. Beck Depression Inventory (BDI) scores indicated the outcome of depression, i.e. remission, partial remission or fully symptomatic, at 6, 12 and 24 months and after 6 years. The prevalence of partial remission varied from 16% to 23% at different follow-ups. All symptom and functioning scale scores indicated at every assessment that the partial depression group managed better than those in the fully symptomatic group, but worse than those in remission. Partial remission was associated with a significant impairment in psychosocial functioning and a high level of symptoms throughout the follow-up. The partial remission group must be recognized and actively treated. | 18,836,926 |
Recognizing the protruding eye. | It is currently unknown how much exophthalmos may be noticeable to an observer. The authors determined the threshold for detection of exophthalmos may be 4 millimeters. To determine the threshold for detection of exophthalmos by an observer. The Massachusetts Eye and Ear Infirmary Ophthalmic Plastics imaging database was used to select 28 photographs of patients with unilateral exophthalmos measuring between 1 to 11 mm for the study group and 28 photographs of patients without exophthalmos for the control group. One hundred ophthalmology attendings, residents, medical students, and technicians reviewed each photograph. Participants commented on whether the patient appeared "normal" or "abnormal." Eighty-one percent of the control patients were correctly identified as "normal." In comparison, 60% of patients with 1 mm of exophthalmos (p < 0.001), 53% of patients with 2 mm of exophthalmos (p < 0.001), 46% of patients with 3 mm of exophthalmos (p < 0.001), 35% of patients with 4 mm of exophthalmos (p < 0.001), and 40% of patients with 5 mm of exophthalmos (p < 0.001) were identified as "normal." The vast majority of patients (91.9%, p < 0.001) with 6 mm of exophthalmos were identified as "abnormal," and almost all patients (97.9%, p < 0.001) with more than 6 mm of exophthalmos were also described as having an "abnormal" appearance. Greater than half of the patients with 1-2 mm of exophthalmos appear as "normal" as the control patients. In comparison, the majority of patients with 4-5 mm of exophthalmos and nearly all the patients with 6 mm of exophthalmos and greater appear "abnormal." Our data suggests that the point at which exophthalmos becomes clinically perceptible to the majority of observers is 4 mm. There may be patients with 3 mm of exophthalmos and greater with orbital pathology being "missed" on cursory external examinations by general ophthalmologists, optometrists, and general practitioners. | 18,836,932 |
[Providing grief counseling to a major depressive elderly widower: a nurse's experience]. | The death of a spouse is both a major loss and a tremendous life stressor for the partner left behind. Such has been shown to be particularly hard on the elderly. This article describes a nurse's experience caring for an elderly patient suffering from major depression resulting from the death of his wife. While providing nursing care to the client, the author, employing holistic nursing assessment, identified a reciprocal influence between his depressive symptoms and grief reaction. In applying the Inventory of Complicated Grief to ascertain grief reaction intensity to help the client discern between major depressive symptoms and grief reaction, the author found that the client (1) could not accept the loss of his wife, (2) had difficulty adjusting to life after his wife's death, and (3) faced a tense and distant relationship with his son. Such resulted in suicidal ideation and planning and feelings of loneliness, helplessness, hopelessness and incapability, which triggered major depression and a complicated grief reaction. Therefore, the author applied grief counseling to help the client accept the loss of his spouse, communicate his grief, overcome the difficult adjustment to life after his spouse's death, bid farewell to his wife, and establish new relationships. Such counseling gradually helped the client accept the inevitability of death and his wife's passing. To help the client establish new relationships under existing circumstances of negligible external support systems, the author encouraged the client to establish a new relationship with himself and integrate the old-age stage of life cycle naturally into his daily routine. Based on this care experience, we recommend psychiatric nurses assess cautiously the loss experience and grief reaction in elderly widowers under their care in order to provide timely grief counseling intervention to help the client pass quickly through the grieving phase and free him or her from the haze of depression. | 18,836,981 |
Breast radiation therapy guideline implementation in low- and middle-income countries. | Radiation therapy plays a critical role in the management of breast cancer and often is unavailable to patients in low- and middle-income countries (LMCs). There is a need to provide appropriate equipment and to improve the techniques of administration, quality assurance, and use of resources for radiation therapy in LMCs. Although the linear accelerator is the preferred equipment, telecobalt machines may be considered as an acceptable alternative in LMCs. Applying safe and effective treatment also requires well trained staff, support systems, geographic accessibility, and the initiation and completion of treatment without undue delay. In early-stage breast cancer, standard treatment includes the irradiation of the entire breast with an additional boost to the tumor site and should be delivered after treatment planning with at least 2-dimensional imaging. Although postmastectomy radiation therapy (PMRT) has demonstrated local control and overall survival advantages in all patients with axillary lymph node metastases, preference in limited resource settings could be reserved for patients who have >or=4 positive lymph nodes. The long-term risks of cardiac morbidity and mortality require special attention to the volume of heart and lungs exposed. Alternative treatment schedules like hypofractionated radiation and partial breast irradiation currently are investigational. Radiation therapy is an integral component for patients with locally advanced breast cancer after initial systemic treatment and surgery. For patients with distant metastases, radiation is an effective tool for palliation, especially for bone, brain, and soft tissue metastases. The implementation of quality-assurance programs applied to equipment, the planning process, and radiation treatment delivery must be instituted in all radiation therapy centers. | 18,837,022 |
Locally advanced breast cancer: treatment guideline implementation with particular attention to low- and middle-income countries. | The management of locally advanced breast cancer (LABC) is guided by scientific advances but is limited by local resources and expertise. LABC remains very common in low-resource countries. The Systemic Therapy Focus Group met as part of the Breast Health Global Initiative (BHGI) Summit in Budapest, Hungary, in October 2007 to discuss management and implementation of primary systemic therapy (PST) for LABC. PST is standard treatment for large operable breast cancer in enhanced-resource settings and, in all resource settings, should be standard treatment for inoperable breast cancer and for LABC. Standard PST includes anthracycline-based chemotherapy. The addition of sequential taxanes after anthracycline improves pathologic responses and breast-conservation rates and is appropriate at enhanced-resource levels; however, costs and lack of clear survival benefit do not justify their use at limited-resource levels. It remains to define better the role of endocrine therapy as PST, but it is acceptable in elderly women. Aromatase inhibitors have produced better results than tamoxifen in postmenopausal patients and are used in enhanced-resource settings. The less expensive tamoxifen remains useful in low-resource countries. Trastuzumab combined with chemotherapy yields high pathologic response rates in patients with HER2/neu-overexpressing tumors; its use in low-resource countries is limited by high costs. Most studies on PST of LABC were conducted in countries with enhanced resources. BHGI encourages conducting clinical trials in countries with limited resources. | 18,837,023 |
Effective but cost-prohibitive drugs in breast cancer treatment: a clinician's perspective. | New pharmacologic treatments for early-stage breast cancer have been proven effective, but many of them are cost prohibitive in low economic settings. Differences in breast cancer mortality rates between developed and developing countries may be because of differences in screening and treatment options, some of which may be unavailable or limited by cost constraints in countries with limited resources. It is well recognized that treatment choices have to be made within budgetary constraints, and treatment guidelines that address the need to stratify treatment options by available resources have been published by the Breast Health Global Initiative. Practical treatment choices need to be made based on the best available cost-effective information. This article reviews new and emerging medical strategies that may improve the cost-effectiveness equation. | 18,837,028 |
ATP induces long-term potentiation of C-fiber-evoked field potentials in spinal dorsal horn: the roles of P2X4 receptors and p38 MAPK in microglia. | Many studies have shown that adenosine triphosphate (ATP), as a neurotransmitter, is involved in plastic changes of synaptic transmission in central nervous system. In the present study, we tested whether extracellular ATP can induce long-term potentiation (LTP) of C-fiber-evoked field potentials in spinal dorsal horn. The results showed the following: (1) ATP at a concentration of 0.3 mM induced spinal LTP of C-fiber-evoked field potentials, lasting for at least 5 h; (2) spinal application of 2',3'-O-(2,4,6-trinitrophenyl)adenosine-5-triphosphate (TNP-ATP; an antagonist of P2X(1-4) receptors), but not pyridoxal-phosphate-6-azophenyl-2',4'-disulphonic acid (PPADS; an antagonist of P2X(1,2,3,5,7) receptors), 30 min before ATP blocked ATP-induced LTP, indicating that ATP may induce spinal LTP by activation of P2X(4) receptors; (3) at 60 min after LTP induction the level of phospho-p38 mitogen-activated protein kinase (p-p38 MAPK) was significantly elevated and at 180 min after LTP the number of P2X(4) receptors increased significantly; both p-p38 and P2X(4) receptors were exclusively co-located with the microglia marker, but not with neuronal or astrocyte marker; (4) spinal application of TNP-ATP but not PPADS prevented p38 activation; (5) spinal application of SB203580, a p38 MAPK inhibitor, prevented both spinal LTP and the upregulation of P2X(4) receptors. The results suggested that ATP may activate p38 MAPK by binding to intrinsic P2X(4) receptors in microglia, and subsequently enhance the expression of P2X(4) receptors, contributing to spinal LTP. | 18,837,052 |
How we have learned about the complexity of physiology, pathobiology and pharmacology of bile acids and biliary secretion. | During the last decades the concept of bile secretion as merely a way to add detergent components to the intestinal mixture to facilitate fat digestion/absorption and to eliminate side products of heme metabolism has evolved considerably. In the series of mini-reviews that the World Journal of Gastroenterology is to publish in its section of "Highlight Topics", we will intend to give a brief but updated overview of our knowledge in this field. This introductory letter is intended to thank all scientists who have contributed to the development of this area of knowledge in gastroenterology. | 18,837,076 |
Intestinal bile acid physiology and pathophysiology. | Bile acids (BAs) have a long established role in fat digestion in the intestine by acting as tensioactives, due to their amphipatic characteristics. BAs are reabsorbed very efficiently by the intestinal epithelium and recycled back to the liver via transport mechanisms that have been largely elucidated. The transport and synthesis of BAs are tightly regulated in part by specific plasma membrane receptors and nuclear receptors. In addition to their primary effect, BAs have been claimed to play a role in gastrointestinal cancer, intestinal inflammation and intestinal ionic transport. BAs are not equivalent in any of these biological activities, and structural requirements have been generally identified. In particular, some BAs may be useful for cancer chemoprevention and perhaps in inflammatory bowel disease, although further research is necessary in this field. This review covers the most recent developments in these aspects of BA intestinal biology. | 18,837,078 |
Physiology of bile secretion. | The formation of bile depends on the structural and functional integrity of the bile-secretory apparatus and its impairment, in different situations, results in the syndrome of cholestasis. The structural bases that permit bile secretion as well as various aspects related with its composition and flow rate in physiological conditions will first be reviewed. Canalicular bile is produced by polarized hepatocytes that hold transporters in their basolateral (sinusoidal) and apical (canalicular) plasma membrane. This review summarizes recent data on the molecular determinants of this primary bile formation. The major function of the biliary tree is modification of canalicular bile by secretory and reabsorptive processes in bile-duct epithelial cells (cholangiocytes) as bile passes through bile ducts. The mechanisms of fluid and solute transport in cholangiocytes will also be discussed. In contrast to hepatocytes where secretion is constant and poorly controlled, cholangiocyte secretion is regulated by hormones and nerves. A short section dedicated to these regulatory mechanisms of bile secretion has been included. The aim of this revision was to set the bases for other reviews in this series that will be devoted to specific issues related with biliary physiology and pathology. | 18,837,079 |
Chilli anthracnose disease caused by Colletotrichum species. | Anthracnose disease is one of the major economic constraints to chilli production worldwide, especially in tropical and subtropical regions. Accurate taxonomic information is necessary for effective disease control management. In the Colletotrichum patho-system, different Colletotrichum species can be associated with anthracnose of the same host. Little information is known concerning the interactions of the species associated with the chilli anthracnose although several Colletotrichum species have been reported as causal agents of chilli anthracnose disease worldwide. The ambiguous taxonomic status of Colletotrichum species has resulted in inaccurate identification which may cause practical problems in plant breeding and disease management. Although the management and control of anthracnose disease are still being extensively researched, commercial cultivars of Capsicum annuum that are resistant to the pathogens that cause chilli anthracnose have not yet been developed. This paper reviews the causal agents of chilli anthracnose, the disease cycle, conventional methods in identification of the pathogen and molecular approaches that have been used for the identification of Colletotrichum species. Pathogenetic variation and population structure of the causal agents of chilli anthracnose along with the current taxonomic status of Colletotrichum species are discussed. Future developments leading to the disease management strategies are suggested. | 18,837,103 |
Advances in the phylogenesis of Agaricales and its higher ranks and strategies for establishing phylogenetic hypotheses. | We present an overview of previous research results on the molecular phylogenetic analyses in Agaricales and its higher ranks (Agaricomycetes/Agaricomycotina/Basidiomycota) along with the most recent treatments of taxonomic systems in these taxa. Establishing phylogenetic hypotheses using DNA sequences, from which an understanding of the natural evolutionary relationships amongst clades may be derived, requires a robust dataset. It has been recognized that single-gene phylogenies may not truly represent organismal phylogenies, but the concordant phylogenetic genealogies from multiple-gene datasets can resolve this problem. The genes commonly used in mushroom phylogenetic research are summarized. | 18,837,104 |
[Medicinal management of pain and symptoms following the withdrawal of treatment in babies and children]. | We present three cases to illustrate the end-of-life care after withdrawal of mechanical ventilation. In a one-year-old girl with meningococcal septic shock, muscle relaxants were continued when mechanical ventilation was withdrawn. In a 10-day-old girl with perinatal asphyxia a high dose of fentanyl was given before mechanical ventilation was withdrawn. A 6-week-old girl in a vegetative state was fighting for breath after detubation. At the request of the parents to end this condition, vecuronium bromide was given. In these three cases death was probably brought forward by a maximum of 12-24 hours. Three arguments can be presented to justify this: the relief of suffering, the perceptions of the parents and the fact that death was expected within a very short time. The administration of these medicines cannot, however, be considered normal medical practice. Therefore we argue that these cases should be reviewed by the national expert review committee and guidelines should be developed for appropriate palliative care after the withdrawal ofmechanical ventilation. | 18,837,178 |
[Ventricular assist device implantation as a bridge to cardiac transplantation in two adolescents with end-stage cardiomyopathy and heart failure as a result of anthracycline use]. | In a adolescent women aged 15 and 17 years respectively, severe heart failure developed within a few months of anthracycline chemotherapy given for osteosarcoma. In the guidelines of the European Society of Cardiology, malignancy with a remission duration of less than 5 years is an absolute contraindication to cardiac transplantation. Neither patient was eligible to receive a ventricular assist device (VAD) as a bridge to cardiac transplantation in the Netherlands, but they were accepted in Germany. One patient received a cardiac transplant 13 months later and at the last follow-up check she was in good health with a remission of 3 years. The other patient developed bone metastases 6 months after the VAD implantation. Cardiac transplantation was not a treatment option for her. Dose-dependent cardiotoxicity is a serious complication of the use of anthracyclines. In severe heart failure the prognosis is often worse than in adjuvantly treated malignancies like osteosarcoma. VAD may therefore be a valid option for patients with severe heart failure after anthracycline use for a malignancy. In cases of sustained remission VAD may be the bridge to transplantation. | 18,837,186 |
Motor threshold as indicator of premotor and motor cortex excitability. | The premotor cortex is a second generator of motorics, involved in mass inborn movements performance, and in pathology--in genesis of spasticity and other motor disorders. As far as the repetitive transcranial magnetic stimulation (TMS) is expected to be a therapeutic tool in some movement disorders, the investigation of premotor cortex response to TMS seems to be an important first step. The goal of our work was to picture the difference in motor responses of premotor and primary motor areas to TMS, by means of motor threshold (MT), and to give a simple and easy testing method, which may be of use before trying therapeutic TMS in some motor disorders. It is based on the motor threshold values for arms and legs motor responses, as a primary motor and premotor cortex excitabity indicator. Only a transcranial magnetic stimulator is necessary for the investigation. A MagPro stimulator (Medtronic, Denmark) with an original C125 coil have been used. The hand and finger contraction motor threshold by TMS at C(z) was measured. After that the stimulation intensity (combined with facilitation), necessary for gaining muscle contraction in every arm and leg, contra- and ipsilaterally, by TMS at C(z), C3, C4, CF1 and CF2 (left and right premotor zones) was tried. The responses have been assessed visually. The results showed a bilateral arm and leg motor response to unilateral TMS of premotor area. The stimulation intensity necessary to evoke contraction in leg musculature was significant lower at premotor area than this at C(z). On the contrary the TMS at C3 and C4 resulted always only in a contra-lateral arm and sometimes leg contraction. The visual assessment of contra- and ipsilateraly leg and arm muscles participation allowed this to be scanned all over the body. The two motor generators (premotor and primary motor) show different behavior by TMS. The proposed method of motor threshold comparison in TMS of both motor and premotor cortex, necessary to gain motor responses in four limbs may be useful as an easy, fast and noninvasive functional test. | 18,837,191 |
eToims twitch relief method in chronic refractory myofascial pain (CRMP). | CRMP management involves electrical stimulation of motor points. To demonstrate that Electrical Twitch-Obtaining Intramuscular Stimulation (eToims) using ET127 system for noninvasive motor point stimulation is safe and efficacious in CRMP management. Longitudinal observation of consecutive self-pay outpatients treated from 10/06 through 4/08, divided into Preferred Group ("PG", N = 49, 3 Hz, 4 stimuli/site) and Basic Group ("BG", N = 43, 1 Hz stimulation, 1 stimulus/site). PG and BG had comparable ages, symptom durations, treatment session durations and treatment intervals. Each session involved treatment to large muscles of C4-C7 and L3-S1 myotomes. Outcome measures include prior week's verbal pain levels, pre and immediate post-session pain levels, blood pressure (BP), pulse rate (PR), symptomatic (S) and asymptomatic (A) side range-of-motion (ROM) for neck rotation (NR), shoulder external rotation (ER), shoulder internal rotation (IR), straight leg raising (SLR) and FABERE testing. PG and BG showed significant improvements (p < 0.01) in immediate post-session pain levels and measured ROM. Significantly higher ERS (pre and post session percentage changes) noted for BG over PG (p < 0.05). Post-session PR decreased in both groups, more so in PG Systolic BP was mildly elevated in PG but was mildly reduced in BG Both groups showed no diastolic BP changes. Significant negative correlation noted between increasing number of treatments and pain level only in PG (r = -0.3, p = 0.00). Increasing number of treatments in PG correlated significantly with improvement in NRS, NRA, IRS, SLRS, LRA, FABERES and FABEREA whereas BG significantly correlated only for improvement in LRS. PG had lower average pain levels than BG (3.4 +/- 1.9 vs. 4.3 +/- 2.5, p < 0.02). eToims using ET127 electrical stimulator appears safe and efficacious in CRMP management. | 18,837,197 |
Prevalence of opioid dispensings and concurrent gastrointestinal medications in an elderly population from Ontario, Canada. | Although opioid analgesics are effective therapeutic agents, gastrointestinal (GI) side effects represent a challenging consequence of treatment. In an elderly population, age-related physiological changes, such as decreased GI functioning and dehydration, may compound the adverse effects of opioids; therefore, appropriate prophylactic treatment, utilizing laxatives and/or acid suppressants, is particularly important in an elderly population. This study describes the prevalence of outpatient opioid dispensings and the concomitant dispensing of opioids and GI medications in a population 65 years or older enrolled in the Ontario Drug Benefit Program in 2005. Using a retrospective cohort design, dispensings of opioids, laxatives, and acid suppressants were identified using claims reimbursement data. Concurrent dispensings were defined as having at least one "GI medication-dispensed day" overlapping an "opioid-dispensed day". More than 18 percent of the elderly, drug plan population was dispensed an opioid in 2005. Women had more opioid dispensings and were dispensed opioids for extended periods of time as compared with men. Approximately half of patients with an opioid dispensing were concomitantly dispensed a GI medication; these medications were dispensed nearly twice as frequently among people with chronic opioid dispensings when compared with people with nonchronic opioid dispensings. Although laxatives are commonly recommended in patients taking opioids, only half of the older adults in Ontario who were dispensed an opioid also received a concomitant GI medication dispensing. As the elderly are more likely to develop opioid-induced constipation, the prophylactic use of laxatives and/or acid suppressant medications is often necessary to mitigate the side effects associated with their pain management. | 18,837,202 |
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