Family Perspectives on Hospice Care Experiences of Patients with Cancer.
Purpose To determine whether hospice use by patients with cancer is associated with their families' perceptions of patients' symptoms, goal attainment, and quality of end-of-life (EOL) care. Methods We interviewed 2,307 families of deceased patients with advanced lung or colorectal cancer who were enrolled in the Cancer Care Outcomes Research and Surveillance study (a multiregional, prospective, observational study) and died by 2011. We used propensity-score matching to compare family-reported outcomes for patients who did and did not receive hospice care, including the presence and relief of common symptoms (ie, pain, dyspnea), concordance with patients' wishes for EOL care and place of death, and quality of EOL care. We also examined associations between hospice length of stay and these outcomes among hospice enrollees. Results In a propensity-score-matched sample of 1,970 individuals, families of patients enrolled in hospice reported more pain in their patient compared with those not enrolled in hospice. However, families of patients enrolled in hospice more often reported that patients received "just the right amount" of pain medicine (80% v 73%; adjusted difference, 7 percentage points; 95% confidence interval [CI], 1 to 12 percentage points) and help with dyspnea (78% v 70%; adjusted difference, 8 percentage points; 95% CI, 2 to 13 percentage points). Families of patients enrolled in hospice also more often reported that patients' EOL wishes were followed (80% v 74%; adjusted difference, 6 percentage points; 95% CI, 2 to 11 percentage points) and "excellent" quality EOL care (57% v 42%; adjusted difference, 15 percentage points; 95% CI, 11 to 20). Families of patients who received > 30 days of hospice care reported the highest quality EOL outcomes. Conclusion Hospice care is associated with better symptom relief, patient-goal attainment, and quality of EOL care. Encouraging earlier and increased hospice enrollment may improve EOL experiences for patients with cancer and their families.


Cetuximab plus chemotherapy as first-line treatment for metastatic colorectal cancer: effect of KRAS mutation on treatment efficacy in Taiwanese patients.
Cetuximab, either alone or in combination with chemotherapy, is approved for treatment of patients with metastatic colorectal cancer (mCRC). We reviewed retrospectively records of 50 patients with mCRC from a single center in Taiwan. All patients had ECOG performance status grade 2, histological diagnosis of advanced CRC based on RECIST criteria, and were given at least three cycles of chemotherapy plus cetuximab. We compared the effectiveness of therapy in patients with wild-type and mutant KRAS genes, assessed the overall response (OR) rate of patients with locally advanced or metastatic non-resectable CRC, and assessed the progression-free survival (PFS) time. The ten patients with KRAS mutations had poorer response rates than the 40 patients with the wild-type KRAS gene. Patients with the wild-type and mutant genes had similar progression free survival (PFS) status and median time to PFS. The median overall survival time was significantly greater in patients with the wild-type gene than in those with the mutant gene (28.77 ± 6.43 months vs. 15.13 ± 0.50 months, p=0.014). Taiwanese patients with mCRC respond better to a cetuximab plus chemotherapy regime if their tumors have the wild-type KRAS gene.


On the nature of the stimulus information necessary for estimating mean size of visual arrays.
This paper explores the nature of the representations used for computing mean visual size of an array of visual objects of different sizes. In Experiment 1 we found that mean size judgments are accurately made even when the individual objects (circles) upon which those judgments were based were distributed between the two eyes. Mean size judgments were impaired, however, when a subset of the constituent objects involved in the estimation of mean size were rendered invisible by interocular suppression. These findings suggest that mean size is computed from relatively refined stimulus information represented at stages of visual processing beyond those involved in binocular combination and interocular suppression. In Experiment 2 we used an attentional blink paradigm to learn whether this refined information was susceptible to the constraints of attention. Accuracy of mean size judgments was unchanged when one of the two arrays of circles was presented within a rapid serial visual presentation sequence, regardless of task requirement (single vs. dual task) and the array's time of presentation relative to the brief appearance of a target that was the focus of attention. Evidently the refined stimulus information used for computing mean size remains available even in the absence of focused attention.


Fetal hemoglobin in sickle cell anemia: genetic studies of the Arab-Indian haplotype.
Sickle cell anemia is common in the Middle East and India where the HbS gene is sometimes associated with the Arab-Indian (AI) β-globin gene (HBB) cluster haplotype. In this haplotype of sickle cell anemia, fetal hemoglobin (HbF) levels are 3-4 fold higher than those found in patients with HbS haplotypes of African origin. Little is known about the genetic elements that modulate HbF in AI haplotype patients. We therefore studied Saudi HbS homozygotes with the AI haplotype (mean HbF 19.2±7.0%, range 3.6 to 39.6%) and employed targeted genotyping of polymorphic sites to explore cis- and trans- acting elements associated with high HbF expression. We also described sequences which appear to be unique to the AI haplotype for which future functional studies are needed to further define their role in HbF modulation. All cases, regardless of HbF concentration, were homozygous for AI haplotype-specific elements cis to HBB. SNPs in BCL11A and HBS1L-MYB that were associated with HbF in other populations explained only 8.8% of the variation in HbF. KLF1 polymorphisms associated previously with high HbF were not present in the 44 patients tested. More than 90% of the HbF variance in sickle cell patients with the AI haplotype remains unexplained by the genetic loci that we studied. The dispersion of HbF levels among AI haplotype patients suggests that other genetic elements modulate the effects of the known cis- and trans-acting regulators. These regulatory elements, which remain to be discovered, might be specific in the Saudi and some other populations where HbF levels are especially high.


Effects of N-acetyl cysteine on lipid levels and on leukocyte and platelet count in rats after splenectomy.
Many of studies have shown that increased lipid levels play a significant role in the pathogenesis of atherosclerosis after splenectomy. We investigated the effects of N-acetyl cysteine (NAC) on lipid parameters and leukocyte and platelet (PLT) levels following splenectomy. 32 Sprague-Dawley rats weighing from 200 to 250 g were placed into four experimental groups. For 42 days post-operatively, all rats were fed standard rat food and water and the rats in the first group ( n = 8) received no intraperitoneal infusion. Rats in the second group ( n = 6) were given a 50 mg/kg saline solution (SF); those in the third group ( n = 8) received 50 mg/kg NAC and the rats in the fourth group ( n = 8) were administered a 100 mg/kg NAC infusion intraperitoneally. All parameters other than white blood cell count were significantly different between the four groups. There were no significant differences between the control and SF groups in terms of total cholesterol and PLT levels. Triglyceride (TG), very-low-density lipoprotein (VLDL) and high-density lipoprotein (HDL) levels were significantly elevated in the SF group compared with the control rats. There was no statistically significant difference between the SF and NAC 50/100 groups in terms of low-density lipoprotein levels. Total cholesterol, TG, HDL and VLDL levels were significantly reduced and the PLT level was significantly elevated in the NAC 50 and NAC 100 groups compared with the SF group. Serum VLDL and TG levels should be monitored in patients after splenectomy. For reduction in these lipid parameters, early NAC treatment should be initiated. More prospective larger studies are needed to confirm our results.


Removal of disinfection by-product precursors by coagulation and an innovative suspended ion exchange process.
This investigation aimed to compare the disinfection by-product formation potentials (DBPFPs) of three UK surface waters (1 upland reservoir and 2 lowland rivers) with differing characteristics treated by (a) a full scale conventional process and (b) pilot scale processes using a novel suspended ion exchange (SIX) process and inline coagulation (ILCA) followed by ceramic membrane filtration (CMF). Liquid chromatography-organic carbon detection analysis highlighted clear differences between the organic fractions removed by coagulation and suspended ion exchange. Pretreatments which combined SIX and coagulation resulted in significant reductions in dissolved organic carbon (DOC), UV absorbance (UVA), trihalomethane and haloacetic acid formation potential (THMFP, HAAFP), in comparison with the SIX or coagulation process alone. Further experiments showed that in addition to greater overall DOC removal, the processes also reduced the concentration of brominated DBPs and selectively removed organic compounds with high DBPFP. The SIX/ILCA/CMF process resulted in additional removals of DOC, UVA, THMFP, HAAFP and brominated DBPs of 50, 62, 62, 62% and 47% respectively compared with conventional treatment.


Analyses of genome architecture and gene expression reveal novel candidate virulence factors in the secretome of Phytophthora infestans.
Phytophthora infestans is the most devastating pathogen of potato and a model organism for the oomycetes. It exhibits high evolutionary potential and rapidly adapts to host plants. The P. infestans genome experienced a repeat-driven expansion relative to the genomes of Phytophthora sojae and Phytophthora ramorum and shows a discontinuous distribution of gene density. Effector genes, such as members of the RXLR and Crinkler (CRN) families, localize to expanded, repeat-rich and gene-sparse regions of the genome. This distinct genomic environment is thought to contribute to genome plasticity and host adaptation. We used in silico approaches to predict and describe the repertoire of P. infestans secreted proteins (the secretome). We defined the "plastic secretome" as a subset of the genome that (i) encodes predicted secreted proteins, (ii) is excluded from genome segments orthologous to the P. sojae and P. ramorum genomes and (iii) is encoded by genes residing in gene sparse regions of P. infestans genome. Although including only ~3% of P. infestans genes, the plastic secretome contains ~62% of known effector genes and shows >2 fold enrichment in genes induced in planta. We highlight 19 plastic secretome genes induced in planta but distinct from previously described effectors. This list includes a trypsin-like serine protease, secreted oxidoreductases, small cysteine-rich proteins and repeat containing proteins that we propose to be novel candidate virulence factors. This work revealed a remarkably diverse plastic secretome. It illustrates the value of combining genome architecture with comparative genomics to identify novel candidate virulence factors from pathogen genomes.


Effect of corticosteroid withdrawal on tacrolimus and mycophenolate mofetil exposure in a randomized multicenter study.
As corticosteroid-sparing protocols are increasingly utilized in kidney transplant recipients, it is crucial to understand potential drug interactions between tacrolimus (TAC) and the effect of corticosteroid withdrawal as well as to characterize dose adjustments of mycophenolate mofetil (MMF) in this setting. This prospective, multicenter, randomized, double-blind study included 397 patients who were randomized on posttransplant day 8 to receive either placebo (CSWD) or corticosteroid continuance (CCS). TAC trough levels at week two posttransplant were significantly greater in the CSWD group whereas TAC doses were comparable to the CCS group. This interaction was not observed in the African American subgroup. Higher serum creatinine and potassium levels were also observed in the CSWD group. MMF dose was significantly reduced in the CSWD group by the investigators because of decreased WBC counts, mostly outside of study protocol criteria, despite similar incidence of neutropenia and reported cytomegalovirus infection. Understanding TAC and MMF exposure in the context of corticosteroid-sparing protocols should allow for improved dosing of immunosuppressants and better management of posttransplant patients.


Bone Components Downregulate Expression of Toll-Like Receptor 4 on the Surface of Human Monocytic U937 Cells: A Cell Model for Postfracture Immune Dysfunction.
To mimic the immune status of monocyte in the localized fracture region, toll-like receptor 4 (TLR4) surface expression in human monocytic U937 cells was used as the main target to assess immune dysfunction following bone component exposure. We first identified the effects of bone components (including the marrow content) on TLR4 surface expression and then examined the mechanisms underlying the changes. The level of microRNA-146a expression, an indicator of endotoxin tolerance, was also assayed. Bone component exposure downregulated TLR4 surface expression at 24 h by flow cytometry analysis, compatible with the result obtained from the membranous portion of TLR4 by western blot analysis. The cytoplasmic portion of TLR4 paradoxically increased after bone component exposure. Impaired TLR4 trafficking from the cytoplasm to the membrane was related to gp96 downregulation, as observed by western blot analysis, and this was further evidenced by gp96-TLR4 colocalization under confocal microscopy. TaqMan analysis revealed that the expression of microRNA-146a was also upregulated. This cell model demonstrated that bone component exposure downregulated TLR4 surface expression in a gp96-related manner in human monocytic U937 cells, an indicator of immunosuppression at 24 h. Immune dysfunction was further evidenced by upregulation of microRNA-146a expression at the same time point.


Radioimmunoassay for ovine, caprine and bovine prolactin in plasma and tissue extracts.
1. A radioimmunoassay for ovine prolactin is described based on the inhibition of the reaction between (131)I-labelled ovine prolactin and guinea-pig or rabbit antiserum to ovine prolactin. The extent of the reaction after a 4-day incubation period is determined by chromatoelectrophoresis or by adsorption of unchanged (131)I-labelled ovine prolactin on charcoal. The sensitivity is equal to 5.9ng. of prolactin/ml. of plasma with chromatoelectrophoresis, or 0.2ng. of prolactin/ml. of tissue extracts with the charcoal separation. 2. A complete cross-reaction demonstrated between ovine prolactin and caprine pituitary extracts allows the assay to be used to measure caprine prolactin. The partial cross-reactions between ovine prolactin and bovine prolactin and between ovine prolactin and bovine pituitary extract differ, and an alteration in the immunological activity of bovine prolactin during its isolation is suggested. Bovine prolactin in plasma may be measured against a bovine pituitary extract as standard. No cross-reactions were demonstrated with pituitary extracts from a number of other species. The extent of the contamination of ovine and bovine growth hormone preparations by their respective prolactins is shown. 3. Dilutions of ovine and caprine plasma inhibit the reaction between (131)I-labelled ovine prolactin and antiserum with the same characteristics as ovine prolactin. 4. The immunoreactive material in plasma fractionates on Sephadex G-200 and in sucrose density gradients as a single peak similar to that shown by freshly dissolved ovine prolactin. There is no evidence that ovine prolactin is bound to a plasma protein. 5. By suppressing prolactin secretion and assaying serial samples of plasma thereafter it is shown that the immunological activity of the surviving hormone becomes progressively altered with time. It is suggested that this alteration is usually not detected but introduces an element of uncertainty into the quantitative but not the qualitative value of the measurements obtained by reference to standard ovine prolactin.


Concise Review: Canine Diabetes Mellitus as a Translational Model for Innovative Regenerative Medicine Approaches.
Diabetes mellitus (DM) is a common spontaneous endocrine disorder in dogs, which is defined by persistent hyperglycemia and insulin deficiency. Like type 1 diabetes (T1D) in people, canine DM is a complex and multifactorial disease in which genomic and epigenomic factors interact with environmental cues to induce pancreatic β-cell loss and insulin deficiency, although the pathogenesis of canine DM is poorly defined and the role of autoimmunity is further controversial. Both diseases are incurable and require life-long exogenous insulin therapy to maintain glucose homeostasis. Human pancreatic islet physiology, size, and cellular composition is further mirrored by canine islets. Although pancreatic or isolated islets transplantation are the only clinically validated methods to achieve long-term normoglycemia and insulin independence, their availability does not meet the clinical need; they target a small portion of patients and have significant potential adverse effects. Therefore, providing a new source for β-cell replacement is an unmet need. Naturally occurring DM in pet dogs, as a translational platform, is an untapped resource for various regenerative medicine applications that may offer some unique advantages given dogs' large size, longevity, heterogenic genetic background, similarity to human physiology and pathology, and long-term clinical management. In this review, we outline different strategies for curative approaches, animal models used, and consider the value of canine DM as a translational animal/disease model for T1D in people. Stem Cells Translational Medicine 2019;8:450-455.


Expression Screening of Integral Membrane Proteins by Fusion to Fluorescent Reporters.
The production of recombinant integral membrane proteins for structural and functional studies remains technically challenging due to their relatively low levels of expression. To address this problem, screening strategies have been developed to identify the optimal membrane sequence and expression host for protein production. A common approach is to genetically fuse the membrane protein to a fluorescent reporter, typically Green Fluorescent Protein (GFP) enabling expression levels, localization and detergent solubilisation to be assessed. Initially developed for screening the heterologous expression of bacterial membrane proteins in Escherichia coli, the method has been extended to eukaryotic hosts, including insect and mammalian cells. Overall, GFP-based expression screening has made a major impact on the number of membrane protein structures that have been determined in the last few years.


The spatial organization of proton and lactate transport in a rat brain tumor.
Tumors create a heterogeneous acidic microenvironment which assists their growth and which must be taken into account in the design of drugs and their delivery. In addition, the acidic extracellular pH (pHe) is itself exploited in several experimental techniques for drug delivery. The way the acidity is created is not clear. We report here the spatial organization of key proton-handling proteins in C6 gliomas in rat brain. The mean profiles across the tumor rim of the Na+/H+ exchanger NHE1, and the lactate-H+ cotransporter MCT1, both showed peaks. NHE1, which is important for extension and migration of cells in vitro, showed a peak 1.55 times higher than in extratumoural tissue at 0.33 mm from the edge. MCT1 had a broader peak, further into the tumor (maximum 1.76 fold at 1.0 mm from the edge). In contrast, MCT4 and the carbonic anhydrase CAIX, which are associated with hypoxia, were not significantly upregulated in the rim. The spatial distribution of MCT4 was highly correlated with that of CAIX, suggesting that their expression is regulated by the same factors. Since protons extruded by NHE1 diffuse away through extracellular clefts, NHE1 requires a continuous source of intracellular protons. From the stoichiometries of metabolic pathways that produce or consume H+, and the greater availability of glucose compared to oxygen in most parts of a tumor, we support the classic view that most of the net proton efflux from C6 gliomas originates in glycolytic formation of lactate and H+ inside the tumor, but add that some lactate is taken up into cells in the rim on MCT1, and some lactate diffuses away, leaving its associated protons available to re-enter cells for extrusion on NHE1. Therapeutic inhibition of NHE1, MCT1 or CAIX is predicted to affect different parts of a tumor.


Impact of thioctic acid on glycemic indices and associated inflammatory-induced endothelial dysfunction in patients with type 2 diabetes mellitus: A case control study.
To evaluate the effects of thioctic acid (TA) add-on metformin therapy on glycemic indices and associated inflammatory reactions induced-endothelial dysfunction (ED) in patients with type 2 diabetes mellitus (T2DM). In this case-control clinical study, a total number of 70 patients with T2DM compared with 30 healthy controls were divided into three groups: Group A (n = 30), healthy controls; Group B (n = 36), T2DM patients on metformin and Group C (n = 34), T2DM patients on metformin plus TA 600 mg/day. Anthropometric measurements, lipid profile, and routine biochemical variables were estimated. Serum human vascular cell adhesion molecule-1 (VCAM-1) and E-selectin were measured before and after 10 consecutive week's therapy with metformin and/or TA. Metformin therapy led to significant reduction of fasting insulin and insulin resistance (IR) with an increment in the insulin sensitivity (P < 0.01). Metformin therapy improved lipid profile compared to the baseline (P < 0.01) with significant reduction of atherogenic index. Metformin plus TA therapy reduced fasting blood glucose, glycated hemoglobin, and IR and showed increment in the insulin sensitivity (P < 0.01) with insignificant effect on fasting insulin (P = 0.09) compared with metformin monotherapy. sVCAM-1 level was high in patients with T2DM (3.74 ± 1.34 ng/ml) at baseline, which decreased by metformin monotherapy to 2.32 ± 0.67 ng/ml or metformin plus TA to 1.98 ± 0.31 ng/ml (P < 0.01), but metformin plus TA illustrated insignificant difference compared to metformin alone (P = 0.29). TA add on metformin therapy improves glycemic indices and associated inflammatory mediators in patients with T2DM through modulation of IR , IS , and direct direct anti-inflammatory effect.


Gluconeogenesis: An ancient biochemical pathway with a new twist.
Synthesis of sugars from simple carbon sources is critical for survival of animals under limited nutrient availability. Thus, sugar-synthesizing enzymes should be present across the entire metazoan spectrum. Here, we explore the evolution of glucose and trehalose synthesis using a phylogenetic analysis of enzymes specific for the two pathways. Our analysis reveals that the production of trehalose is the more ancestral biochemical process, found in single cell organisms and primitive metazoans, but also in insects. The gluconeogenic-specific enzyme glucose-6-phosphatase (G6Pase) first appears in Cnidaria, but is also present in Echinodermata, Mollusca and Vertebrata. Intriguingly, some species of nematodes and arthropods possess the genes for both pathways. Moreover, expression data from Drosophila suggests that G6Pase and, hence, gluconeogenesis, initially had a neuronal function. We speculate that in insects-and possibly in some vertebrates-gluconeogenesis may be used as a means of neuronal signaling.


Wilson disease: description of 282 patients evaluated over 3 decades.
The clinical manifestations of Wilson disease (WD) are varied and challenging. We conducted the current study to present the phenotypic characteristics and follow-up for a large cohort of patients with WD. We reviewed the medical records of 282 cases of WD (male:female ratio, 196:86) for clinical features, investigations, treatment, and outcome data. The clinical presentations were as follows: hepatic, 42 (14.9%); hepato-neurologic, 10 (3.5%); neurologic, 195 (69.1%); pure psychiatric, 7 (2.4%); osseomuscular, 6 (2.1%); and "presymptomatic," 15 (5.3%). Mean age was 15.9 years. Presymptomatic patients and those with the hepatic form of WD were younger and patients with osseomuscular and psychiatric forms were older than neurologic patients. The mean duration of illness at the time of diagnosis was 28 months. Predominant neurologic features were as follows: parkinsonism, 62.3%; dystonia, 35.4%; cerebellar, 28%; pyramidal signs, 16%; chorea, 9%; athetosis, 2.2%; myoclonus, 3.4%; and behavioral abnormalities, 16%. Kayser-Fleischer (KF) rings were seen as follows: neurologic patients, 100%; hepatic patients, 86%; and presymptomatic patients, 59%. Positive family history was noted in 47% and consanguinity in 54%. Patients born of consanguineous parents had an earlier age of onset and shorter duration of illness before presentation. Serum ceruloplasmin was decreased in 93% and 24-hour urinary copper excretion was increased in 70% of patients. Neuroimaging (computed tomography/magnetic resonance imaging) and electrophysiologic abnormalities were seen in many patients. Overall, 195 patients were on D-penicillamine therapy and 182 on zinc sulphate. Follow-up data, available for 225 patients, for a mean duration of 46 months, revealed improvement in 176, no change in 20, and deterioration in 6. Twenty-three patients died. To conclude, despite increased awareness and recognition and significant inroads into therapeutic frontiers, follow-up remains poor in developing countries and a return to previous level of functioning is not universal.


Development of oseltamivir and zanamivir resistance in influenza A(H1N1)pdm09 virus, Denmark, 2014.
Antiviral treatment of immunocompromised patients with prolonged influenza virus infection can lead to multidrug resistance. This study reveals the selection of antiviral resistance mutations in influenza A(H1N1)pdm09 virus in an immunocompromised patient during a 6-month period. The patient was treated with two courses of oseltamivir (5 days and 2 months, respectively), with the first course starting at symptom onset, and subsequently zanamivir (2 months and 10 days, respectively). Respiratory samples were investigated by Sanger and next generation sequencing (NGS) and, for NGS data, low-frequency-variant-detection analysis was performed. Neuraminidase-inhibition tests were conducted for samples isolated in Madin-Darby canine kidney cells. In a sample collected 15 days after the end of the first treatment with oseltamivir (Day 20 post-symptom onset), oseltamivir resistance was detected (mutation H275Y with 60.3% frequency by NGS). Day 149 when the patient had almost completed the second zanamivir treatment, mixes of the following resistance mutations were detected; H275Y(65.1%), I223R(9.2%), and E119G(89.6%), accompanied by additional mutations, showing a more complex viral population in the long-term treated patient. Two samples obtained on Day 151 from bronchoalveolar lavage (BAL) and nasopharyngeal swab, respectively, showed different mutation profiles, with a higher frequency of antiviral resistance mutations in BAL. The results emphasise the importance of timely antiviral resistance testing both for treatment of individual patients as well as for preventive measures to control the development and transmission of antiviral resistant viruses.


Chamazulene Attenuates ROS Levels in Bovine Aortic Endothelial Cells Exposed to High Glucose Concentrations and Hydrogen Peroxide.
Endothelial cells surround the lumen of blood vessels and modulate many physiological processes, including vascular tone, blood fluidity, inflammation, immunity and neovascularization. Many pathological conditions, including hyperglycemia, may alter endothelial function through oxidative stress, leading to impaired nitric oxide bioavailability and to the onset of an inflammatory state. As widely shown in the last decade, dietary intervention could represent a good strategy to control endothelial dysfunction and atherosclerosis. In particular, extensive research in the field of antioxidant natural derivatives has been conducted. In this study, we evaluated the capability of Chamazulene (Cham), an azulene compound from chamomile essential oil, to attenuate ROS levels in bovine aortic endothelial cells (BAECs) stressed with either high glucose or H2O2. Cell viability at different concentrations of Cham was evaluated through the WST-1 assay, while ROS production acutely induced by High Glucose (HG, 4.5 g/L) treatment or H2O2 (0.5 mM) for 3 h, was quantified with 2'-7'-Dichlorofluorescein diacetate (DCFH-DA) probe using confocal microscopy and flow cytometry. Our results showed a reduction in ROS produced after simultaneous treatment with High Glucose or H2O2 and Cham, thus suggesting an in vitro antioxidant activity of the compound. On the whole, this study shows for the first time the potential role of Cham as a scavenging molecule, suggesting its possible use to prevent the rise of endothelial ROS levels and the consequent vascular damage.


Comparison of the prognostic usefulness of N-terminal pro-brain natriuretic Peptide in patients with heart failure with versus without chronic kidney disease.
In patients with chronic heart failure (CHF), N-terminal pro-brain natriuretic peptide (NT-pro-BNP) predicted poor outcome. Clinical predictors of NT-pro-BNP and its usefulness in the presence of chronic kidney disease (CKD) are largely unknown. A total of 341 patients with stable CHF were enrolled, of whom 183 (54%) had CKD. During a follow-up of 620 +/- 353 days, 57 patients (17%) experienced a cardiac event (cardiac death, need for extracorporeal assist device, or urgent cardiac transplantation), and 64 patients (20%) were rehospitalized because of worsening CHF. NT-pro-BNP was related to New York Heart Association functional class (R = 0.44, p <0.001) and inversely related to ejection fraction (R = -0.52, p <0.001) and glomerular filtration rate (R = -0.32, p <0.001). A cardiac event was independently predicted by NT-pro-BNP (hazard ratio [HR] 1.56, p <0.001), ejection fraction (HR 0.95, p = 0.018), and serum sodium (HR 0.89, p = 0.004). Using receiver-operator characteristic analysis, NT-pro-BNP > or =1,474 pg/ml best separated patients with or without cardiac events. In patients without CKD, outcome was significantly worse in patients with NT-pro-BNP >1,474 pg/ml in comparison to patients with NT-pro-BNP <1,474 pg/ml (event-free survival rate 0% vs 75%; p <0.001). In patients with CKD, outcome was also significantly worse in subjects with NT-pro-BNP >1,474 pg/ml in comparison to those with NT-pro-BNP <1,474 pg/ml (event-free survival rate 48% vs 93%; p <0.001). NT-pro-BNP independently predicted rehospitalization caused by worsening CHF (HR 1.26, p = 0.023), and a cut-off value of 1,474 pg/ml also separated patients with poor and intermediate prognosis in the CKD and non-CKD groups. In conclusion, NT-pro-BNP independently predicted morbidity and mortality in patients with CHF with and without CKD.


High-Sensitivity Cardiac Troponin-Based Strategies for the Assessment of Chest Pain Patients-A Review of Validation and Clinical Implementation Studies.
The introduction of high-sensitivity cardiac troponin (hs-cTn) assays has improved the early assessment of chest pain patients. A number of hs-cTn-based algorithms and accelerated diagnostic protocols (ADPs) have been developed and tested subsequently. In this review, we summarize the data on the performance and clinical utility of these strategies. We reviewed studies investigating the diagnostic and prognostic performance of hs-cTn algorithms [level of detection (LoD) strategy, 0/1-h, 0/2-h, and 0/3-h algorithms) and of hs-cTn-based ADPs, together with the implications of these strategies when implemented as clinical routine. The LoD strategy, when combined with a nonischemic electrocardiogram, is best suited for safe rule-out of myocardial infarction and the identification of patients eligible for early discharge from the emergency department. The 0/1-h algorithms appear to identify most patients as being eligible for rule-out. The hs-cTn-based ADPs mainly focus on prognostic assessment, which is in contrast with the hs-cTn algorithms. They identify smaller proportions of rule-out patients, but there is increasing evidence from prospective studies on their successful clinical implementation. Such information is currently lacking for hs-cTn algorithms. There is a trade-off between safety and efficacy for different hs-cTn-based strategies. This trade-off should be considered for the intended strategy, along with its user-friendliness and evidence from clinical implementation studies. However, several gaps in knowledge remain. At present, we suggest the use of an ADP in conjunction with serial hs-cTn results to optimize the early assessment of chest pain patients.


Effectiveness of interventions to improve the health and housing status of homeless people: a rapid systematic review.
Research on interventions to positively impact health and housing status of people who are homeless has received substantially increased attention over the past 5 years. This rapid review examines recent evidence regarding interventions that have been shown to improve the health of homeless people, with particular focus on the effect of these interventions on housing status. A total of 1,546 articles were identified by a structured search of five electronic databases, a hand search of grey literature and relevant journals, and contact with experts. Two reviewers independently screened the first 10% of titles and abstracts for relevance. Inter-rater reliability was high and as a result only one reviewer screened the remaining titles and abstracts. Articles were included if they were published between January 2004 and December 2009 and examined the effectiveness of an intervention to improve the health or healthcare utilization of people who were homeless, marginally housed, or at risk of homelessness. Two reviewers independently scored all relevant articles for quality. Eighty-four relevant studies were identified; none were of strong quality while ten were rated of moderate quality. For homeless people with mental illness, provision of housing upon hospital discharge was effective in improving sustained housing. For homeless people with substance abuse issues or concurrent disorders, provision of housing was associated with decreased substance use, relapses from periods of substance abstinence, and health services utilization, and increased housing tenure. Abstinent dependent housing was more effective in supporting housing status, substance abstinence, and improved psychiatric outcomes than non-abstinence dependent housing or no housing. Provision of housing also improved health outcomes among homeless populations with HIV. Health promotion programs can decrease risk behaviours among homeless populations. These studies provide important new evidence regarding interventions to improve health, housing status, and access to healthcare for homeless populations. The additional studies included in this current review provide further support for earlier evidence which found that coordinated treatment programs for homeless persons with concurrent mental illness and substance misuse issues usually result in better health and access to healthcare than usual care. This review also provides a synthesis of existing evidence regarding interventions that specifically support homeless populations with HIV.


The atherogenic potential of dietary carbohydrate.
To investigate the role of dietary carbohydrate in atherogenesis. Search of the literature for relevant papers concerning the relationship of insulin/hyperinsulinemia and carbohydrate on the one hand, and the renin-angiotensin system, the sympathetic nervous system, growth factors, i.e. platelet-derived growth factor and insulin-like growth factor-I, C-reactive protein, and dyslipemia, on the other hand, factors well known to be involved in the atherogenic process, as well as for epidemiologic studies investigating the relationship between high-carbohydrate diets and the development of cardiovascular disease. High-carbohydrate nutrition is shown to have the ability to induce vascular inflammation and plaque formation through an insulin-mediated activation of the RAS, growth factors, cytokines, the SNS, and C-reactive protein and to cause an atherogenic lipid profile in normal humans. Epidemiologic studies as well as studies in experimental animals corroborate an important role of dietary carbohydrate in atherogenesis. High-carbohydrate diets, particularly in the form of high-glycemic index carbohydrate, have the ability to directly induce atherosclerosis. Based on anthropologic facts, the reason for these dietary-induced, insulin-mediated, atherogenic metabolic perturbations are suggested to be an insufficient adaptation to starch and sugars during human evolution. Restriction of insulinogenic food (starch and sugars) may help to prevent the development of atherosclerosis, one of the most common and costliest human diseases.


The Northwick Park Study of first episodes of schizophrenia. I. Presentation of the illness and problems relating to admission.
Patients referred over 28 months from nine medical centres for a trial of prophylactic neuroleptic medication following first episodes of schizophrenic illness (462) were assessed with the Present State Examination, WHO scales for disability, past history, and sociodemographic factors, and a rating of disturbed behaviour; 253 fulfilled the study criteria; of the 209 who did not, 54 did not meet the diagnostic criteria, 65 had a history of a previous episode, and in 15 the psychotic illness was found to have an organic basis. The interval between onset of illness and admission varied widely, but was often more than one year and associated with severe behavioural disturbance and family difficulty e.g. in arranging appropriate care. Current arrangements for initiating management of first schizophrenic illnesses are frequently unsatisfactory.


Understanding the role of echocardiography in remodeling after acute myocardial infarction and development of heart failure with preserved ejection fraction.
Despite the use of reperfusion therapies in the last decades, acute myocardial infarction further remains one of the most frequent causes of mortality. This is mainly caused by changes in the ventricular architecture leading to ventricular remodeling, followed by progressive development of heart failure. Transthoracic echocardiography is a non-invasive instrument which can provide information about the extent of the ischemic process and its consequences but can also predict the outcomes after myocardial infarction. Although standard echocardiographic parameters are currently used for risk stratification of these patients, they might not truly reflect left ventricular systolic dysfunction in acute myocardial infarct patients, since the detection of subtle changes in the myocardial function is beyond their limits. The aim of this review is to underline the use of advanced echocardiographic parameters in identifying patients at risk for developing post-acute myocardial infarction heart failure and subsequent adverse events. Advanced echocardiographic parameters derived from speckle tracking echocardiography provide a detailed assessment on the global and regional left ventricular deformation. Therefore, speckle tracking echocardiography has a major role in predicting the prognosis of acute myocardial infarction patients and particularly in the development ofsubsequent heart failure, which might be prevented with early initiation of adequate therapy.


Mapping the homotypic binding sites in CD31 and the role of CD31 adhesion in the formation of interendothelial cell contacts.
CD31 is a member of the immunoglobulin superfamily consisting of six Ig-related domains. It is constitutively expressed by platelets, monocytes, and some lymphocytes, but at tenfold higher levels on vascular endothelial cells. CD31 has both homotypic and heterotypic adhesive properties. We have mapped the homotypic binding sites using a deletion series of CD31-Fc chimeras and a panel of anti-CD31 monoclonal antibodies. An extensive surface of CD31 is involved in homotypic binding with domains 2 and 3 and domains 5 and 6 playing key roles. A model consistent with the experimental data is that CD31 on one cell binds to CD31 on an apposing cell in an antiparallel interdigitating mode requiring full alignment of the six domains of each molecule. In addition to establishing intercellular homotypic contacts. CD31 binding leads to augmented adhesion via beta 1 integrins. The positive cooperation between CD31 and beta 1 integrins can occur in heterologous primate cells (COS cells). The interaction is specific to both CD31 and beta 1 integrins. Neither intercellular adhesion molecule-1 (ICAM-1)/leukocyte function-associated antigen-1 (LCAM-1) nor neural cell adhesion molecule (NCAM)/NCAM adhesion leads to recruitment of beta 1 integrin adhesion pathways. Establishment of CD31 contacts have effects on the growth and morphology of endothelial cells. CD31(D1-D6)Fc inhibits the growth of endothelial cells in culture. In addition, papain fragments of anti-CD31 antibodies (Fab fragments) disrupt interendothelial contact formation and monolayer integrity when intercellular contacts are being formed. The same reagents are without effect once these contacts have been established, suggesting that CD31-CD31 interactions are critically important only in the initial phases of intercellular adhesion.


Electrogoniometer for the measurement of human elbow joint rotation.
Since the electrogoniometric method has been justified for the measurement of lower extremity joint motion, a similar device is developed for the measurement of elbow joint and forearm rotations. In this design, the axis of forearm rotation coincides with the anatomical axis which eliminates the cross talk existing in the regular triaxial goniometer. Although the axis of abduction-adduction is still offset from the elbow joint, special linkage arrangement was used to obtain equivalent motion. Experimental method was used to validate the accuracy of the device and model simulation was performed to emphasize the importance of accurate placement of the instrument on test subjects. Application of the present apparatus to normal subjects was studied to illustrate the range of elbow motion required in performing normal activities of daily living. This device is currently used in the functional evaluation of patients with elbow and forearm problems.


Measuring mental illness stigma.
The effectiveness of efforts designed to address mental illness stigma will rest on our ability to understand stigma processes, the factors that produce and sustain such processes, and the mechanisms that lead from stigmatization to harmful consequences. Critical to such an understanding is our capacity to observe and measure the essential components of stigma processes. This article is designed to assist researchers in selecting or creating measures that can address critical research questions regarding stigma. Our conceptualization of stigma processes leads us to consider components of labeling, stereotyping, cognitive separating, emotional reactions, status loss, and discrimination. We review 123 empirical articles published between January 1995 and June 2003 that have sought to assess mental illness stigma and use these articles to provide a profile of current measurement in this area. From the articles we identify commonly used and promising measures and describe those measures in more detail so that readers can decide whether the described measures might be appropriate for their studies. We end by identifying gaps in stigma measurement in terms of concepts covered and populations assessed.


Magnetic order in a novel 3D oxalate-based coordination polymer {[Cu(bpy)3][Mn2(C2O4)3]·H2O}n.
A heterometallic coordination polymer {[Cu(bpy)3][Mn2(C2O4)3]·H2O}n (1; bpy = 2,2'-bipyridine) was synthesized using a building-block approach and characterized by IR spectroscopy, single-crystal X-ray diffraction, magnetization measurement, and X-band ESR spectroscopy both on a single crystal and a polycrystalline sample. The molecular structure of 1 is made of a three-dimensional (3D) anionic network [Mn2(C2O4)3]n(2n-) and tris-chelated cations [Cu(bpy)3](2+) occupying the vacancies of the framework. In compound 1 magnetic order is confirmed below 12.8 K - magnetization measurements reveal an antiferromagnetic-like network of canted Mn(2+) spins with incorporated paramagnetic Cu(2+) centres. The ESR spectroscopy distinctly shows the phase transition; above T≈ 13 K, single isotropic Lorentzian lines of Mn(2+) ions in the high spin state S = 5/2 were observed, while below this temperature, only characteristic Cu(2+) signals from cations were detected. Thermal decomposition residues of 1 at different temperatures (800-1000 °C) were analyzed by powder X-ray diffraction; by heating the sample up to 1000 °C the spinel oxide CuMn2O4 [94.1(2) wt%] was formed. From the refined structural parameters, it could be seen that the obtained spinel is characterized by the inversion parameter δ∼ 0.8, and therefore the structural formula at room temperature can be written as (tet)[Cu0.17Mn0.83](oct)[Mn1.17Cu0.83]O4.


The effect of cluster loading on force, velocity, and power during ballistic jump squat training.
The purpose of this study was to investigate the effect of set structure, in terms of repetition work:rest ratios on force, velocity, and power during jump squat training. Twenty professional and semiprofessional rugby players performed training sessions comprising four sets of 6 repetitions of a jump squat using four different set configurations. The first involved a traditional configuration (TR) of 4 × 6 repetitions with 3 min of rest between sets, the second (C1) 4 × 6 × singles (1 repetition) with 12 s of rest between repetitions, the third (C2) 4 × 3 × doubles (2 repetitions) with 30 s of rest between pairs, and the third (C3) 4 × 2 × triples (3 repetitions) with 60 s of rest between triples. A spreadsheet for the analysis of controlled trials that calculated the P-value, and percent difference and Cohen's effect size from log-transformed data was used to investigate differences in repetition force, velocity, and power profiles among configurations. Peak power was significantly lower (P < .05) for the TR condition when compared with C1 and C3 for repetition 4, and all cluster configurations for repetitions 5 and 6. Peak velocity was significantly lower (P < .05) for the TR condition compared with C3 at repetition 4, significantly lower compared with C2 and C3 at repetition 5, and significantly lower compared with all cluster conditions for repetition 6. Providing inter-repetition rest during a traditional set of six repetitions can attenuate decreases in power and velocity of movement through the set.


Somatostatin receptors in differentiated ovarian tumors.
The presence of somatostatin receptors was investigated in 57 primary human ovarian tumors using in vitro receptor autoradiography with three different somatostatin radioligands, 125I-[Tyr11]-somatostatin-14, 125I-[Leu8, D-Trp22, Tyr25]-somatostatin-28, or 125I-[Tyr3]-SMS 201-995. Three cases, all belonging to epithelial tumors, were receptor positive; specifically 1 of 42 adenocarcinomas, 1 of 3 borderline malignancies, and 1 of 2 cystadenomas. Four other epithelial tumors (3 fibroadenomas, 1 Brenner tumor), 4 sex cord-stromal tumors (2 fibrothecomas, 2 granulosa cell tumors), and 2 germ cell tumors (1 dysgerminoma, 1 teratoma) were receptor negative. In the positive cases, the somatostatin receptors were localized on epithelial cells exclusively, were of high affinity (KD = 4.6 nmol/l [nanomolar]), and specific for somatostatin analogs. These receptors bound somatostatin-14 and somatostatin-28 radioligands with a higher affinity than the octapeptide [Tyr3]-SMS 201-995. Healthy ovarian tissue had no somatostatin receptors. A subpopulation of relatively well-differentiated ovarian tumors, therefore, was identified pathobiochemically on the basis of its somatostatin receptor content. This small group of somatostatin receptor-positive tumors may be a target for in vivo diagnostic imaging with somatostatin ligands.


Preference for polyethylene glycol by sheep fed a quebracho tannin diet.
Tannins decrease food intake by reducing digestion and by causing illness, whereas polyethylene glycol (PEG) attenuates the aversive effects of tannins. Our objective was to determine whether sheep recognize the benefits of ingesting substances such as PEG when consuming tannins. If so, then ingestion of PEG should be 1) PEG-specific, 2) a function of previous experience with recovery from tannin-toxicosis, and 3) dependent on the presence/absence of tannins. During conditioning, lambs in Group 1 (n = 10) were offered a meal of high-tannin food, which presumably caused malaise, and then offered PEG (molecular weight, 3,350), which presumably led to recovery from malaise. Subsequently, lambs ingested a control food (wheat straw) that did not have the "medicinal" effects of PEG in the absence of the tannin diet. In contrast, lambs in Group 2 (n = 10) ingested PEG in the absence of the tannin diet, and they ingested the tannin diet only in association with wheat straw. Ingestion of PEG and straw by both groups of lambs increased as a function of the presence of tannins in the diet (P < 0.05). However, when offered a choice among the tannin diet, PEG and straw, or when given the tannin diet and then offered a choice between PEG and straw, lambs trained to associate PEG with tannins ate more PEG than lambs that ingested PEG without tannins (P < 0.05). The responses were apparently PEG-specific; straw intake did not differ between groups of lambs during testing (P > 0.05), and differences in PEG intake disappeared in the absence of tannins (P > 0.05). In summary, our results suggest that lambs fed high-tannin diets discriminated the effects of PEG from those provided by a "nonmedicinal" food (straw). Thus, it may be possible to formulate PEG supplements that allow herbivores to self-regulate intake of PEG under extensive management conditions.


Diabetes recovery by age-dependent conversion of pancreatic δ-cells into insulin producers.
Total or near-total loss of insulin-producing β-cells occurs in type 1 diabetes. Restoration of insulin production in type 1 diabetes is thus a major medical challenge. We previously observed in mice in which β-cells are completely ablated that the pancreas reconstitutes new insulin-producing cells in the absence of autoimmunity. The process involves the contribution of islet non-β-cells; specifically, glucagon-producing α-cells begin producing insulin by a process of reprogramming (transdifferentiation) without proliferation. Here we show the influence of age on β-cell reconstitution from heterologous islet cells after near-total β-cell loss in mice. We found that senescence does not alter α-cell plasticity: α-cells can reprogram to produce insulin from puberty through to adulthood, and also in aged individuals, even a long time after β-cell loss. In contrast, before puberty there is no detectable α-cell conversion, although β-cell reconstitution after injury is more efficient, always leading to diabetes recovery. This process occurs through a newly discovered mechanism: the spontaneous en masse reprogramming of somatostatin-producing δ-cells. The juveniles display 'somatostatin-to-insulin' δ-cell conversion, involving dedifferentiation, proliferation and re-expression of islet developmental regulators. This juvenile adaptability relies, at least in part, upon the combined action of FoxO1 and downstream effectors. Restoration of insulin producing-cells from non-β-cell origins is thus enabled throughout life via δ- or α-cell spontaneous reprogramming. A landscape with multiple intra-islet cell interconversion events is emerging, offering new perspectives for therapy.


Surgery is safe and effective when indicated in the acute phase of hematogenous pyogenic vertebral osteomyelitis.
The overall benefit of surgical management in the acute phase of hematogenous pyogenic vertebral osteomyelitis remains difficult to evaluate because of the balance between potential functional benefit versus complications of surgery. Between 2000 and 2013, in a tertiary care hospital, we analyzed a cohort of patients with hematogenous pyogenic vertebral osteomyelitis treated surgically and compared them to those treated medically. Neurologic deficit (using the ASIA impairment scale) and pain (using the analgesic level required) 4 months later, recurrences and infection-related deaths 12 months later were evaluated. A propensity score was developed to adjust for nonrandomized allocation to surgery. Ninety patients were included (mean age 64 years, 63% male); 28 (31%) were treated surgically. After adjustment for the propensity score, the improvement in neurological deficit at 4 months did not differ between surgical and medical treatment (p = .82), but the reduction of pain tended to be greater in surgical versus medical treatment (p = .051). Recurrences of infection (5%) and infection-related deaths (12%) occurred at similar rates in both groups at 12 months (p = 1.00 for both). Patients with hematogenous pyogenic vertebral osteomyelitis requiring surgery improved equally as non-surgical patients in terms of neurological deficit and residual pain. This result was not hampered by increased complications related to surgery. When indicated, surgery is safe and effective in patients suffering from hematogenous pyogenic vertebral osteomyelitis.


Caffeine Consuming Children and Adolescents Show Altered Sleep Behavior and Deep Sleep.
Caffeine is the most commonly ingested psychoactive drug worldwide with increasing consumption rates among young individuals. While caffeine leads to decreased sleep quality in adults, studies investigating how caffeine consumption affects children's and adolescents' sleep remain scarce. We explored the effects of regular caffeine consumption on sleep behavior and the sleep electroencephalogram (EEG) in children and adolescents (10-16 years). While later habitual bedtimes (Caffeine 23:14 ± 11.4, Controls 22:17 ± 15.4) and less time in bed were found in caffeine consumers compared to the control group (Caffeine 08:10 ± 13.3, Controls 09:03 ± 16.1), morning tiredness was unaffected. Furthermore, caffeine consumers exhibited reduced sleep EEG slow-wave activity (SWA, 1-4.5 Hz) at the beginning of the night compared to controls (20% ± 9% average reduction across all electrodes and subjects). Comparable reductions were found for alpha activity (8.25-9.75 Hz). These effects, however, disappeared in the morning hours. Our findings suggest that caffeine consumption in adolescents may lead to later bedtimes and reduced SWA, a well-established marker of sleep depth. Because deep sleep is involved in recovery processes during sleep, further research is needed to understand whether a caffeine-induced loss of sleep depth interacts with neuronal network refinement processes that occur during the sensitive period of adolescent development.


Increased efficiency of endocrine procedures performed in an ambulatory operating room.
Thyroid and parathyroid procedures historically have been viewed as inpatient procedures. Because of the advancements in surgical techniques, these procedures were transferred from the inpatient operating room (OR) to the outpatient OR at a single academic institution approximately 7 y ago. The goal of this study was to determine whether this change has decreased turnover times and maximized OR utilization. We performed a retrospective review of 707 patients undergoing thyroid (34%) and parathyroid (66%) procedures by a single surgeon at our academic institution between 2005 and 2008. Inpatient and outpatient groups were compared using Student t-test, chi-square test, or the Kruskal-Wallis test where appropriate. Multiple regression analysis was used to determine how patient and hospital factors influenced turnover times. Turnover times were significantly lower in the outpatient OR (mean 18 ± 0.7 min) when compared with the inpatient OR (mean 36 ± 1.4 min) (P < 0.001). When compared by type of procedure, all turnover times remained significantly lower in the outpatient OR. Patients in both ORs were similar in age, gender, and comorbidities. However, inpatients had a higher mean American Society of Anesthesiologists score (2.30 versus 2.13, P < 0.001) and were more likely to have an operative indication of cancer (23.1% versus 9.2%, P < 0.001). Using multiple regression, the inpatient OR remained highly significantly associated with higher turnover times when controlling for these small differences (P < 0.001). Endocrine procedures performed in the outpatient OR have significantly faster turnover times leading to cost savings and greater OR utilization for hospitals.


Persistence of an intact HIV reservoir in phenotypically naive T cells.
Despite the efficacy of antiretroviral therapy (ART), HIV persists in a latent form and remains a hurdle to eradication. CD4+ T lymphocytes harbor the majority of the HIV reservoir, but the role of individual subsets remains unclear. CD4+ T cells were sorted into central, transitional, effector memory, and naive T cells. We measured HIV DNA and performed proviral sequencing of more than 1900 proviruses in 2 subjects at 2 and 9 years after ART initiation to estimate the contribution of each subset to the reservoir. Although our study was limited to 2 subjects, we obtained comparable findings with publicly available sequences. While the HIV integration levels were lower in naive compared with memory T cells, naive cells were a major contributor to the intact proviral reservoir. Notably, proviral sequences isolated from naive cells appeared to be unique, while those retrieved from effector memory cells were mainly clonal. The number of clones increased as cells differentiated from a naive to an effector memory phenotype, suggesting naive cells repopulate the effector memory reservoir as previously shown for central memory cells. Naive T cells contribute substantially to the intact HIV reservoir and represent a significant hurdle for HIV eradication.


The effect of cigarette smoke and arsenic exposure on urothelial carcinoma risk is modified by glutathione S-transferase M1 gene null genotype.
Inter-individual variation in the metabolism of xenobiotics, caused by factors such as cigarette smoking or inorganic arsenic exposure, is hypothesized to be a susceptibility factor for urothelial carcinoma (UC). Therefore, our study aimed to evaluate the role of gene-environment interaction in the carcinogenesis of UC. A hospital-based case-control study was conducted. Urinary arsenic profiles were measured using high-performance liquid chromatography-hydride generator-atomic absorption spectrometry. Genotyping was performed using a polymerase chain reaction-restriction fragment length polymorphism technique. Information about cigarette smoking exposure was acquired from a lifestyle questionnaire. Multivariate logistic regression was applied to estimate the UC risk associated with certain risk factors. We found that UC patients had higher urinary levels of total arsenic, higher percentages of inorganic arsenic (InAs%) and monomethylarsonic acid (MMA%) and lower percentages of dimethylarsinic acid (DMA%) compared to controls. Subjects carrying the GSTM1 null genotype had significantly increased UC risk. However, no association was observed between gene polymorphisms of CYP1A1, EPHX1, SULT1A1 and GSTT1 and UC risk after adjustment for age and sex. Significant gene-environment interactions among urinary arsenic profile, cigarette smoking, and GSTM1 wild/null polymorphism and UC risk were observed after adjustment for potential risk factors. Overall, gene-environment interactions simultaneously played an important role in UC carcinogenesis. In the future, large-scale studies should be conducted using tag-SNPs of xenobiotic-metabolism-related enzymes for gene determination.


Technical modifications of ureteroneocystostomy in renal transplantation: an 18-year experience.
The treatment of choice for patients with end-stage renal disease is renal transplantation. Urinary tract reconstruction is usually done by anti-reflux ureteroneocystostomy, of which there are several techniques. In this study, a comparison of previous studies related to complications and outcome of various extra-vesical uereteroneocystostomy techniques that were used in our center was made. From the year 1988, when renal transplantation was first performed in our center, we utilized many ureteroneocystostomy techniques including Lich-Grigoir, Barry, Tagochi, and finally Barry-Tagochi. With each conversion, we compared the results of the earlier technique with the new one. In addition, we collected the results of four previous studies conducted by our surgeons and analyzed the complications seen with ureteroneocystostomy. A total of 717 renal transplant recipients were included in our study; 214 of these patients were reimplanted by the Barry-Tagochi technique, 155 cases by the Barry technique, 44 cases by the Tagochi technique, and finally, 304 cases by the Lich-Grigor technique. There was no significant difference in the overall complications, urinary leakage and ureteral stenosis, and obstruction between the four groups. However, complicated hematuria was significantly more frequently seen in the Tagochi group (P = 0.002). Also, the mean time taken for ureteroneocystostomy was longer in the Lich-Grigor group (P = 0.001). We found that the Barry-Tagochi technique had an overall incidence of urological complications similar to that of the other extravesical techniques and was less time consuming.


Bonding of articular cartilage using a combination of biochemical degradation and surface cross-linking.
After trauma, articular cartilage often does not heal due to incomplete bonding of the fractured surfaces. In this study we investigated the ability of chemical cross-linkers to facilitate bonding of articular cartilage, either alone or in combination with a pre-treatment with surface-degrading agents. Articular cartilage blocks were harvested from the femoropatellar groove of bovine calves. Two cartilage blocks, either after pre-treatment or without, were assembled in a custom-designed chamber in partial apposition and subjected to cross-linking treatment. Subsequently, bonding of cartilage was measured as adhesive strength, that is, the maximum force at rupture of bonded cartilage blocks divided by the overlap area. In a first approach, bonding was investigated after treatment with cross-linking reagents only, employing glutaraldehyde, 1-ethyl-3-diaminopropyl-carbodiimide (EDC)/N-hydroxysuccinimide (NHS), genipin, or transglutaminase. Experiments were conducted with or without compression of the opposing surfaces. Compression during cross-linking strongly enhanced bonding, especially when applying EDC/NHS and glutaraldehyde. Therefore, all further experiments were performed under compressive conditions. Combinations of each of the four cross-linking agents with the degrading pre-treatments, pepsin, trypsin, and guanidine, led to distinct improvements in bonding compared to the use of cross-linkers alone. The highest values of adhesive strength were achieved employing combinations of pepsin or guanidine with EDC/NHS, and guanidine with glutaraldehyde. The release of extracellular matrix components, that is, glycosaminoglycans and total collagen, from cartilage blocks after pre-treatment was measured, but could not be directly correlated to the determined adhesive strength. Cytotoxicity was determined for all substances employed, that is, surface degrading agents and cross-linkers, using the resazurin assay. Taking the favourable cell vitality after treatment with pepsin and EDC/NHS and the cytotoxic effects of guanidine and glutaraldehyde into account, the combination of pepsin and EDC/NHS appeared to be the most advantageous treatment in this study. In conclusion, bonding of articular cartilage blocks was achieved by chemical fixation of their surface components using cross-linking reagents. Application of compressive forces and prior modulation of surface structures enhanced cartilage bonding significantly. Enzymatic treatment in combination with cross-linkers may represent a promising addition to current techniques for articular cartilage repair.


Ligand redox effects in the synthesis, electronic structure, and reactivity of an alkyl-alkyl cross-coupling catalyst.
The ability of the terpyridine ligand to stabilize alkyl complexes of nickel has been central in obtaining a fundamental understanding of the key processes involved in alkyl-alkyl cross-coupling reactions. Here, mechanistic studies using isotopically labeled (TMEDA)NiMe(2) (TMEDA = N,N,N',N'-tetramethylethylenediamine) have shown that an important catalyst in alkyl-alkyl cross-coupling reactions, (tpy')NiMe (2b, tpy' = 4,4',4' '-tri-tert-butylterpyridine), is not produced via a mechanism that involves the formation of methyl radicals. Instead, it is proposed that (terpyridine)NiMe complexes arise via a comproportionation reaction between a Ni(II)-dimethyl species and a Ni(0) fragment in solution upon addition of a terpyridine ligand to (TMEDA)NiMe(2). EPR and DFT studies on the paramagnetic (terpyridine)NiMe (2a) both suggest that the unpaired electron resides heavily on the terpyridine ligand and that the proper electronic description of this nickel complex is a Ni(II)-methyl cation bound to a reduced terpyridine ligand. Thus, an important consequence of these results is that alkyl halide reduction by (terpyridine)NiR(alkyl) complexes appears to be substantially ligand based. A comprehensive survey investigating the catalytic reactivity of related ligand derivatives suggests that electronic factors only moderately influence reactivity in the terpyridine-based catalysis and that the most dramatic effects arise from steric and solubility factors.


Growth of large sized two-dimensional MoS2 flakes in aqueous solution.
A large lateral size and low dimensions are prerequisites for next generation electronics. Since the first single layer MoS2 transistor reported by Kis's group in 2011, layered transition metal dichalcogenides (TMDs) have been demonstrated to be the ideal candidate for next generation electronics. However, the development of large scale and low cost growth techniques is a crucial step towards TMDs' inclusion in modern electronics and photoelectronics. In this work we develop a cheap, wet chemical, and environment friendly deposition process for two dimensional MoS2 flakes with extended size. For our deposition process, ammonium tetrathiomolybdate (ATTM) dissolved in deionized water was used as precursor solution and was deposited on a SiO2/Si substrate through a Langmuir-Blodgett like deposition process. To our knowledge, this is the first time MoS2 flakes have been grown in an aqueous solution. Large-sized MoS2 flakes exceeding 150 μm in lateral size were obtained after thermal decomposition. Thicknesses ranging from a monolayer to 5 monolayers were confirmed by AFM and Raman spectroscopy. Further investigations revealed that the quality of the produced flakes strongly depends on the post growth thermal treatment and its atmosphere. This simple and nontoxic deposition method is suitable for the preparation of large (hybrid) transition metal dichalcogenide nanostructures for applications in next generation electronics.


Detection and incidence of drug-induced agranulocytosis in hospital: a prospective analysis from laboratory signals.
Our objectives were to assess the detection and incidence of drug-induced agranulocytosis in two university hospitals using hematology laboratory data. A prospective study was undertaken at Toulouse University Hospital (France) and Navarra University Hospital (Spain) for 1 year (from 1 May 2004 to 30 April 2005). Using a computerized process and hematology laboratory data, all neutrophil counts with a value less than 500/mm(3) were registered, allowing identification of inpatients suffering from agranulocytosis during the period of the study. Medical records of all selected patients were then consulted. Cytostatic drugs were excluded from this study. During the period of the study, 225,659 neutrophil counts were performed in both hospitals, of which 2,835 (1.26%) had a neutrophil count less than 500/mm(3), corresponding to 739 patients. Seventeen patients were excluded because of lack of data, and 20 cases of infants younger than 3 months were excluded. Among the remaining patients (n = 702), 23 cases of drug-induced agranulocytosis (excluding cytostatic drugs) were suspected. All cases were classified as "serious" since they led to death in 2 cases, hospitalization or prolongation of hospitalization in 19 cases and threatening of vital prognosis in 2 cases. Withdrawal of suspected drugs was done in all cases with regression of neutropenia in 21 cases. According to hospitalization data, the annual incidence of drug-induced agranulocytosis was 1.62 (1.0-2.6) per 10,000 inpatients in Toulouse University hospital (based on 534 cases) and 3.24 (0.9-8.3) per 10,000 inpatients in Navarra University Hospital (based on 168 cases). The involved drugs were mainly antibacterial (30.4%), immunosuppressive (17.4%), antithyroid (13.0%), antiplatelet (8.7%) and nonsteroidal anti-inflammatory (8.7%) ones. Only seven cases from Toulouse University Hospital were spontaneously reported by physicians during the same period. Thus, the underreporting coefficient (U) was 2.71 (63.2%) in France. Our survey allowed us to identify the suspected drug-induced agranulocytosis through a prospective study in a large sample of inpatients using only laboratory data analysis. We also note an important underreporting rate of this serious adverse drug reaction (ADR) to the official French pharmacovigilance system. Laboratory data analysis could be used for identifying serious ADRs.


Homologous and heterologous desensitization of capsaicin and mustard oil responses utilize different cellular pathways in nociceptors.
The transient receptor potential channel subtypes V1 (TRPV1) and A1 (TRPA1) play a critical role in the development of hyperalgesia in inflammatory pain models. Although several studies in animals and humans have demonstrated that capsaicin (CAP), a TRPV1-specific agonist, and mustard oil (MO), a TRPA1 agonist, evoke responses that undergo functional cross-desensitization in various models, the mechanisms mediating this phenomenon are largely unknown. In the present study, we evaluated the mechanisms underlying homologous and heterologous desensitization between CAP and MO responses in peripheral nociceptors using an in vitro neuropeptide release assay from acutely isolated rat hindpaw skin preparation and in vivo behavioral assessments. The pretreatment with CAP or MO significantly inhibited (50-60%) both CAP- and MO-evoked CGRP release indicating homologous and heterologous desensitization using this assay. Further studies evaluating the requirement of calcium in these phenomena revealed that homologous desensitization of CAP responses was calcium-dependent while homologous desensitization of MO responses was calcium-independent. Moreover, heterologous desensitization of both CAP and MO responses was calcium-dependent. Further studies evaluating the role of calcineurin demonstrated that heterologous desensitization of CAP responses was calcineurin-dependent while heterologous desensitization of MO responses was calcineurin-independent. Homologous and heterologous desensitization of CAP and MO was also demonstrated using in vivo behavioral nocifensive assays. Taken together, these results indicate that TRPV1 and TRPA1 could be involved in a functional interaction that is regulated via different cellular pathways. The heterologous desensitization of these receptors and corresponding inhibition of nociceptor activity might have potential application as a therapeutic target for developing novel analgesics.


The coherent gradient sensor for film curvature measurements at cryogenic temperature.
Coherent Gradient Sensor (CGS) system is presented for measurement of curvatures and nonuniform curvatures changes in film-substrate systems at cryogenic temperature. The influences of the interface of refrigerator and itself on the interferograms which are accounting for the temperature effect are successfully eliminated. Based on the measurement technique, the thermal stresses (including the radial stress, circumferential stress and shear stress) of superconducting YBCO thin-film are obtained by the extended Stoney's formula during the heating process from 30K to 150K. Take the superconducting YBCO thin film as an example, the thermal stresses of which are gained successfully.


PET genes of Saccharomyces cerevisiae.
We describe a collection of nuclear respiratory-defective mutants (pet mutants) of Saccharomyces cerevisiae consisting of 215 complementation groups. This set of mutants probably represents a substantial fraction of the total genetic information of the nucleus required for the maintenance of functional mitochondria in S. cerevisiae. The biochemical lesions of mutants in approximately 50 complementation groups have been related to single enzymes or biosynthetic pathways, and the corresponding wild-type genes have been cloned and their structures have been determined. The genes defined by an additional 20 complementation groups were identified by allelism tests with mutants characterized in other laboratories. Mutants representative of the remaining complementation groups have been assigned to one of the following five phenotypic classes: (i) deficiency in cytochrome oxidase, (ii) deficiency in coenzyme QH2-cytochrome c reductase, (iii) deficiency in mitochondrial ATPase, (iv) absence of mitochondrial protein synthesis, and (v) normal composition of respiratory-chain complexes and of oligomycin-sensitive ATPase. In addition to the genes identified through biochemical and genetic analyses of the pet mutants, we have cataloged PET genes not matched to complementation groups in the mutant collection and other genes whose products function in the mitochondria but are not necessary for respiration. Together, this information provides an up-to-date list of the known genes coding for mitochondrial constituents and for proteins whose expression is vital for the respiratory competence of S. cerevisiae.


Observation of Spectral Structures in the Flux of Cosmic-Ray Protons from 50 GeV to 60 TeV with the Calorimetric Electron Telescope on the International Space Station.
A precise measurement of the cosmic-ray proton spectrum with the Calorimetric Electron Telescope (CALET) is presented in the energy interval from 50 GeV to 60 TeV, and the observation of a softening of the spectrum above 10 TeV is reported. The analysis is based on the data collected during ∼6.2 years of smooth operations aboard the International Space Station and covers a broader energy range with respect to the previous proton flux measurement by CALET, with an increase of the available statistics by a factor of ∼2.2. Above a few hundred GeV we confirm our previous observation of a progressive spectral hardening with a higher significance (more than 20 sigma). In the multi-TeV region we observe a second spectral feature with a softening around 10 TeV and a spectral index change from -2.6 to -2.9 consistently, within the errors, with the shape of the spectrum reported by DAMPE. We apply a simultaneous fit of the proton differential spectrum which well reproduces the gradual change of the spectral index encompassing the lower energy power-law regime and the two spectral features observed at higher energies.


Recurrent intestinal volvulus in midgut malrotation causing acute bowel obstruction: A case report.
Intestinal malrotation occurs when there is a disruption in the normal embryological development of the bowel. The majority of patients present with clinical features in childhood, though rarely a first presentation can take place in adulthood. Recurrent bowel obstruction in patients with previous abdominal operation for midgut malrotation is mostly due to adhesions but very few reported cases have been due to recurrent volvulus. We present the case of a 22-year-old gentleman who had laparotomy in childhood for small bowel volvulus and then presented with acute bowel obstruction. Preoperative computerised tomography scan showed small bowel obstruction and features in keeping with midgut malrotation. Emergency laparotomy findings confirmed midgut malrotation with absent appendix, abnormal location of caecum, ascending colon and small bowel. In addition, there were small bowel volvulus and a segment of terminal ileal stricture. Limited right hemicolectomy was performed with excellent postoperative recovery. This case is presented to illustrate a rare occurrence and raise an awareness of the possibility of dreadful recurrent volvulus even several years following an initial Ladd's procedure for midgut malrotation. Therefore, one will need to exercise a high index of suspicion and this becomes very crucial in order to ensure prompt surgical intervention and thereby preventing an attendant bowel ischaemia with its associated high fatality.


Difference between Primary and Secondary Infertility in Morocco: Frequencies and Associated Factors.
The main objective of this survey was to determine the difference between primary and secondary infertility in Morocco and the associated factors among women, who are referred to public and private health centers in Morocco. In this cross-sectional study, 619 infertile women referring to public and private health centers in Marrakech-Safi region, were selected by simple random sampling method. This study was conducted between 1 October 2013 and 31 December 2015. Socio-economic status, demographic characteristics, couple's age, nutritional status and other data related to both male and female reproductive organs were collected by a questionnaire. Logistic regression was used to identify the associated factors to infertility. Statistical significance was set at 0.05. The rates of primary and secondary infertility were 67.37, and 32.63%, respectively. Multivariate analysis identified a model with three significant predictive factors of secondary infertility: duration of marriage [odds ratio (OR)=12.263: 2.289-65.685], socio-economic status (OR=3.83: 1.011-14.70) and the ages of women (OR=1.268: 1.038-1.549). The causes of primary and secondary infertility were not always a woman's problem, but both man and woman contribute to infertility. Multiple regression analysis showed that women's age, duration of marriage, and socioeconomic status are predictive variables that decrease the chance of fertility among women with secondary infertility.


[Epidemiology of severe acute renal failure in Metropolitan Santiago].
There is a paucity of information about the epidemiology of acute renal failure in Chile. To perform a prospective multicentric survey of severe acute renal failure in Chile. All patients admitted to ten hospitals in Metropolitan Santiago, during a period of six months with severe acute renal failure, were studied. The criteria for severity was the requirement of renal replacement therapy. All patients information was gathered in special forms and the type of renal replacement therapy and evolution was registeres. One hundred fourteen patients were studied (65 males, age range 18 to 87 years). The calculated incidence of acute renal failure was 1.03 cases per 1000 hospital discharges. The onset was nosocomial in 79 subjects (69%) and community acquired in the rest. Renal failure was oliguric in 64 cases (56%) and in 60% of patients it had two or more causative factors. Sepsis, isolated or combined with other causes, was present in 51 of patients. Other causes included ischemia in 47%, surgery in 26%, exogenous toxicity in 25%, endocenous toxicity in 11%, acute glomerular damage in 6% and obstructive uropathy in 6%. Cardiac surgery was responsible for 47% of post operative cases of acute renal failure. Intermittent conventional hemodialysis, continuous renal replacement techniques and daily prolonged hemodialysis were used in 66%, 29% and 2% of patients, respectively. Overall mortality was 45% and it was higher in oliguric patients. Gender, age, cause or the type of therapy did not influence survival. Nine percent of surviving patients had some degree of kidney dysfunction at discharge. There is still a great space for prevention of severe acute renal failure in Chile, considering the main etiologies found in this study.


Pathogenesis, diagnosis and management of primary melanoma of the colon.
Melanomas within the alimentary tract are usually metastatic in origin. On the other hand, primary melanomas of the gastrointestinal tract are relatively uncommon. There are several published reports of melanomas occurring in the esophagus, stomach, small bowel, and anorectum. The occurrence of primary melanoma of the colon has, however, only been rarely reported. The optimum modus operandi for the management of primary colonic melanoma remains nebulous due to the limited number of reports in literature. A comprehensive search of Medline, Cochrane and Highwire was performed using the following keywords: 'melanoma', 'malignant melanoma', 'primary melanoma', 'colon', 'gastrointestinal tract', 'alimentary tract', 'digestive tract', and 'large bowel'. All patients with primary melanoma localized to the colon were included in the review. Patients with metastatic melanomas to the gastrointestinal (GI) tract and primary melanomas localized to the GI tract in anatomic locations other than colon were excluded. There have been only 12 reported cases of primary melanoma of the colon to date. The average age of patients on presentation was 60.4 years without any significant gender predilection. Right colon (33%) and cecum (33%) were the most common sites for the occurrence of primary colonic melanoma while abdominal pain (58%) and weight loss (50%) were the most common presenting complaints. Colonoscopy is the most reliable diagnostic investigation and offers the additional advantage of obtaining tissue for diagnosis. S-100 and HMB-45 are highly sensitive and specific for the diagnosis of this malignancy. For primary colonic melanomas that have not metastasized to any distant parts of the body, surgical resection with wide margins appears to be the treatment of choice. Although the management was individualized in every case, most of the authors preferred traditional hemicolectomy as the favored surgical approach. Chemotherapeutic agents including interferons, cytokines, biological agents and radiation therapy for brain metastases have been reported as adjuvant and palliative options while considering malignant melanomas in general. The average recurrence-free interval was 2.59 years. Nine of the 12 reports documented follow-up in their patients. Two of these 9 (22.2%) patients died. Primary melanoma of the colon is a rare clinical entity. Whenever a seemingly primary melanoma is detected in an atypical location such as the colon, it is prudent to conduct a thorough clinical investigation to consider the possibility of metastatic disease. Further studies are needed to document the long term follow-up, survival advantage and safety of the management approaches employed in patients with primary colonic melanoma. Based on current data, surgical resection appears to be appropriate management for primary colonic melanomas; unless the disease has metastasized to distant sites where surgery may have a limited palliative role.


Recent advances in understanding and managing contact dermatitis.
About 20% of the general population is contact-sensitized to common haptens such as fragrances, preservatives, and metals. Many also develop allergic contact dermatitis (ACD), the clinical manifestation of contact sensitization. ACD represents a common health issue and is also one of the most important occupational diseases. Although this inflammatory skin disease is mediated predominantly by memory T lymphocytes recognizing low-molecular-weight chemicals after skin contact, the innate immune system also plays an important role. Along that line, the presence of irritants may increase the risk of ACD and therefore ACD is often seen in the context of irritant contact dermatitis. In this review article, we discuss recent progress in basic research that has dramatically increased our understanding of the pathomechanisms of ACD and provides a basis for the development of novel diagnostic and therapeutic measures. Current methods for diagnosis as well as treatment options of ACD are also discussed.


Disturbed cortico-subcortical interactions during motor task switching in traumatic brain injury.
The ability to suppress and flexibly adapt motor behavior is a fundamental mechanism of cognitive control, which is impaired in traumatic brain injury (TBI). Here, we used a combination of functional magnetic resonance imaging and diffusion weighted imaging tractography to study changes in brain function and structure associated with motor switching performance in TBI. Twenty-three young adults with moderate-severe TBI and twenty-six healthy controls made spatially and temporally coupled bimanual circular movements. A visual cue signaled the right hand to switch or continue its circling direction. The time to initiate the switch (switch response time) was longer and more variable in the TBI group and TBI patients exhibited a higher incidence of complete contralateral (left hand) movement disruptions. Both groups activated the basal ganglia and a previously described network for task-set implementation, including the supplementary motor complex and bilateral inferior frontal cortex (IFC). Relative to controls, patients had significantly increased activation in the presupplementary motor area (preSMA) and left IFC, and showed underactivation of the subthalamic nucleus (STN) region. This altered functional engagement was related to the white matter microstructural properties of the tracts connecting preSMA, IFC, and STN. Both functional activity in preSMA, IFC, and STN, and the integrity of the connections between them were associated with behavioral performance across patients and controls. We suggest that damage to these key pathways within the motor switching network because of TBI, shifts the patients toward the lower end of the existing structure-function-behavior spectrum.


Exceptionally High Levels of Genetic Diversity in Wheat Curl Mite (Acari: Eriophyidae) Populations from Turkey.
Recent research on the wheat curl mite species complex has revealed extensive genetic diversity that has distinguished several genetic lineages infesting bread wheat (Triticum aestivum L.) and other cereals worldwide. Turkey is the historical region of wheat and barley (Hordeum vulgare L.) domestication and diversification. The close relationship between these grasses and the wheat curl mite provoked the question of the genetic diversity of the wheat curl mite in this region. The scope of the study was to investigate genetic differentiation within the wheat curl mite species complex on grasses in Turkey. Twenty-one wheat curl mite populations from 16 grass species from nine genera (Agropyron sp., Aegilops sp., Bromus sp., Elymus sp., Eremopyrum sp., Hordeum sp., Poa sp., Secale sp., and Triticum sp.) were sampled in eastern and southeastern Turkey for genetic analyses. Two molecular markers were amplified: the cytochrome oxidase subunit I coding region of mtDNA (COI) and the D2 region of 28S rDNA. Phylogenetic analyses revealed high genetic variation of the wheat curl mite in Turkey, primarily on Bromus and Hordeum spp., and exceptionally high diversity of populations associated with bread wheat. Three wheat-infesting wheat curl mite lineages known to occur on other continents of the world, including North and South America, Australia and Europe, were found in Turkey, and at least two new genetic lineages were discovered. These regions of Turkey exhibit rich wheat curl mite diversity on native grass species. The possible implications for further studies on the wheat curl mite are discussed.


Vascular graph model to simulate the cerebral blood flow in realistic vascular networks.
At its most fundamental level, cerebral blood flow (CBF) may be modeled as fluid flow driven through a network of resistors by pressure gradients. The composition of the blood as well as the cross-sectional area and length of a vessel are the major determinants of its resistance to flow. Here, we introduce a vascular graph modeling framework based on these principles that can compute blood pressure, flow and scalar transport in realistic vascular networks. By embedding the network in a computational grid representative of brain tissue, the interaction between the two compartments can be captured in a truly three-dimensional manner and may be applied, among others, to simulate oxygen extraction from the vessels. Moreover, we have devised an upscaling algorithm that significantly reduces the computational expense and eliminates the need for detailed knowledge on the topology of the capillary bed. The vascular graph framework has been applied to investigate the effect of local vascular dilation and occlusion on the flow in the surrounding network.


The societal cost of tuberculosis: Tarrant County, Texas, 2002.
Cost analyses of tuberculosis (TB) in the United States have not included elements that may be prevented if TB were prevented, such as losses associated with TB-related disability, personal and other costs to society. Unmeasured TB costs lead to underestimates of the benefit of prevention and create conditions that could result in a resurgence of TB. We gathered data from Tarrant County, Texas, for 2002, to estimate the societal cost due to TB. We estimated societal costs due to the presence or suspicion of TB using known variable and fixed costs incurred to all parties. These include costs for infrastructure; diagnostics and surveillance; inpatient and outpatient treatment of active, suspected, and latent TB infection (LTBI); epidemiologic activities; personal costs borne by patients and by others for lost time, disability, and death; and the cost of secondary transmission. A discount rate of 3% was used. During 2002, 108 TB cases were confirmed in Tarrant County, costing an estimated $40,574,953. The average societal cost per TB illness was $ 376,255. Secondary transmission created 47% and pulmonary impairment after TB created 35.4% of the total societal cost per illness. Prior estimates have concluded that treatment costs constitute most (86%) TB-related expenditures. From a societal perspective treatment and other direct costs account for little (3.3%) of the full burden. These data predict that preventing infection through earlier TB diagnosis and treatment of LTBI and expanding treatment of LTBI may be the most feasible strategies to reduce the cost of TB.


Polar patterns of driven filaments.
The emergence of collective motion exhibited by systems ranging from flocks of animals to self-propelled microorganisms to the cytoskeleton is a ubiquitous and fascinating self-organization phenomenon. Similarities between these systems, such as the inherent polarity of the constituents, a density-dependent transition to ordered phases or the existence of very large density fluctuations, suggest universal principles underlying pattern formation. This idea is followed by theoretical models at all levels of description: micro- or mesoscopic models directly map local forces and interactions using only a few, preferably simple, interaction rules, and more macroscopic approaches in the hydrodynamic limit rely on the systems' generic symmetries. All these models characteristically have a broad parameter space with a manifold of possible patterns, most of which have not yet been experimentally verified. The complexity of interactions and the limited parameter control of existing experimental systems are major obstacles to our understanding of the underlying ordering principles. Here we demonstrate the emergence of collective motion in a high-density motility assay that consists of highly concentrated actin filaments propelled by immobilized molecular motors in a planar geometry. Above a critical density, the filaments self-organize to form coherently moving structures with persistent density modulations, such as clusters, swirls and interconnected bands. These polar nematic structures are long lived and can span length scales orders of magnitudes larger than their constituents. Our experimental approach, which offers control of all relevant system parameters, complemented by agent-based simulations, allows backtracking of the assembly and disassembly pathways to the underlying local interactions. We identify weak and local alignment interactions to be essential for the observed formation of patterns and their dynamics. The presented minimal polar-pattern-forming system may thus provide new insight into emerging order in the broad class of active fluids and self-propelled particles.


beta2-adrenergic receptor polymorphisms and salbutamol-stimulated energy expenditure.
The beta-adrenergic system is involved in the control of energy metabolism and expenditure. The beta2-adrenergic receptor (beta2-AR) gene shows polymorphisms that have been associated with obesity in several studies. In vitro and in vivo studies suggest differences in beta2-AR-mediated function between these polymorphisms. The aim of this study was to investigate the influence of genetic variation in codon 16 of the beta2-AR gene on energy metabolism in humans. Thirty-four subjects were recruited [Gly16Gly (n = 13), Gly16Arg (n = 16), or Arg16Arg (n = 5)]. The beta2-AR was stimulated with two doses of salbutamol (50 and 100 ng/kg fat-free mass per minute) after blockade of the beta1-adrenergic receptors with atenolol. Energy expenditure and plasma substrate and hormone concentrations were measured. The increase in energy expenditure (DeltaEE) was significantly different among groups in which the Arg16Arg group showed the lowest increase (P < 0.05 vs. Gly carriers). In a multiple regression model, variations in the increase in nonesterified fatty acid concentration during salbutamol infusion (partial r = 0.51) and the polymorphism contributed significantly to the variation in DeltaEE. Thirty-five percent of the variation in DeltaEE was explained by these two factors. We conclude that subjects with the Arg16Arg polymorphism of the beta2-AR gene have a reduced thermogenic response to beta2-adrenergic stimulation. Although this relatively small study needs confirmation, the findings support a role for this polymorphism in the development and maintenance of overweight and obesity.


The economic burden of skeletal-related events among elderly men with metastatic prostate cancer.
Advanced prostate cancer patients with bone metastasis are predisposed to skeletal complications termed skeletal-related events (SREs). There is limited information available on Medicare costs associated with treating SREs. The objective of this study was to ascertain SRE-related costs among older men with metastatic prostate cancer in the US. We analysed patients aged 66 years or older who were diagnosed with incident stage IV (M1) prostate cancer between 2000 and 2007 from the linked Surveillance, Epidemiology and End Results (SEER)-Medicare dataset. A propensity score for the incidence of an SRE was estimated using a logistic regression model including demographic and clinical baseline variables. Patients with SREs (cases) were matched to patients without SREs (controls) based on the propensity score, length of follow-up (i.e. date of prostate cancer diagnosis to last date of observation) and death. Health resource utilization cost differences between cases and controls over time were compared using generalized linear models. Healthcare costs were examined by type of SRE (pathological fracture only, pathological fracture with concurrent surgery, spinal cord compression only, spinal cord compression with concurrent surgery, and bone surgery only) and by source of care (inpatient, physician/non-institutional provider, skilled nursing facility, outpatient and hospice). All costs were adjusted to 2009 US dollars, using the medical care component of the Consumer Price Index. Application of the inclusion criteria resulted in 1,131 metastatic prostate cancer patients with SREs and 6,067 patients without SREs during follow-up. The average age of the sample was 79 years, and 14 % were African American. A total of 928 patients with SREs were matched to 928 patients without SREs. The average health care utilization cost of patients with SREs was US$29,696 (95 % confidence interval [CI] US$24,730-US$34,662) higher than that of the controls. The most expensive SRE group was spinal cord compression with concurrent surgery (US$82,868: 95 % CI US$67,472-US$98,264) followed by bone surgery only (US$37,496: 95 % CI US$29,684-US$45,308), pathological fracture with concurrent surgery (US$34,169: 95 % CI US$25,837-US$ 42,501), spinal cord compression only (US$25,793: 95 % CI US$20,933-US$30,653) and pathological fracture only (US$14,649: 95 % CI US$6,537-US$22,761). The largest cost difference by source of care was observed for hospitalizations (p < 0.01). Metastatic prostate cancer patients with SREs incur higher costs compared to similar patients without SREs. SRE costs among older stage IV (M1) prostate cancer patients vary by SRE type, with spinal cord compression and concurrent surgery costing at least twice as much as other SREs.