Genetic differentiation at microsatellite loci among populations of Mycosphaerella graminicola from California, Indiana, Kansas, and North Dakota.
Mycosphaerella graminicola causes Septoria tritici blotch (STB) in wheat (Triticum aestivum) and is considered one of the most devastating pathogens of that crop in the United States. Although the genetic structures of M. graminicola populations from different countries have been analyzed using various molecular markers, relatively little is known about M. graminicola populations from geographically distinct areas of the United States and, in particular, of those from spring versus winter wheat. These are exposed to great differences in environmental conditions, length and season of host-free periods, and resistance sources used in geographically separated wheat breeding programs. Thus, there is more likely to be genetic differentiation between populations from spring versus winter wheat than there is among those within each region. To test this hypothesis, 330 single-spore isolates of M. graminicola representing 11 populations (1 from facultative winter wheat in California, 2 from spring wheat in North Dakota, and 8 from winter wheat in Indiana and Kansas) were analyzed for mating type frequency and for genetic variation at 17 microsatellite or simple-sequence repeat (SSR) loci. Analysis of clone-corrected data revealed an equal distribution of both mating types in the populations from Kansas, Indiana, and North Dakota, but a deviation from a 1:1 ratio in the California population. In total, 306 haplotypes were detected, almost all of which were unique in all 11 populations. High levels of gene diversity (H = 0.31 to 0.56) were observed within the 11 populations. Significant (P ≤ 0.05) gametic disequilibrium, as measured by the index of association (rBarD), was observed in California, one Indiana population (IN1), and three populations (KS1, KS2, and KS3) in Kansas that could not be explained by linkage. Corrected standardized fixation index (G″(ST)) values were 0.000 to 0.621 between the 11 populations and the majority of pairwise comparisons were statistically significant (P ≤ 0.001), suggesting some differentiation between populations. Analysis of molecular variance showed that there was a small but statistically significant level of genetic differentiation between populations from spring versus winter wheat. However, most of the total genetic variation (>98%) occurred within spring and winter wheat regions while <2% was due to genetic differentiation between these regions. Taken together, these results provide evidence that sexual recombination occurs frequently in the M. graminicola populations sampled and that most populations are genetically differentiated over the major spring- and winter-wheat-growing regions of the United States.


Predictors of survival in patients with chronic obstructive pulmonary disease receiving long-term oxygen therapy.
Chronic obstructive pulmonary disease (COPD) affects 2-4% of the UK's population and has significant mortality, however prognostication is difficult. Long-term oxygen therapy (LTOT) has been identified by the Gold Standards Framework as a clinical indicator of advancing disease. We hypothesised the ADO index (for 'Age, Dyspnoea and airflow Obstruction'), which predicts mortality, could be applied to our LTOT population to help identify patients with poor prognosis. We aimed to compare this to the Medical Research Council dyspnoea scale, body mass index, forced expiratory volume in 1 s and gas transfer. This was a retrospective study on 136 patients with COPD started on LTOT, June 2003 to August 2010. Data were collected from LTOT databases and medical records. Patients' length of survival was calculated from initiation of LTOT. Patients were grouped by individual parameters. Survival rates at 6 months, 1 year and 4 years were calculated. GraphPad Prism V.5.0 software was used to construct Kaplan-Meier curves and perform log-rank tests. The ADO index discriminated survival at 6 months, 1 year and 4 years, p=0.0027. Low body mass index (<20) was associated with poor prognosis after 1 and 4 years, p=0.0015. Medical Research Council grade predicted survival at 4 years. Diffusion capacity of the lung for carbon monoxide (DLCO)% predicted and forced expiratory volume in 1 s (FEV1)% predicted did not predict survival. This study showed wide variation in survival in a patient population on LTOT. The ADO score could be used as an early trigger for referral to palliative services, thus enhancing end-of-life care, which improves quality of life in COPD. A prospective study of this application would be required to prove this hypothesis.


A new approach to the analysis of antibiotic resistance data from hospitals.
We aimed to develop a new approach to the analysis of antimicrobial resistance data from the hospitals, which allows simultaneous analysis of both individual- and population-level determinants of bacterial resistance. This was a retrospective cohort study that included adult patients who stayed in the hospital >2 days. We analyzed data using shared frailty Cox models and tested our approach using a priori hypotheses based on biology and epidemiology of antibiotic resistance. For gram-negative bacteria, the use of the major selecting antibiotic by an individual was the main risk factor for acquiring resistant species. Hazard ratios (HRs) were strikingly high for ceftazidime-resistant Enterobacter species (HR=11.17; 95% confidence interval [CI]: 5.67-22.02), ciprofloxacin-resistant Pseudomonas aeruginosa (HR=4.41; 95% CI: 2.14-9.08), and imipenem-resistant P. aeruginosa (HR=7.92; 95% CI: 4.35-14.43). Ward-level use was significant for vancomycin-resistant enterococci (VRE) (HR=1.40; 95% CI: 1.07-1.83) and for imipenem-resistant P. aeruginosa (HR=1.40; 95% CI: 1.08-1.83). Previous incidence of infection in the same ward increased the risk of acquiring methicillin-resistant Staphylococcus aureus (HR=1.22; 95% CI: 1.15-1.30) and VRE (HR=1.53; 95% CI: 1.38-1.70). Our results were consistent with our hypotheses and showed that combining population- and individual-level data is crucial for the exploration of antimicrobial resistance development.


A Polysome-Based microRNA Screen Identifies miR-24-3p as a Novel Promigratory miRNA in Mesothelioma.
The expression of miRNAs in cancer has been widely studied and has allowed the definition of oncomirs and oncosuppressors. We note that it is often underestimated that many mRNAs are expressed, but translationally silent. In spite of this, systematic identification of miRNAs in equilibrium with their target mRNAs on polysomes has not been widely exploited. To identify biologically active oncomirs, we performed a screen for miRNAs acting on the polysomes of malignant mesothelioma (MPM) cells. Only a small percentage of expressed miRNAs physically associated with polysomes. On polysomes, we identified miRNAs already characterized in MPM, as well as novel ones like miR-24-3p, which acted as a promigratory miRNA in all cancer cells tested. miR-24-3p positively regulated Rho-GTP activity, and inhibition of miR-24-3p reduced growth in MPM cells. Analysis of miR-24-3p common targets, in two mesothelioma cell lines, identified a common subset of downregulated genes. These same genes were downregulated during the progression of multiple cancer types. Among the specific targets of miR-24-3p was cingulin, a tight junction protein that inhibits Rho-GTP activity. Overexpression of miR-24-3p only partially abrogated cingulin mRNA, but completely abrogated cingulin protein, confirming its action via translational repression. We suggest that miR-24-3p is an oncomir and speculate that identification of polysome-associated miRNAs efficiently sorts out biologically active miRNAs from inactive ones.Significance: Subcellular localization of miRNAs may predict their role in cancer and identify novel oncogenic miRNAs involved in cancer progression.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/20/5741/F1.large.jpg Cancer Res; 78(20); 5741-53. ©2018 AACR.


The accuracy of surrogate decision makers: a systematic review.
Clinicians currently rely on patient-designated and next-of-kin surrogates to make end-of-life treatment decisions for incapacitated patients. Surrogates are instructed to use the substituted judgment standard, which directs them to make the treatment decision that the patient would have made if he or she were capacitated. However, commentators have questioned the accuracy with which surrogates predict patients' treatment preferences. A systematic literature search was conducted using PubMed, the Cochrane Library, and manuscript references, to identify published studies that provide empirical data on how accurately surrogates predict patients' treatment preferences and on the efficacy of commonly proposed methods to improve surrogate accuracy. Two of us (D.I.S. and D.W.) reviewed all articles and extracted data on the hypothetical scenarios used to assess surrogate accuracy and the percentage of agreement between patients and surrogates. The search identified 16 eligible studies, involving 151 hypothetical scenarios and 2595 surrogate-patient pairs, which collectively analyzed 19 526 patient-surrogate paired responses. Overall, surrogates predicted patients' treatment preferences with 68% accuracy. Neither patient designation of surrogates nor prior discussion of patients' treatment preferences improved surrogates' predictive accuracy. Patient-designated and next-of-kin surrogates incorrectly predict patients' end-of-life treatment preferences in one third of cases. These data undermine the claim that reliance on surrogates is justified by their ability to predict incapacitated patients' treatment preferences. Future studies should assess whether other mechanisms might predict patients' end-of-life treatment preferences more accurately. Also, they should assess whether reliance on patient-designated and next-of-kin surrogates offers patients and/or their families benefits that are independent of the accuracy of surrogates' decisions.


A secretory cellulose-binding protein cDNA cloned from the root-knot nematode (Meloidogyne incognita).
A cDNA encoding a secretory cellulose-binding protein was cloned from the root-knot nematode (Meloidogyne incognita) with RNA fingerprinting. The putative full-length cDNA, named Mi-cpb-1, encoded a 203 amino acid protein containing an N-terminal secretion signal peptide. The C-terminal sequence of the putative MI-CBP-1 was similar to a bacterial-type cellulose-binding domain, whereas the N-terminal sequence did not show significant similarity to any proteins in data bases. Recombinant MI-CBP-1 lacked cellulase activity, but bound to cellulose and plant cell walls. In Southern blot hybridization, Mi-cbp-1 hybridized with genomic DNA from M. incognita, M. arenaria, and M. javanica, but not M. hapla, Heterodera glycines, or Caenorhabditis elegans. Polyclonal antibodies raised against recombinant MI-CBP-1 strongly labeled secretory granules in subventral gland cells of second-stage juveniles in indirect immunofluorescence microscopy. Enzyme-linked immunosorbent assay detection of MI-CBP-1 in stylet secretions of second-stage juveniles with the polyclonal antibodies indicated MI-CBP-1 could be secreted through the nematodes' stylet, suggesting that the cellulose-binding protein may have a role in pathogenesis.


Yttrium-90-labeled anti-CD20 monoclonal antibody therapy of recurrent B-cell lymphoma.
A Phase I/II dose escalation study of 90Y-murine anti-CD20 monoclonal antibody (mAb) in patients with recurrent B-cell lymphoma was performed. The primary objectives of the study were: (a) to determine the effect of the preinfusion of unlabeled anti-CD20 mAb on the biodistribution of 111In-anti-CD20 mAb; (b) to determine the maximal tolerated dose of 90Y-anti-CD20 mAb that does not require bone marrow transplantation; and (c) to evaluate the safety and antitumor effect of 90Y-anti-CD20 mAb in patients with recurrent B-cell lymphoma. Eighteen patients with relapsed low- or intermediate-grade non-Hodgkin's lymphoma were treated. Biodistribution studies with 111In-anti-CD20 mAb were performed prior to therapy. Groups of three or four patients were treated at dose levels of approximately 13.5, 20, 30, 40, and 50 mCi 90Y-anti-CD20 mAb. Three patients were retreated at the 40-mCi dose level. The use of unlabeled antibody affected the biodistribution favorably. Nonhematological toxicity was minimal. The only significant toxicity was myelosuppression. The overall response rate following a single dose of 90Y-anti-CD20 mAb therapy was 72%, with six complete responses and seven partial responses and freedom from progression of 3-29+ months following treatment. Radioimmunotherapy with </=50 mCi 90Y-anti-CD20 mAb resulted in minimal nonhematological toxicity and durable clinical responses in patients with recurrent B-cell lymphoma. Doses of </=40 mCi 90Y-anti-CD20 mAb were not myeloablative.


INCIDENCE OF GASTRIC ULCER IN ALBINO RATS FED DIETS DEFICIENT IN VITAMIN B (B(1)).
73 per cent of a group of albino rats whose diet was deficient in vitamin B have been found to have ulcerations of the gastric mucosa. A control group was found to be free from gastric lesions. Of 74 observed lesions eight were chronic, indurated ulcers resembling chronic peptic ulcer in man. The chronicity of the ulcers seems to be related to the duration rather than the degree of the deficiency. The lesions were generally located along the lesser curvature of the stomach, as is true in man. The size of the lesions in rat and man are comparable if adjustment is made for differences in the sizes of the organs.


Universal health coverage in 'One ASEAN': are migrants included?
As the Association of South East Asian Nations (ASEAN) gears toward full regional integration by 2015, the cross-border mobility of workers and citizens at large is expected to further intensify in the coming years. While ASEAN member countries have already signed the Declaration on the Protection and Promotion of the Rights of Migrant Workers, the health rights of migrants still need to be addressed, especially with ongoing universal health coverage (UHC) reforms in most ASEAN countries. This paper seeks to examine the inclusion of migrants in the UHC systems of five ASEAN countries which exhibit diverse migration profiles and are currently undergoing varying stages of UHC development. A scoping review of current migration trends and policies as well as ongoing UHC developments and migrant inclusion in UHC in Indonesia, Malaysia, Philippines, Singapore, and Thailand was conducted. In general, all five countries, whether receiving or sending, have schemes that cover migrants to varying extents. Thailand even allows undocumented migrants to opt into its Compulsory Migrant Health Insurance scheme, while Malaysia and Singapore are still yet to consider including migrants in their government-run UHC systems. In terms of predominantly sending countries, the Philippines's social health insurance provides outbound migrants with portable insurance yet with limited benefits, while Indonesia still needs to strengthen the implementation of its compulsory migrant insurance which has a health insurance component. Overall, the five ASEAN countries continue to face implementation challenges, and will need to improve on their UHC design in order to ensure genuine inclusion of migrants, including undocumented migrants. However, such reforms will require strong political decisions from agencies outside the health sector that govern migration and labor policies. Furthermore, countries must engage in multilateral and bilateral dialogue as they redefine UHC beyond the basis of citizenship and reimagine UHC systems that transcend national borders. By enhancing migrant coverage, ASEAN countries can make UHC systems truly 'universal'. Migrant inclusion in UHC is a human rights imperative, and it is in ASEAN's best interest to protect the health of migrants as it pursues the path toward collective social progress and regional economic prosperity.


Assessing the Longitudinal Impact of Physician-Patient Relationship on Functional Health.
Access to a usual source of care is associated with improved health outcomes, but research on how the physician-patient relationship affects a patient's health, particularly long-term, is limited. The aim of this study was to investigate the longitudinal effect of changes in the physician-patient relationship on functional health. We conducted a prospective cohort study using the Medical Expenditure Panel Survey (MEPS, 2015-2016). The outcome was 1-year change in functional health (12-Item Short-Form Survey). The predictors were quality of physician-patient relationship, and changes in this relationship, operationalized with the MEPS Primary Care (MEPS-PC) Relationship subscale, a composite measure with preliminary evidence of reliability and validity. Confounders included age, sex, race/ethnicity, educational attainment, insurance status, US region, and multimorbidity. We conducted analyses with survey-weighted, covariate-adjusted, predicted marginal means, used to calculate Cohen effect estimates. We tested differences in trajectories with multiple pairwise comparisons with Tukey contrasts. Improved physician-patient relationships were associated with improved functional health, whereas worsened physician-patient relationships were associated with worsened functional health, with 1-year effect estimates ranging from 0.05 (95% CI, 0-0.10) to 0.08 (95% CI, 0.02-0.13) compared with -0.16 (95% CI, -0.35 to -0.03) to -0.33 (95% CI, -0.47 to -0.02), respectively. The quality of the physician-patient relationship is positively associated with functional health. These findings could inform health care strategies and health policy aimed at improving patient-centered health outcomes.


The effect of hydrogen bonding on the diffusion of water in n-alkanes and n-alcohols measured with a novel single microdroplet method.
While the Stokes-Einstein (SE) equation predicts that the diffusion coefficient of a solute will be inversely proportional to the viscosity of the solvent, this relation is commonly known to fail for solutes, which are the same size or smaller than the solvent. Multiple researchers have reported that for small solutes, the diffusion coefficient is inversely proportional to the viscosity to a fractional power, and that solutes actually diffuse faster than SE predicts. For other solvent systems, attractive solute-solvent interactions, such as hydrogen bonding, are known to retard the diffusion of a solute. Some researchers have interpreted the slower diffusion due to hydrogen bonding as resulting from the effective diffusion of a larger complex of a solute and solvent molecules. We have developed and used a novel micropipette technique, which can form and hold a single microdroplet of water while it dissolves in a diffusion controlled environment into the solvent. This method has been used to examine the diffusion of water in both n-alkanes and n-alcohols. It was found that the polar solute water, diffusing in a solvent with which it cannot hydrogen bond, closely resembles small nonpolar solutes such as xenon and krypton diffusing in n-alkanes, with diffusion coefficients ranging from 12.5x10(-5) cm(2)/s for water in n-pentane to 1.15x10(-5) cm(2)/s for water in hexadecane. Diffusion coefficients were found to be inversely proportional to viscosity to a fractional power, and diffusion coefficients were faster than SE predicts. For water diffusing in a solvent (n-alcohols) with which it can hydrogen bond, diffusion coefficient values ranged from 1.75x10(-5) cm(2)/s in n-methanol to 0.364x10(-5) cm(2)/s in n-octanol, and diffusion was slower than an alkane of corresponding viscosity. We find no evidence for solute-solvent complex diffusion. Rather, it is possible that the small solute water may be retarded by relatively longer residence times (compared to non-H-bonding solvents) as it moves through the liquid.


Repetitive genome elements in a European corn borer, Ostrinia nubilalis, bacterial artificial chromosome library were indicated by bacterial artificial chromosome end sequencing and development of sequence tag site markers: implications for lepidopteran genomic research.
The European corn borer, Ostrinia nubilalis, is a serious pest of food, fiber, and biofuel crops in Europe, North America, and Asia and a model system for insect olfaction and speciation. A bacterial artificial chromosome library constructed for O. nubilalis contains 36 864 clones with an estimated average insert size of >or=120 kb and genome coverage of 8.8-fold. Screening OnB1 clones comprising approximately 2.76 genome equivalents determined the physical position of 24 sequence tag site markers, including markers linked to ecologically important and Bacillus thuringiensis toxin resistance traits. OnB1 bacterial artificial chromosome end sequence reads (GenBank dbGSS accessions ET217010 to ET217273) showed homology to annotated genes or expressed sequence tags and identified repetitive genome elements, O. nubilalis miniature subterminal inverted repeat transposable elements (OnMITE01 and OnMITE02), and ezi-like long interspersed nuclear elements. Mobility of OnMITE01 was demonstrated by the presence or absence in O. nubilalis of introns at two different loci. A (GTCT)n tetranucleotide repeat at the 5' ends of OnMITE01 and OnMITE02 are evidence for transposon-mediated movement of lepidopteran microsatellite loci. The number of repetitive elements in lepidopteran genomes will affect genome assembly and marker development. Single-locus sequence tag site markers described here have downstream application for integration within linkage maps and comparative genomic studies.


Dissecting the Anticancer Mechanism of Trifluoperazine on Pancreatic Ductal Adenocarcinoma.
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers with almost no curative chemotherapeutic treatment. Besides the development of new compounds, repurposing of approved drugs to treat cancer, alone or in combination, has become an attractive strategy, showing many therapeutic and economic advantages. However, it is necessary to improve our knowledge about the mechanism of cell death elicited by approved drugs itself, but also to rationally develop more powerful multidrug treatments. In this work, we focus our attention on determining the mechanism promoting cell death following trifluoperazine (TFP) treatment, which is an antipsychotic drug with strong anticancer activity in PDAC. We demonstrate that TFP induces cell death by apoptosis and necroptosis, which can be partially inhibited by Z-VAD-FMK as well as necrostatin-1, respectively. This cell death promotion is triggered by a poor ATP content, observed in TFP-treated cells as a consequence of a dramatic decrease in OXPHOS metabolism due to mitochondrial stress. Remarkably, mitochondrial homeostasis was seriously affected, and a loss of mitochondrial membrane potential and ROS overproduction was observed. Moreover, this mitochondrial stress was coupled with an ER stress and the activation of the endoplasmic-reticulum-associated protein degradation (ERAD) and the unf olded protein response (UPR) pathways. We took advantage of this information and inhibited this process by using the proteasome inhibitors MG-132 or bortezomib compounds in combination with TFP and found a significant improvement of the anticancer effect of the TFP on primary PDAC-derived cells. In conclusion, this study not only uncovers the molecular mechanisms that are triggered upon TFP-treatment but also its possible combination with bortezomib for the future development of therapies for pancreatic cancer.


Comparison of the hospice systems in the United States, Japan and taiwan.
The aim of hospice care is to provide the best possible quality of life both for people approaching the end of life and for their families and carers. The Korean government has been implementing a pilot project for hospital hospice services and trying to develop the national hospice system. To assist in the development of the Korean hospice system, the Korean government supported the present study comparing the hospice systems of three countries, United States, Japan, and Taiwan, which currently have a developed hospice system. Data from three countries were collected in the following ways: reviewing hospice related literature, searching government documents on the Internet, collecting government hospice data, surveying six hospice institutions in each country, and conducting an international workshop. The hospice system was evaluated by comparing hospice management systems and hospice cost systems. The comparison of the hospice management system included five items of hospice infra structures and four items of hospice services. The hospice cost system included four items: funding source, hospital hospice cost, day care hospice cost, and home hospice cost. Based on the comparison of three countries, the most interesting thing was that home hospice care accounted for more than 90% of all hospice services in the United States and Taiwan. The results of this study will aid the countries that are in the process of developing a hospice system including Korea, which has been implementing a pilot project only for hospital hospice services.


Risk factors of poor prognosis after whiplash injury.
Whiplash, a common injury following motor vehicle crashes, is associated with high costs and a prognosis that is variable and difficult to predict. In this paper, we review findings from the Quebec cohort epidemiological study on predictive factors of recovery from whiplash injury after a motor vehicle crash. We formed a population-based incident cohort of all 4,759 individuals who sustained a whiplash injury resulting from a motor vehicle crash in the province of Québec, Canada, in 1987, and followed these patients for up to seven years. The data were obtained from the universal automobile insurance plan (SAAQ) that covers all seven million residents of the Province for all vehicular-related injuries. From this cohort, we formed the cohort of 3,014 for whom a police report was completed. For this cohort, we obtained data on crash-related factors directly from the police report. We also formed the cohort of 2,627 subjects who had strictly a whiplash injury, without associated injuries. For this cohort, the data on signs and symptoms were obtained from the medical charts kept by the SAAQ. For both cohorts, data on the outcome, the recovery time from whiplash, was obtained from the SAAQ databases. The crash-related cohort study found that socio-demographic factors associated with a longer recovery from whiplash include older age, female sex, having dependents and not being employed full time and that each decreases the rate of recovery by 14 to 16 per cent. Factors related to the crash conditions indicate that being in a truck or bus, with a decrease of 52% in the rate of recovery, being a passenger in the vehicle (15%), colliding with a moving vehicle (16%), and a side or frontal collision (15%) all decrease the rate of recovery. We introduce a combined risk score that predicts longer recovery. In the cohort of subjects with signs and symptoms, the median recovery time was 32 days and 12% of subjects had still not recovered after 6 months. The signs and symptoms that were found to be independently associated with a slower recovery from whiplash, besides female gender and older age, were neck pain on palpation; muscle pain; pain or numbness radiating from neck to arms, hands or shoulders; and headache. Together, the presence of all these factors in females aged 60 predicted a median recovery time of 262 days, compared with 17 days for younger males aged 20 who do not have any of these factors. In contrast, using the Quebec classification of signs and symptoms, the median recovery time varied from 17 to 123 days. We conclude that several socio-demographic and crash-related factors, as well as several signs and symptoms, including a combination of specific musculoskeletal and neurological ones that whiplash patients present with, are predictive of a longer recovery period. These patients should be targeted for an early intervention programme aimed at managing whiplash patients with a poor prognosis.


Adjuvant therapy in rectal cancer: analysis of stage, sex, and local control--final report of intergroup 0114.
The gastrointestinal Intergroup studied postoperative adjuvant chemotherapy and radiation therapy in patients with T3/4 and N+ rectal cancer after potentially curative surgery to try to improve chemotherapy and to determine the risk of systemic and local failure. All patients had a potentially curative surgical resection and were treated with two cycles of chemotherapy followed by chemoradiation therapy and two additional cycles of chemotherapy. Chemotherapy regimens were bolus fluorouracil (5-FU), 5-FU and leucovorin, 5-FU and levamisole, and 5-FU, leucovorin, and levamisole. Pelvic irradiation was given to a dose of 45 Gy to the whole pelvis and a boost to 50.4 to 54 Gy. One thousand six hundred ninety-five patients were entered and fully assessable, with a median follow-up of 7.4 years. There was no difference in overall survival (OS) or disease-free survival (DFS) by drug regimen. DFS and OS decreased between years 5 and 7 (from 54% to 50% and 64% to 56%, respectively), although recurrence-free rates had only a small decrease. The local recurrence rate was 14% (9% in low-risk [T1 to N2+] and 18% in high-risk patients [T3N+, T4N]). Overall, 7-year survival rates were 70% and 45% for the low-risk and high-risk groups, respectively. Males had a poorer overall survival rate than females. There is no advantage to leucovorin- or levamisole-containing regimens over bolus 5-FU alone in the adjuvant treatment of rectal cancer when combined with irradiation. Local and distant recurrence rates are still high, especially in T3N+ and T4 patients, even with full adjuvant chemoradiation therapy.


Effect of marriage on duration of chest pain associated with acute myocardial infarction before seeking care.
Coronary artery disease is the most common cause of death in the Western world, and being married decreases the risk of death from cardiovascular causes. We aimed to determine whether marital status was a predictor of the duration of chest pain endured by patients with acute myocardial infarction before they sought care and whether the patient's sex modified the effect. We conducted a retrospective, population-based cohort analysis of patients with acute myocardial infarction admitted to 96 acute care hospitals in Ontario, Canada, from April 2004 to March 2005. We excluded patients who did not experience chest pain. Using multivariable regression analyses, we assessed marital status in relation to delayed presentation to hospital (more than six hours from onset of pain), both overall and stratified by sex. In patients who reported the exact duration of chest pain, we assessed the effect of marital status on the delay in seeking care. Among 4403 eligible patients with acute myocardial infarction, the mean age was 67.3 (standard deviation 13.6) years, and 1486 (33.7%) were women. Almost half (2037 or 46.3%) presented to a hospital within two hours, and 3240 (73.6%) presented within six hours. Overall, 75.3% (2317/3079) of married patients, 67.9% (188/277) of single patients, 68.5% (189/276) of divorced patients and 70.8% (546/771) of widowed patients presented within six hours of the onset of chest pain. Being married was associated with lower odds of delayed presentation (odds ratio [OR] 0.46, 95% confidence interval [CI] 0.30-0.71, p < 0.001) relative to being single. Among men, the OR was 0.35 (95% CI 0.21-0.59, p < 0.001), whereas among women the effect of marital status was not significant (OR 1.36, 95% CI 0.49-3.73, p = 0.55). Among men experiencing acute myocardial infarction with chest pain, being married was associated with significantly earlier presentation for care, a benefit that was not observed for married women. Earlier presentation for medical care appears to be one reason for the observed lower risk of cardiovascular death among married men, relative to their single counterparts.


Scattering at sidewall roughness in photonic crystal slabs.
We have simulated the effect of sidewall roughness in photonic-crystallike structures with different vertical refractive-index contrast. We treated the scattering off a sidewall irregularity as a radiating dipole excited by the incident waveguide mode. We show that the loss that is due to this scattering is significantly larger for structures with a low refractive-index contrast (such as GaAs/AlGaAs waveguides) than for structures with a high vertical index contrast (such as silicon-on-insulators and membranes).


Construction and characterization of a full-length infectious simian T-cell lymphotropic virus type 3 molecular clone.
Together with their simian T-cell lymphotropic virus (STLV) equivalent, human T-cell lymphotropic virus type 1 (HTLV-1), HTLV-2, and HTLV-3 form the primate T-cell lymphotropic virus (PTLV) group. Over the years, understanding the biology and pathogenesis of HTLV-1 and HTLV-2 has been widely improved by the creation of molecular clones. In contrast, so far, PTLV-3 experimental studies have been restricted to the overexpression of the tax gene using reporter assays. We have therefore decided to construct an STLV-3 molecular clone. We generated a full-length STLV-3 proviral clone (8,891 bp) by PCR amplification of overlapping fragments. This STLV-3 molecular clone was then transfected into 293T cells. Reverse transcriptase PCR experiments followed by sequence analysis of the amplified products allowed us to establish that both gag and tax/rex mRNAs were transcribed. Western blotting further demonstrated the presence of the STLV-3 p24gag protein in the cell culture supernatant from transfected cells. Transient transfection of 293T cells and of 293T-long terminal repeat-green fluorescent protein cells with the STLV-3 clone promoted syncytium formation, a hallmark of PTLV Env expression, as well as the appearance of fluorescent cells, also demonstrating that the Tax3 protein was expressed. Virus particles were visible by electron microscopy. These particles are infectious, as demonstrated by our cell-free-infection experiments with purified virions. All together, our data demonstrate that the STLV-3 molecular clone is functional and infectious. This clone will give us a unique opportunity to study in vitro the different pX transcripts and the putative presence of antisense transcripts and to evaluate the PTLV-3 pathogenicity in vivo.


The representation of health professionals on governing boards of health care organizations in New York City.
The Representation of Health Professionals on Governing Boards of Health Care Organizations in New York City. The heightened importance of processes and outcomes of care-including their impact on health care organizations' (HCOs) financial health-translate into greater accountability for clinical performance on the part of HCO leaders, including their boards, during an era of health care reform. Quality and safety of care are now fiduciary responsibilities of HCO board members. The participation of health professionals on HCO governing bodies may be an asset to HCO governing boards because of their deep knowledge of clinical problems, best practices, quality indicators, and other issues related to the safety and quality of care. And yet, the sparse data that exist indicate that physicians comprise more than 20 % of the governing board members of hospitals while less than 5 % are nurses and no data exist on other health professionals. The purpose of this two-phased study is to examine health professionals' representations on HCOs-specifically hospitals, home care agencies, nursing homes, and federally qualified health centers-in New York City. Through a survey of these organizations, phase 1 of the study found that 93 % of hospitals had physicians on their governing boards, compared with 26 % with nurses, 7 % with dentists, and 4 % with social workers or psychologists. The overrepresentation of physicians declined with the other HCOs. Only 38 % of home care agencies had physicians on their governing boards, 29 % had nurses, and 24 % had social workers. Phase 2 focused on the barriers to the appointment of health professionals to governing boards of HCOs and the strategies to address these barriers. Sixteen health care leaders in the region were interviewed in this qualitative study. Barriers included invisibility of health professionals other than physicians; concerns about "special interests"; lack of financial resources for donations to the organization; and lack of knowledge and skills with regard to board governance, especially financial matters. Strategies included developing an infrastructure for preparing and getting appointed various health professionals, mentoring, and developing a personal plan of action for appointments.


Effects of mechanosensitive ion channels on ventricular electrophysiology: experimental and theoretical models.
The heart is an electrically driven mechanical pump, somewhat like an electric motor. Interestingly, like an electric motor in 'dynamo mode', the heart can also convert mechanical stimuli into electrical signals. This feedback from cardiac mechanics to electrical activity involves mechanosensitive ion channels, whose properties and pathophysiological relevance are reviewed in the context of experimental and theoretical modelling of ventricular beat-by-beat electromechanical function.


Glycosidic Tn-based vaccines targeting dermal dendritic cells favor germinal center B-cell development and potent antibody response in the absence of adjuvant.
In vivo targeting of C-type lectin receptors is an effective strategy for increasing antigen uptake and presentation by dendritic cells (DCs). To induce efficient immune response, glycosylated tumor-associated Tn antigens were used to target DCs through binding to macrophage galactose-type lectin (MGL). The capacity of Tn-glycosylated antigens-and the multiple antigenic glycopeptide Tn3 therapeutic candidate vaccine-to target mouse and human MGL(+) DCs are demonstrated, especially regarding dermal DCs. In mice, MGL(+) CD103(-) dermal DCs efficiently captured and processed glycosylated Tn antigen in vivo, inducing a potent major histocompatibility complex (MHC) class II-restricted T-cell response. Intradermal immunization with Tn-glycopeptides induced high levels of Th2 cytokines-even in the presence of unmethylated cytosine-phosphate-guanosine-and was associated with increased expansion of the germinal center B-cell population. Therefore, MGL acts as an efficient endocytic antigen receptor on dermal DCs in vivo, able to prime Tn-specific T- and B-cell responses. Moreover, even in the absence of adjuvant, immunization with this glycosidic Tn-based vaccine induced high levels of anti-Tn antibody responses, recognizing human tumor cells. In vivo DC-targeting strategies, based on Tn-MGL interactions, constitute a promising strategy for enhancing antigen presentation and inducing potent antibody response.


T-box transcription factors in cancer biology.
The evolutionarily conserved T-box family of transcription factors have critical and well-established roles in embryonic development. More recently, T-box factors have also gained increasing prominence in the field of cancer biology where a wide range of cancers exhibit deregulated expression of T-box factors that possess tumour suppressor and/or tumour promoter functions. Of these the best characterised is TBX2, whose expression is upregulated in cancers including breast, pancreatic, ovarian, liver, endometrial adenocarcinoma, glioblastomas, gastric, uterine cervical and melanoma. Understanding the role and regulation of TBX2, as well as other T-box factors, in contributing directly to tumour progression, and especially in suppression of senescence and control of invasiveness suggests that targeting TBX2 expression or function alone or in combination with currently available chemotherapeutic agents may represent a therapeutic strategy for cancer.


Data fraud in clinical trials.
Highly publicized cases of fabrication or falsification of data in clinical trials have occurred in recent years and it is likely that there are additional undetected or unreported cases. We review the available evidence on the incidence of data fraud in clinical trials, describe several prominent cases, present information on motivation and contributing factors and discuss cost-effective ways of early detection of data fraud as part of routine central statistical monitoring of data quality. Adoption of these clinical trial monitoring procedures can identify potential data fraud not detected by conventional on-site monitoring and can improve overall data quality.


Human respiration at rest in rapid compression and at high pressures and gas densities.
Ventilation (V), end-tidal PCO2 (PACO2), and CO2 elimination rate were measured in men at rest breathing CO2-free gas over the pressure range 1-50 ATA and the gas density range 0.4-25 g/l, during slow and rapid compressions, at stable elevated ambient pressures and during slow decompressions in several phases of Predictive Studies III-1971 and Predictive Studies IV-1975. Inspired O2 was at or near natural O2 levels during compressions and at stable high pressures; it was 0.5 ATA during decompressions. Rapid compressions to high pressures did not impair respiratory homeostasis. Progressive increase in pulmonary gas flow resistance due to elevation of ambient pressure and inspired gas density to the He-O2 equivalent of 5,000 feet of seawater was not observed to progressively decrease resting V, or to progressively increase resting PACO2. Rather, a complex pattern of change in PACO2 was seen. As both ambient pressure and pulmonary gas flow resistance were progressively raised, PACO2 at first increased, went through a maximum, and then declined towards values near the 1 ATA level. It is suggested that this pattern of PACO2 change results from interaction on ventilation of 1) increase in pulmonary resistance due to elevation of gas density with 2) increase in respiratory drive postulated as due to generalized CNS excitation associated with exposure to high hydrostatic pressure. There may be a similar interaction between increased gas flow resistance and increase in respiratory drive related to nitrogen partial pressure and the narcosis resulting therefrom.


Piloting a Deep Learning Model for Predicting Nuclear BAP1 Immunohistochemical Expression of Uveal Melanoma from Hematoxylin-and-Eosin Sections.
Uveal melanoma (UM) is the most common primary intraocular malignancy in adults. Monosomy 3 and BAP1 mutation are strong prognostic factors predicting metastatic risk in UM. Nuclear BAP1 (nBAP1) expression is a close immunohistochemical surrogate for both genetic alterations. Not all laboratories perform routine BAP1 immunohistochemistry or genetic testing, and rely mainly on clinical information and anatomic/morphologic analyses for UM prognostication. The purpose of our study was to pilot deep learning (DL) techniques to predict nBAP1 expression on whole slide images (WSIs) of hematoxylin and eosin (H&E) stained UM sections. One hundred forty H&E-stained UMs were scanned at 40 × magnification, using commercially available WSI image scanners. The training cohort comprised 66 BAP1+ and 74 BAP1- UM, with known chromosome 3 status and clinical outcomes. Nonoverlapping areas of three different dimensions (512 × 512, 1024 × 1024, and 2048 × 2048 pixels) for comparison were extracted from tumor regions in each WSI, and were resized to 256 × 256 pixels. Deep convolutional neural networks (Resnet18 pre-trained on Imagenet) and auto-encoder-decoders (U-Net) were trained to predict nBAP1 expression of these patches. Trained models were tested on the patches cropped from a test cohort of WSIs of 16 BAP1+ and 28 BAP1- UM cases. The trained model with best performance achieved area under the curve values of 0.90 for patches and 0.93 for slides on the test set. Our results show the effectiveness of DL for predicting nBAP1 expression in UM on the basis of H&E sections only. Our pilot demonstrates a high capacity of artificial intelligence-related techniques for automated prediction on the basis of histomorphology, and may be translatable into routine histology laboratories.


The influence of the urban food environment on diet, nutrition and health outcomes in low-income and middle-income countries: a systematic review.
Diet and nutrition are leading causes of global morbidity and mortality. Our study aimed to identify and synthesise evidence on the association between food environment characteristics and diet, nutrition and health outcomes in low-income and middle-income countries (LMICs), relevant to urban settings, to support development and implementation of appropriate interventions. We conducted a comprehensive search of 9 databases from 1 January 2000 to 16 September 2020 with no language restrictions. We included original peer-reviewed observational studies, intervention studies or natural experiments conducted in at least one urban LMIC setting and reporting a quantitative association between a characteristic of the food environment and a diet, nutrition or health outcome. Study selection was done independently in duplicate. Data extraction and quality appraisal using the National Heart Lung and Blood Institute checklists were completed based on published reports using a prepiloted form on Covidence. Data were synthesised narratively. 74 studies met eligibility criteria. Consistent evidence reported an association between availability characteristics in the neighbourhood food environment and dietary behaviour (14 studies, 10 rated as good quality), while the balance of evidence suggested an association with health or nutrition outcomes (17 of 24 relevant studies). We also found a balance of evidence that accessibility to food in the neighbourhood environment was associated with diet (10 of 11 studies) although evidence of an association with health outcomes was contradictory. Evidence on other neighbourhood food environment characteristics was sparse and mixed. Availability in the school food environment was also found to be associated with relevant outcomes. Studies investigating our other primary outcomes in observational studies of the school food environment were sparse, but most interventional studies were situated in schools. We found very little evidence on how workplace and home food environments are associated with relevant outcomes. This is a substantial evidence gap. 'Zoning' or 'healthy food cart' interventions to alter food availability may be appropriate in urban LMIC. CRD42020207475.


Recognition of the E-C4 element from the C4 complement gene promoter by the upstream stimulatory factor-1 transcription factor.
Activation of complement gene expression plays a major role in the response to antigenic challenge. The induction of complement synthesis occurs primarily in liver and in macrophages and is mediated, at least in part, by increased transcription of the complement genes. For example, transcription of the C4 complement gene, which plays a crucial role in the complement pathway, is induced in response to acute inflammation or tissue injury. Previous work has defined the elements present in the C4 complement gene promoter that are required for its expression. Particularly important is an E-box motif, E-C4, that is conserved between the mouse, human, and rat promoters and that directed up to 90% of transcription from the mouse C4 promoter. Here we have purified the E-C4-binding factor to homogeneity using a novel and rapid affinity purification procedure. Following N-terminal microsequencing and subsequent isolation of the corresponding cDNA, the factor binding the E-C4 element was identified as upstream stimulatory factor-1 (USF-1), a basic helix-loop-helix-leucine zipper transcription factor. We also show for the first time that in vivo USF-1 is a phosphoprotein, but that phosphorylation of USF-1 is severely reduced in cells in culture. Moreover, the phosphorylated form of USF-1 binds DNA preferentially, indicating that phosphorylation may enhance the ability of USF-1 to bind DNA. The implications of USF-1 phosphorylation for C4 complement gene expression and transcription regulation are discussed.


Assessing response bias in random-digit dialling surveys: the telephone-prefix method.
Knowledge of the characteristics of survey non-respondents is important to determine generalizability to the population of interest. In a recent random-digit dialling survey of health behaviours only 73 per cent of the households contacted provided any information about household composition, and only 74 per cent of those actually completed the extended interview, for an overall response rate of 54 per cent. To identify possible biases we grouped all attempted phone numbers by their prefix, and looked for the association between the response rate for that prefix and other summary variables known about the prefix. A simulation study showed that the method can identify non-response biases if certain assumptions are correct. The analysis suggested that our survey data under-represent older people and those with a college education. We found no significant biases in health behaviours, possibly because the basic assumptions did not hold. This method may assist in identification of non-response bias in other studies.


An exploration of China's mortality decline under Mao: A provincial analysis, 1950-80.
Between 1950 and 1980, China experienced the most rapid sustained increase in life expectancy of any population in documented global history. We know of no study that has quantitatively assessed the relative importance of the various explanations proposed for this gain in survival. We have created and analysed a new, province-level panel data set spanning the decades between 1950 and 1980 by combining historical information from China's public health archives, official provincial yearbooks, and infant and child mortality records contained in the 1988 National Survey of Fertility and Contraception. Although exploratory, our results suggest that gains in school enrolment and public health campaigns together are associated with 55-70 per cent of China's dramatic reductions in infant and under-5 mortality during our study period. These results underscore the importance of non-medical determinants of population health, and suggest that, in some circumstances, general education of the population may amplify the effectiveness of public health interventions.


Epileptic seizures and malaria in Kenyan children.
Between October 1990 and November 1991 data were collected on the frequency, causes, and nature of epileptic seizures in children admitted to the paediatric ward at Kilifi District Hospital, Kenya, from a defined study area. During this period, 1324 children were studied, of whom 15.8% had seizures as part of their illness. Malaria was by far the commonest cause of seizures, accounting for 69.0%; no other single condition caused more than 4.4%. The proportion of respiratory infections complicated by seizures was 4.0% compared to 31.3% for malaria. Only 25% of malaria-related epileptic seizures were associated with cerebral malaria; the remainder were associated with otherwise uncomplicated malaria and, in this group, 84% had complex seizures, with 47% being partial and over 70% repetitive. There was no relationship with fever, with 54% of observed seizures occurring at rectal temperatures below 38 degrees C. The minimum community incidence of complex seizures in association with non-cerebral malaria was 5.8 per 1000 per year. Complex epileptic seizures in association with otherwise uncomplicated malaria are common and may be a significant cause of longer term morbidity in malaria endemic areas.


Redox state and mitochondrial respiratory chain function in skeletal muscle of LGMD2A patients.
Calpain-3 deficiency causes oxidative and nitrosative stress-induced damage in skeletal muscle of LGMD2A patients, but mitochondrial respiratory chain function and anti-oxidant levels have not been systematically assessed in this clinical population previously. We identified 14 patients with phenotypes consistent with LGMD2A and performed CAPN3 gene sequencing, CAPN3 expression/autolysis measurements, and in silico predictions of pathogenicity. Oxidative damage, anti-oxidant capacity, and mitochondrial enzyme activities were determined in a subset of muscle biopsies. Twenty-one disease-causing variants were detected along the entire CAPN3 gene, five of which were novel (c.338 T>C, c.500 T>C, c.1525-1 G>T, c.2115+4 T>G, c.2366 T>A). Protein- and mRNA-based tests confirmed in silico predictions and the clinical diagnosis in 75% of patients. Reductions in antioxidant defense mechanisms (SOD-1 and NRF-2, but not SOD-2), coupled with increased lipid peroxidation and protein ubiquitination, were observed in calpain-3 deficient muscle, indicating a redox imbalance primarily affecting non-mitochondrial compartments. Although ATP synthase levels were significantly lower in LGMD2A patients, citrate synthase, cytochrome c oxidase, and complex I+III activities were not different from controls. Despite significant oxidative damage and redox imbalance in cytosolic/myofibrillar compartments, mitochondrial respiratory chain function is largely maintained in skeletal muscle of LGMD2A patients.


Pathogenic features of heterotrophic plate count bacteria from drinking-water boreholes.
Evidence suggests that heterotrophic plate count (HPC) bacteria may be hazardous to humans with weakened health. We investigated the pathogenic potential of HPC bacteria from untreated borehole water, consumed by humans, for: their haemolytic properties, the production of extracellular enzymes such as DNase, proteinase, lipase, lecithinase, hyaluronidase and chondroitinase, the effect simulated gastric fluid has on their survival, as well as the bacteria's antibiotic-susceptible profile. HuTu-80 cells acted as model for the human intestine and were exposed to the HPC isolates to determine their effects on the viability of the cells. Several HPC isolates were α- or β-haemolytic, produced two or more extracellular enzymes, survived the SGF treatment, and showed resistance against selected antibiotics. The isolates were also harmful to the human intestinal cells to varying degrees. A novel pathogen score was calculated for each isolate. Bacillus cereus had the highest pathogen index: the pathogenicity of the other bacteria declined as follows: Aeromonas taiwanensis > Aeromonas hydrophila > Bacillus thuringiensis > Alcaligenes faecalis > Pseudomonas sp. > Bacillus pumilus > Brevibacillus sp. > Bacillus subtilis > Bacillus sp. These results demonstrated that the prevailing standards for HPCs in drinking water may expose humans with compromised immune systems to undue risk.


Dynamic thiol/disulfide homeostasis as oxidative stress marker in diabetic ketoacidosis
The aim of present study was to investigate the dynamic thiol/disulfide homeostasis as oxidative stress marker in diabetic ketoacidosis (DKA). A total of 77 participants consisting of 32 patients with DKA and 45 healthy volunteers were included in the study. Thiol/disulfide homeostasis (TDH) [total thiol-native thiol/disulfide changes] were measured in both groups (patient group and control group) using a brand new method developed by Erel and Neselioglu. Half of the difference between total thiol and native thiol concentrations gives the amount of disulfide bond. Total thiol, native thiol, and disulfide levels in blood were found to be low. The levels of total thiol (P < 0.001) and native thiol (P < 0.001 ) were significantly lower in patients with DKA than in the control group. At the same time, the level of disulfide was nonsignificantly lower in the patient group than the control group (P = 0.388). The level of IMA was higher in the patient group than in the control group (P < 0.001). The total thiol, native thiol, and disulfide levels in DKA decrease in favor of oxidative stress.


Fully-Endoscopic Resection of Deep-Seated Pilocytic Astrocytoma Under 5-Aminolevulinic Acid Fluorescence Guidance: A Technical Note.
To improve the extent and safety of resecting these deep-seated tumors, we report a novel procedure of minimally invasive endoscopic resection of deep-seated pilocytic astrocytomas under the guidance of 5-aminolevulinic acid (5-ALA) fluorescence undescribed until now. A 53-year-old male presented with a gradually progressing mild right hemiparesis. Imaging studies showed a solid tumor with degenerative cystic formation in the left basal ganglia. The tumor was removed endoscopically via right frontal small craniotomy. The tumor was positive for 5-ALA fluorescence and allowed better detection of the dissection margin of the solid tumor from the surrounding brain tissue. The histopathological diagnosis was pilocytic astrocytoma. No recurrence was observed on follow-up magnetic resonance imaging (MRI) 2 years after surgery, and the patient was fully independent after rehabilitation. This minimally invasive technique, enhanced by intraoperative fluorescence, might be a safe and feasible alternative to open surgery in the removal of deeply located gliomas.


Delay from symptom onset to hospital presentation for patients with non-ST-segment elevation myocardial infarction.
Secular trends and factors associated with delay time from symptom onset to hospital presentation are known for patients with ST-segment elevation myocardial infarction (STEMI) but are less well-described for non-STEMI. We studied 104 622 patients with non-STEMI enrolled at 568 hospitals participating in the Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implementation of the American College of Cardiology/American Heart Association Guidelines (CRUSADE) National Quality Improvement Initiative from January 1, 2001, to December 31, 2006. We examined secular trends and factors associated with delay time and the association of delay time with in-hospital mortality. Median delay time from symptom onset to hospital presentation was 2.6 hours (interquartile range, 1.3-6.0) and has been stable from 2001 to 2006 (P value for trend, .16). After multivariable adjustment, factors associated with longer delay time included older age, female sex, nonwhite race, diabetes, and current smoking. In addition, compared with those who presented during weekday daytime (>8 am to 4 pm), patients who presented during weekday and weekend nights (>12 am to 8 am) had a 24.7% and 24.3% shorter delay time, respectively (P < .001). After multivariable adjustment, the odds ratio of in-hospital mortality for patients with delay times of 0 to 1 hour or less, more than 1 to 2 hours, more than 2 to 3 hours, and more than 3 to 6 hours compared with the reference group (delay time >6 hours) were 1.19 (95% confidence interval [CI], 1.08-1.30), 0.91 (95% CI, 0.83-1.00), 0.77 (95% CI, 0.69-0.88), and 0.90 (95% CI, 0.81-1.00), respectively. Long delay times are common and have not changed over time for patients with non-STEMI. Because patients cannot differentiate whether symptoms are due to STEMI or non-STEMI, early presentation is desirable in both instances.


Unsupervided pattern recognition for the classification of EMG signals.
The shapes and firing rates of motor unit action potentials (MUAP's) in an electromyographic (EMG) signal provide an important source of information for the diagnosis of neuromuscular disorders. In order to extract this information from EMG signals recorded at low to moderate force levels, it is required: i) to identify the MUAP's composing the EMG signal, ii) to classify MUAP's with similar shape, and iii) to decompose the superimposed MUAP waveforms into their constituent MUAP's. For the classification of MUAP's two different pattern recognition techniques are presented: i) an artificial neural network (ANN) technique based on unsupervised learning, using a modified version of the self-organizing feature maps (SOFM) algorithm and learning vector quantization (LVQ) and ii) a statistical pattern recognition technique based on the Euclidean distance. A total of 1213 MUAP's obtained from 12 normal subjects, 13 subjects suffering from myopathy, and 15 subjects suffering from motor neuron disease were analyzed. The success rate for the ANN technique was 97.6% and for the statistical technique 95.3%. For the decomposition of the superimposed waveforms, a technique using crosscorrelation for MUAP's alignment, and a combination of Euclidean distance and area measures in order to classify the decomposed waveforms is presented. The success rate for the decomposition procedure was 90%.


The satellite RNAs associated with the groundnut rosette disease complex and pea enation mosaic virus: sequence similarities and ability of each other's helper virus to support their replication.
Pea enation mosaic virus (PEMV) and the causal agents of groundnut rosette disease are diverse examples of disease complexes involving two RNA species, one of which is related to the genomes of luteoviruses and the other to those of umbraviruses. In both complexes, these viral RNA components may be supplemented with satellite RNAs that are dependent on the umbravirus component for replication and systemic movement, and on the luteovirus component for encapsidation and vector transmission. Sequence analysis identified regions of similarity between the satellites of groundnut rosette virus (GRV) and PEMV, particularly at the 5' and 3' termini and around duplicate sequence repeats present in each satellite RNA. The umbravirus GRV and the umbravirus-like PEMV RNA-2 were each able to support the replication and systemic spread of homologous and heterologous satellites. The presence of the PEMV satellite in infections with GRV had no effect on symptom expression in Nicotiana spp. or in Arachis hypogaea. Likewise, in Pisum sativum, the GRV satellite had no effect on the symptoms induced by PEMV. However, the intense yellow blotch symptoms induced in Nicotiana benthamiana by the YB3 GRV satellite in conjunction with GRV were also manifested when PEMV was the helper. Although PEMV RNA-1 was capable of supporting the encapsidation and aphid transmission of the GRV satellite, no evidence was obtained that the essential role of the GRV satellite in the aphid transmission of GRV could be supplied by the PEMV satellite. These data further strengthen the hypothesis of an evolutionary relationship between PEMV and the luteovirus-umbravirus complexes.


Genomic characterization of extensively drug-resistant Acinetobacter baumannii strain, KAB03 belonging to ST451 from Korea.
Extensively drug-resistant (XDR) Acinetobacter baumannii strains have emerged rapidly worldwide. The antibiotic resistance characteristics of XDR A. baumannii strains show regional differences; therefore, it is necessary to analyze both genomic and proteomic characteristics of emerging XDR A. baumannii clinical strains isolated in Korea to elucidate their multidrug resistance. Here, we isolated new sequence type of XDR A. baumannii clinical strain (KAB03) from Korean hospitals and performed comprehensive genome analyses. The strain belongs to new sequence type, ST451. Single nucleotide polymorphism (SNP) analysis with other types of A. baumannii strains revealed that KAB03 has unique SNP pattern in the regions of gyrB and gpi of MLST profiles. A. baumannii KAB03 harbours three antibiotic resistance islands (AbGRI1, 2, and 3). AbGRI1 harbours two copies of Tn2006 containing blaOXA-23, which play an important role in antibiotic resistance. AbGRI2 possesses aminoglycoside resistant gene aph(3')-Ic and class A β-lactamase blaTEM. AbGIR3 has macrolide resistant genes and aminoglycoside resistant gene armA. A. baumannii KAB03 harbours mutations in pmrB and pmrC, which are believed to confer colistin resistance. In addition, proteomic and transcriptional analysis of KAB03 confirmed that β-lactamases (ADC-73 and OXA-23), Ade efflux pumps (AdeIJK), outer membrane proteins (OmpA and OmpW), and colistin resistance genes (PmrCAB) were major proteins responsible for antibiotic resistance. Our proteogenomic results provide valuable information for multi-drug resistance in emerging XDR A. baumannii strains belonging to ST451.


Hypoglycaemia risk with insulin degludec compared with insulin glargine in type 2 and type 1 diabetes: a pre-planned meta-analysis of phase 3 trials.
Hypoglycaemia and the fear of hypoglycaemia are barriers to achieving normoglycaemia with insulin. Insulin degludec (IDeg) has an ultra-long and stable glucose-lowering effect, with low day-to-day variability. This pre-planned meta-analysis aimed to demonstrate the superiority of IDeg over insulin glargine (IGlar) in terms of fewer hypoglycaemic episodes at equivalent HbA1c in type 2 and type 1 diabetes mellitus (T2DM/T1DM). Pooled patient-level data for self-reported hypoglycaemia from all seven (five in T2DM and two in T1DM) randomized, controlled, phase 3a, treat-to-target trials in the IDeg clinical development programme comparing IDeg once-daily (OD) vs. IGlar OD were analysed. Four thousand three hundred and thirty subjects (2899 IDeg OD vs. 1431 IGlar OD) were analysed. Among insulin-naïve T2DM subjects, significantly lower rates of overall confirmed, nocturnal confirmed and severe hypoglycaemic episodes were reported with IDeg vs. IGlar: estimated rate ratio (RR):0.83[0.70;0.98](95%) (CI) , RR:0.64[0.48;0.86](95%) (CI) and RR:0.14[0.03;0.70](95%) (CI) . In the overall T2DM population, significantly lower rates of overall confirmed and nocturnal confirmed episodes were reported with IDeg vs. IGlar [RR:0.83[0.74;0.94](95%) (CI) and RR:0.68[0.57;0.82](95%) (CI) ). In the T1DM population, the rate of nocturnal confirmed episodes was significantly lower with IDeg vs. IGlar during maintenance treatment (RR:0.75[0.60;0.94](95%) (CI) ). Reduction in hypoglycaemia with IDeg vs. IGlar was more pronounced during maintenance treatment in all populations. The limitations of this study include the open-label design and exclusion of subjects with recurrent severe hypoglycaemia. This meta-analysis confirms that similar improvements in HbA1c can be achieved with fewer hypoglycaemic episodes, particularly nocturnal episodes, with IDeg vs. IGlar across a broad spectrum of patients with diabetes.


Petrological and geochemical characterisation of the sarsen stones at Stonehenge.
Little is known of the properties of the sarsen stones (or silcretes) that comprise the main architecture of Stonehenge. The only studies of rock struck from the monument date from the 19th century, while 20th century investigations have focussed on excavated debris without demonstrating a link to specific megaliths. Here, we present the first comprehensive analysis of sarsen samples taken directly from a Stonehenge megalith (Stone 58, in the centrally placed trilithon horseshoe). We apply state-of-the-art petrographic, mineralogical and geochemical techniques to two cores drilled from the stone during conservation work in 1958. Petrographic analyses demonstrate that Stone 58 is a highly indurated, grain-supported, structureless and texturally mature groundwater silcrete, comprising fine-to-medium grained quartz sand cemented by optically-continuous syntaxial quartz overgrowths. In addition to detrital quartz, trace quantities of silica-rich rock fragments, Fe-oxides/hydroxides and other minerals are present. Cathodoluminescence analyses show that the quartz cement developed as an initial <10 μm thick zone of non-luminescing quartz followed by ~16 separate quartz cement growth zones. Late-stage Fe-oxides/hydroxides and Ti-oxides line and/or infill some pores. Automated mineralogical analyses indicate that the sarsen preserves 7.2 to 9.2 area % porosity as a moderately-connected intergranular network. Geochemical data show that the sarsen is chemically pure, comprising 99.7 wt. % SiO2. The major and trace element chemistry is highly consistent within the stone, with the only magnitude variations being observed in Fe content. Non-quartz accessory minerals within the silcrete host sediments impart a trace element signature distinct from standard sedimentary and other crustal materials. 143Nd/144Nd isotope analyses suggest that these host sediments were likely derived from eroded Mesozoic rocks, and that these Mesozoic rocks incorporated much older Mesoproterozoic material. The chemistry of Stone 58 has been identified recently as representative of 50 of the 52 remaining sarsens at Stonehenge. These results are therefore representative of the main stone type used to build what is arguably the most important Late Neolithic monument in Europe.


Current treatment concepts for neuromas-in-continuity.
A neuroma-in-continuity is a neuroma that results from failure of the regenerating nerve growth cone to reach peripheral targets. It occurs within an intact nerve in response to internally damaged fascicles, resulting in a distal portion of the nerve that no longer functions properly. Management of neuromas-in-continuity is challenging. Chemical methods, and microsurgical techniques including fascicular ligation, and burying into muscle and bone have been reported to prevent neuroma-in-continuity formation. The purpose of this article is to present novel techniques for neuroma-in-continuity management, and to discuss the related literature.


Role of Pattern Recognition Receptors in KSHV Infection.
Kaposi's sarcoma-associated herpesvirus or Human herpesvirus-8 (KSHV/HHV-8), an oncogenic human herpesvirus and the leading cause of cancer in HIV-infected individuals, is a major public health concern with recurring reports of epidemics on a global level. The early detection of KSHV virus and subsequent activation of the antiviral immune response by the host's immune system are crucial to prevent KSHV infection. The host's immune system is an evolutionary conserved system that provides the most important line of defense against invading microbial pathogens, including viruses. Viruses are initially detected by the cells of the host innate immune system, which evoke concerted antiviral responses via the secretion of interferons (IFNs) and inflammatory cytokines/chemokines for elimination of the invaders. Type I IFN and cytokine gene expression are regulated by multiple intracellular signaling pathways that are activated by germline-encoded host sensors, i.e., pattern recognition receptors (PRRs) that recognize a conserved set of ligands, known as 'pathogen-associated molecular patterns (PAMPs)'. On the contrary, persistent and dysregulated signaling of PRRs promotes numerous tumor-causing inflammatory events in various human cancers. Being an integral component of the mammalian innate immune response and due to their constitutive activation in tumor cells, targeting PRRs appears to be an effective strategy for tumor prevention and/or treatment. Cellular PRRs are known to respond to KSHV infection, and KSHV has been shown to be armed with an array of strategies to selectively inhibit cellular PRR-based immune sensing to its benefit. In particular, KSHV has acquired specific immunomodulatory genes to effectively subvert PRR responses during the early stages of primary infection, lytic reactivation and latency, for a successful establishment of a life-long persistent infection. The current review aims to comprehensively summarize the latest advances in our knowledge of role of PRRs in KSHV infections.


Indigenous peoples and the morality of the Human Genome Diversity Project.
In addition to the aim of mapping and sequencing one human's genome, the Human Genome Project also intends to characterise the genetic diversity of the world's peoples. The Human Genome Diversity Project raises political, economic and ethical issues. These intersect clearly when the genomes under study are those of indigenous peoples who are already subject to serious economic, legal and/or social disadvantage and discrimination. The fact that some individuals associated with the project have made dismissive comments about indigenous peoples has confused rather than illuminated the deeper issues involved, as well as causing much antagonism among indigenous peoples. There are more serious ethical issues raised by the project for all geneticists, including those who are sympathetic to the problems of indigenous peoples. With particular attention to the history and attitudes of Australian indigenous peoples, we argue that the Human Genome Diversity Project can only proceed if those who further its objectives simultaneously: respect the cultural beliefs of indigenous peoples; publicly support the efforts of indigenous peoples to achieve respect and equality; express respect by a rigorous understanding of the meaning of equitable negotiation of consent, and ensure that both immediate and long term economic benefits from the research flow back to the groups taking part.


Regulation of growth hormone binding protein in man: comparison of gel chromatography and immunoprecipitation methods.
GH circulates in part bound to a high affinity binding protein (GHBP). Gel chromatography is the established method for measuring GH binding activity in plasma, but is slow and tedious. The separation of bound from free GH by immunoprecipitation using a monoclonal antibody to the GH receptor may be a more practical alternative. We have examined the effects of GH and estrogen status on GHBP measured in 24-h pool samples and compared results obtained from gel filtration and immunoprecipitation. GHBP activity (percent specific binding of [125I]GH) was measured in normal, GH-deficient, and acromegalic subjects; and in two groups of postmenopausal women before and after oral (ethinyl estradiol 20 micrograms daily) or transdermal (17 beta-estradiol 100 micrograms daily) estrogen therapy. GHBP activity was not significantly different between normal, GH-deficient, and acromegalic subjects matched for age and sex. Neither GH administration to GH-deficient and normal subjects, nor octreotide treatment of patients with acromegaly, significantly altered GHBP activity. Oral estrogen treatment significantly increased GHBP activity. This change was associated with an increase in binding capacity (P = 0.001) but not affinity, as revealed by Scatchard analysis. GHBP activity did not change significantly with transdermal estrogen therapy. GHBP activity obtained by the two methods was significantly correlated (n = 70, r = 0.92, P = 0.001) although values for the antibody method were 25% higher. Similarly, capacity estimates were highly correlated (r = 0.90, P = 0.0001), with values by immunoprecipitation being 40% higher. We conclude that GH secretory status is not a determinant of GHBP. Oral estrogens increase GHBP activity through an increase in capacity and not affinity. The estrogen effect is route dependent and the oral response is likely to reflect a first pass hepatic effect. The higher binding activity and capacity estimated from immunoprecipitation are likely to reflect a more rapid separation process thereby minimizing dissociation of GHBP complex. Immunoprecipitation offers the advantages of simplicity, convenience, and accuracy for the measurement of GH binding activity and GHBP concentrations in serum.


Organocatalytic enantioselective desymmetrisation.
Organocatalytic enantioselective desymmetrisation of achiral or meso compounds is a powerful strategy for the construction of enantiomerically enriched complex molecules, often with multiple stereocentres and in high selectivities. Recent years have seen increasing use of organocatalysts in desymmetrisation methodology, in contrast to traditional metal- or enzyme-catalysed reactions, with many impressive advances made in the current decade. This review will provide an overview of the field since 2010, with the aim of highlighting both the practical applications and elegance of enantioselective desymmetrisation to the wider synthetic community.


Degenerative disc disease of the lumbar spine on MRI.
A retrospective analysis was done of all patients referred for MRI of the lumbar spine at the University Hospital of the West Indies, Kingston, Jamaica, during the three-year period January 1, 2005 and December 31, 2007. Data were collected to determine patients 'age, gender, weight and the presence or absence of degenerative disc disease (DDD). The patients' presenting symptoms were not evaluated. There were 362 patients examined: 154 males, 204 females and four uncharacterized, aged between 8 and 87 (mean age = 50.45) years. Degenerative Disc Disease (DDD), was found in 283 (78.2%) patients: 121 males, 159 females and three unidentified, with a total of 669 degenerate discs. L 4/5 and L 5/S 1 were most frequently affected accounting for 31.2% and 30.6% of degenerate discs respectively. Patients with DDD were significantly heavier and significantly older than patients without disc disease. Gender was not predictive of DDD in general nor of involvement of any particular disc though a marginally significant tendency was found for males to more frequently have DDD at L1/2 and L5/S1. Degenerative disc disease of the lumbar spine occurred more frequently in older and heavier patients. Gender did not affect the presence or the extent of the disease; compared to females, males showed a marginally increased tendency to have DDD at L1/2 and L5/S1.


Inhibition of neuronal nitric oxide synthase by 7-nitroindazole attenuates acute lung injury in an ovine model.
Nitric oxide (NO) has been shown to play a major role in acute lung injury (ALI) after smoke inhalation. In the present study, we developed an ovine sepsis model, created by exposing sheep to smoke inhalation followed by instillation of bacteria into the airway, that mimics human sepsis and pneumonia. We hypothesized that the inhibition of neuronal NO synthase (nNOS) might be beneficial in treating ALI associated with this model. Female sheep (n = 26) were surgically prepared for the study and given a tracheostomy. This was followed by insufflation of 48 breaths of cotton smoke (40 degrees C) into the airway of each animal and subsequent instillation of live Pseudomonas aeruginosa [5 x 10(11) colony forming units (CFU)] into each sheep's lung. All sheep were mechanically ventilated using 100% O2. Continuous infusion of 7-nitroindazole (7-NI), an nNOS inhibitor, NG-monomethyl-l-arginine (l-NMMA), a nonspecific NOS inhibitor, or aminoguanidine (AG), an inducible NOS inhibitor, was started 1 h after insult. The administration of 7-NI improved pulmonary gas exchange (PaO2/FiO2; where PaO2 is arterial PO2 and FiO2 is fractional inspired oxygen concentration) and pulmonary shunt fraction and attenuated the increase in lung wet-to-dry weight ratio seen in the nontreated sheep. Histologically, 7-NI prevented airway obstruction. The increase in airway blood flow after injury in the nontreated group was significantly inhibited by 7-NI. The increase in plasma concentration of nitrate and nitrite (NOx) was inhibited by 7-NI as well. Posttreatment with l-NMMA improved the pulmonary gas exchange, but AG did not. The results of the present study show that nNOS may be involved in the pathogenesis of ALI after smoke inhalation injury followed by bacterial instillation in the airway.


Age, Loss Minimization, and the Role of Probability for Decision-Making.
Older adults are stereotypically considered to be risk averse compared to younger age groups, although meta-analyses on age and the influence of gain/loss framing on risky choices have not found empirical evidence for age differences in risk-taking. The current study extends the investigation of age differences in risk preference by including analyses on the effect of the probability of a risky option on choices in gain versus loss situations. Participants (n = 130 adults aged 19-80 years) chose between a certain option and a risky option of varying probability in gain- and loss-framed gambles with actual monetary outcomes. Only younger adults displayed an overall framing effect. Younger and older adults responded differently to probability fluctuations depending on the framing condition. Older adults were more likely to choose the risky option as the likelihood of avoiding a larger loss increased and as the likelihood of a larger gain decreased. Younger adults responded with the opposite pattern: they were more likely to choose the risky option as the likelihood of a larger gain increased and as the likelihood of avoiding a (slightly) larger loss decreased. Results suggest that older adults are more willing to select a risky option when it increases the likelihood that larger losses be avoided, whereas younger adults are more willing to select a risky option when it allows for slightly larger gains. This finding supports expectations based on theoretical accounts of goal orientation shifting away from securing gains in younger adulthood towards maintenance and avoiding losses in older adulthood. Findings are also discussed in respect to the affective enhancement perspective and socioemotional selectivity theory.


In vitro and in vivo targeting of gene expression to melanoma cells.
Gene therapy protocols for cancer usually involve removal of tumor cells, culture in vitro to allow gene transfer, and subsequent reintroduction in vivo. Targeting therapeutic genes to tumor cells in situ requires an accuracy of gene delivery that currently is not possible with the use of existing techniques. To overcome these limitations we have used two promoters, which are preferentially active in melanocytic cells, to direct gene expression specifically to melanoma cells both in vitro and in vivo. Here we describe experiments showing that as little as 769 base pairs of the 5'-flanking regions of the tyrosinase, and 1.4 kilobase pair of the tyrosinase-related protein 1, genes are sufficient to direct expression of the beta-galactosidase gene to both human and murine melanoma cells and melanocytes, while not permitting expression in a range of other cell types in vitro. These promoters showed high levels of activity in 12 of 14 murine and human melanoma cell lines tested but showed only basal levels of activity, similar to that of a promoterless construct, in a range of 12 other cell types. Cell type specificity is maintained when the construct is delivered to cells either by physical means or by inclusion of the cell type-specific expression cassette into a retroviral vector. Direct injection of DNA, encoding the beta-galactosidase gene expressed from either promoter, into established B16 melanomas or Colo 26 tumors in syngeneic mice resulted in extensive transduction of tumor cells in the B16 melanomas (approximately 10% of tumor cells expressing 10 days after DNA injection), whereas no blue-staining cells were seen in the Colo 26 tumors. The reporter gene was expressed in melanoma cells and in some normal melanocytes but not in other surrounding normal tissue. We propose that the combination of a tissue-specific promoter driving a therapeutic gene, with delivery of such a construct directly to sites of tumor growth in vivo, either by direct DNA injection or by retroviral infection, may provide significantly enhanced safety for gene therapy for solid tumors.


Protein-lipid interactions at membrane surfaces: a deuterium and phosphorus nuclear magnetic resonance study of the interaction between bovine rhodopsin and the bilayer head groups of dimyristoylphosphatidylcholine.
Rhodopsin, isolated from bovine retinal rod outer segment disk membranes, has been reconstituted into bilayers of 1,2-dimyristoyl-sn-glycero-3-phosphocholine which was deuterated in the terminal methyl groups of the choline polar head group. By use of a mixed detergent system of cholate and octyl glucoside to solubilize the phospholipid and rhodopsin, 15 membrane complexes of predetermined phospholipid to rhodopsin mole ratios of between 350:1 and 65:1 have been produced by exhaustive dialysis and studied by a variety of techniques. Electron micrographs of replicas from freeze-fractured membrane complexes showed that the majority of the lipid, for all rhodopsin:phospholipid ratios, was contained in large bilayer vesicles with diameters in excess of 400 nm. Complexes produced with rhodopsin from frozen retina produced an absorption maximum at 478 nm after photobleaching whereas rhodopsin from fresh retina could be bleached more completely to an absorption maximum at 380 nm. Deuterium nuclear magnetic resonance (NMR) spectra from the lipid head groups of bilayers above the gel to liquid-crystalline phase transition temperature were shown to be sensitive in a systematic way to the presence of rhodopsin which could be bleached to 380 nm. The measured quadrupole splittings, taken as the separation of the turning points of the recorded NMR spectra, decreased from a value of 1.28 kHz for protein-free bilayers to approximately 0.40 kHz for bilayers containing 65 molecules of phospholipid for each rhodopsin at 32 degrees C.(ABSTRACT TRUNCATED AT 250 WORDS)


A loop chain and a three-dimensional network assembled from a multi-dentate nitronyl nitroxide radical and M(hfac)2 (M = CoII, CuII).
A multi-dentate nitronyl nitroxide radical Nit-Ph-3,5-bIm (Nit-Ph-3,5-bIm = 2-[3,5-bis(1-imidazole)-phenyl]-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide) reacted with Co(hfac)2·2H2O or Cu(hfac)2 to yield two novel 3d-radical complexes {[Co(hfac)2]2(Nit-Ph-3,5-bIm)}n1 and {[Cu(hfac)2]7(Nit-Ph-3,5-bIm)3}n2 (hfac- = hexafluoroacetylacetonate). In both compounds, the Nit-Ph-3,5-bIm radical ligand behaves as a tetradentate ligand to link four M(hfac)2 units in a μ4-η1:η1:η1:η1-coordination mode via its two NO groups and two N atoms of imidazole, generating a unique loop chain for 1 and a three-dimensional framework for 2. The magnetic studies revealed a strong antiferromagnetic Co-ON exchange interaction in 1 while a ferromagnetic Cu-ON interaction is observed in 2. The dc magnetic behaviors of two complexes are analyzed by means of appropriate magnetic models. Furthermore, ac magnetic susceptibilities of the Co complex reveal slow relaxation of magnetization.


Effects of providing two forms of supplemental methionine to periparturient Holstein dairy cows on feed intake and lactational performance.
Eighteen primiparous and 42 multiparous Holstein cows were blocked according to parity and expected calving date and assigned randomly to 1 of 3 dietary treatments: 1) a basal diet (negative control), 2) the basal diet plus 2-hydroxy-4-methylthio butanoic acid isopropyl ester (MetaSmart, Adisseo Inc., Antony, France), or 3) the basal diet plus rumen-protected Met (Smartamine M, Adisseo Inc., Alpharetta, GA). Treatments were initiated 21 d before expected calving and continued through 140 d postpartum. Diets were similar in ingredient and chemical composition, except for the content of Met in metabolizable protein. MetaSmart [0.35% prepartum and 0.54% postpartum in diet dry matter (DM)] and Smartamine M (0.06% prepartum and 0.10% postpartum in diet DM) were added to the basal diet in amounts needed to achieve a 3.0:1 ratio of Lys to Met in metabolizable protein. Prepartum DM intake (DMI; 13.5 kg/d), body weight (687 kg), body condition score (3.81), postpartum milk yield (42.0 kg/d), milk fat yield (1,549 g/d), milk fat content (3.66%), milk true protein yield (1,192 g/d), and milk urea N content (12.9 mg/dL) were not different among treatments. Postpartum DMI and body condition score were greater and the ratios of milk:DMI and milk N:feed N were less for cows fed the MetaSmart diet than for cows fed the control and Smartamine M diets. Milk protein content was greater for the Smartamine M (2.87%) and MetaSmart (2.81%) treatments than for the control treatment (2.72%). Concentrations of Met and Met + Cys in total plasma AA were different among treatments, with values for the Smartamine M treatment being the highest, followed by the MetaSmart and control treatments. The results indicated that both MetaSmart and Smartamine M are effective in providing metabolizable Met, but clarification of their relative contributions to metabolizable Met is still needed.


Cost effectiveness of amoxicillin for lower respiratory tract infections in primary care: an economic evaluation accounting for the cost of antimicrobial resistance.
Lower respiratory tract infections (LRTIs) are a major disease burden and are often treated with antibiotics. Typically, studies evaluating the use of antibiotics focus on immediate costs of care, and do not account for the wider implications of antimicrobial resistance. This study sought to establish whether antibiotics (principally amoxicillin) are cost effective in patients with LRTIs, and to explore the implications of taking into account costs associated with resistance. Multinational randomised double-blinded trial in 2060 patients with acute cough/LRTIs recruited in 12 European countries. A cost-utility analysis from a health system perspective with a time horizon of 28 days was conducted. The primary outcome measure was the quality-adjusted life year (QALY). Hierarchical modelling was used to estimate incremental cost-effectiveness ratios (ICERs). Amoxicillin was associated with an ICER of €8216 (£6540) per QALY gained when the cost of resistance was excluded. If the cost of resistance is greater than €11 (£9) per patient, then amoxicillin treatment is no longer cost effective. Including possible estimates of the cost of resistance resulted in ICERs ranging from €14 730 (£11 949) per QALY gained - when only multidrug resistance costs and health care costs are included - to €727 135 (£589 856) per QALY gained when broader societal costs are also included. Economic evaluation of antibiotic prescribing strategies that do not include the cost of resistance may provide misleading results that could be of questionable use to policymakers. However, further work is required to estimate robust costs of resistance.


Resveratrol, at concentrations attainable with moderate wine consumption, stimulates human platelet nitric oxide production.
The mechanisms through which moderate wine consumption reduces ischemic cardiovascular events are not yet fully unraveled. Grape extracts or a mixture of the polyphenols contained in wine were previously shown to increase nitric oxide (NO); however, little information is available on the effect of resveratrol, one of the main polyphenols of wine, on platelet NO production. We assessed the effects of resveratrol, at the concentrations attainable after moderate wine intake, on platelet NO production and the mechanism of this activity. Twenty healthy volunteers were studied before and after 15 d of controlled white or red wine intake (300 mL/d). After wine intake, plasma resveratrol and the release of NO by stimulated platelets increased significantly. Resveratrol, at the concentrations detected in plasma after wine intake, was incubated in vitro with washed platelets and several variables related to NO production and to signal transduction were measured. Resveratrol in vitro enhanced significantly the production of NO by stimulated platelets, the activity of platelet NO synthase (NOS), phosphorylation of protein kinase B, an activator of the endothelial NOS (eNOS), and phosphorylation of vasodilator-activated protein (VASP), an expression of the biologic activity of NO in platelets. Simultaneously, we observed decreased phosphorylation of P38 mitogen-activated protein kinase (p38MAPK), a proinflammatory pathway in human platelets, a reduction of the activity of NADPH oxidase, a major source of reactive oxygen species (ROS) and of the generation of O(2)(-) radicals, as detected by cytochrome C reduction. In conclusion, resveratrol, at concentrations attainable after moderate wine intake, activates platelet eNOS and in this way blunts the proinflammatory pathway linked to p38MAPK, thus inhibiting ROS production and ultimately platelet function. This activity may contribute to the beneficial effects of moderate wine intake on ischemic cardiovascular disease.


ADP-ribosylation: new facets of an ancient modification.
Rapid response to environmental changes is achieved by uni- and multicellular organisms through a series of molecular events, often involving modification of macromolecules, including proteins, nucleic acids and lipids. Amongst these, ADP-ribosylation is of emerging interest because of its ability to modify different macromolecules in the cells, and its association with many key biological processes, such as DNA-damage repair, DNA replication, transcription, cell division, signal transduction, stress and infection responses, microbial pathogenicity and aging. In this review, we provide an update on novel pathways and mechanisms regulated by ADP-ribosylation in organisms coming from all kingdoms of life.


Conditional Approvals for Autologous Stem Cell-Based Interventions: Conflicting norms and institutional legitimacy.
Demands from patients, health-care professionals, and industry to streamline the market approval process for promising new therapies has prompted the introduction of programs that can provide more rapid access to stem cell-based products before evidence of safety and efficacy has been demonstrated in clinical trials. These products may be approved for marketing under "conditional authorizations," while uncertainty around safety and efficacy is reduced through the collection of clinical data in observational trials or registries. The rationale for conditional approval programs assumes that patients with unmet medical needs will benefit with rapid access to novel stem cell therapies. It also assumes that data gathered in actual clinical contexts is inherently better at reducing uncertainty than conventional clinical trial methods of demonstrating safety and efficacy. These assumptions may be overly optimistic and do not account for the broader societal burdens of prematurely releasing high-cost therapies with uncertain safety risks and benefits on to health-care markets. This essay focuses on the introduction of conditional approval programs for autologous somatic stem cell therapies and argues that these programs may conflict with, and potentially undermine, the normative commitments of regulatory agencies charged with promoting population health and protecting vulnerable groups from harm and exploitation. It concludes with suggestions of how programs designed to accelerate access to potentially helpful but experimental interventions could be reconfigured to be more equitable.


Healing of gingival recessions using a collagen membrane with a hemineralized xenograft: a randomized controlled clinical trial.
This study compared the results following treatment of gingival recessions by a coronally advanced flap procedure alone (CAF) or combined with a bioabsorbable membrane and a demineralized xenograft (GTRF). Sixteen nonsmokers with 20 Miller Class I or Class II buccal gingival recessions at canines or premolars were included in the study. Sites were randomly assigned to either CAF treatment (control, n = 10) or GTRF treatment (test, n = 10) and examined at baseline and at 6 months postoperatively. Both treatments resulted in a significant reduction in recession and gain in clinical attachment level; there was no significant difference between treatments. No differences were found in probing depths among or between the groups. The increase in keratinized tissue from baseline to 6 months was slightly greater for the GTRF group than for the CAF group, but without statistical significance. The test group experienced a statistically significant increase in gingival thickness from baseline to the 6-month evaluation, while little gain was detected in the control group; the between-group difference was statistically significant in favor of the test group. Both procedures offer a predictable, simple, and convenient means of root coverage in Miller Class I and II recession defects, but the GTRF-supported procedure resulted in more keratinized tissue and a significant increase in gingival thickness than the CAF-only approach.


Who's in the driver's seat? The influence of patient and physician enthusiasm on regional variation in degenerative lumbar spinal surgery: a population-based study.
Cross-sectional population-based study using administrative databases, census data, and surveys of orthopedic/neurosurgeons, family physicians (FPs) and patients in Ontario, Canada. To determine the influence of the enthusiasm of patients, FPs, and surgeons for surgery on the regional variation in surgical rates for degenerative diseases of the lumbar spine (DDLS), such as spinal stenosis and degenerative spondylolisthesis. Rates of surgery and healthcare costs for treating DDLS have been increasing. Regional variation in spinal surgical rates has been observed and it is thought that the enthusiasm of patients and physicians for surgery contributes to this variation. Using population-based administrative databases, we included all patients aged 50 years and older who underwent DDLS surgery (i.e., decompression/laminectomy, fusion) from 2002 to 2006 and calculated standardized utilization rates across counties. We measured regional "enthusiasm for surgery" for surgeons, FPs, and patients, using responses from a province-wide survey. Small-area variation analysis and multivariate Poisson regression models were performed calculating incidence rate ratios (IRRs) controlling for county demographics, socioeconomic measures, prevalence of disease, and community resources. We identified 10,318 DDLS surgeries (mean age 65 years, 50.6% female). Significant regional variation was observed (extremal quotient 5.0, coefficient of variation 28.0). Counties with higher rates of surgery had higher surgeon enthusiasm for surgery (IRR: 1.26, P < 0.013), older (IRR: 2.17, P < 0.0001) male patients (IRR: 1.19, P < 0.0001), lower income (IRR: 0.89, P < 0.0015), more knowledge of official languages (IRR: 1.12, P < 0.0003), and the presence of magnetic resonance imaging scanners (IRR: 1.30, P < 0.004). FP and patient enthusiasm for surgery, physician supply, and prevalence of disease were not statistically associated with higher surgical rates. Prior studies have not addressed the role of patient enthusiasm for surgery. Although patients and FPs had variable enthusiasm for surgery, surgeon enthusiasm was the dominant potentially modifiable factor influencing surgical rates. Prevalence of disease and community resources were not related to surgical rates. Strategies targeting surgeon practices may reduce regional variation in care and improve access disparities.