[Anatomy practice and medical education].
Medical education is committed to a distant and impersonal model of medical care that does not take into consideration the complexity of the encounter between physician and patient. Some authors believe that the "dehumanizing posture" of physicians is encouraged by the pedagogical practice of dissecting cadavers. In this sense the relationship between student and cadaver would be a model preceding and shaping the relationship between physician and patient. This article describes a study on the impact of anatomy practice on first-semester medical students enrolled in the anatomy course at the Federal University of Rio de Janeiro, Brazil. Groups of 16 students attended four 1-hour meetings over the semester. Thirty-two groups were assessed over four semesters, with a total of 384 students. The activity was coordinated by medical psychology and anatomy professors, who took notes during the sessions. At the end of each semester the students filled out a questionnaire to help evaluate this teaching activity. In the groups, the most frequent themes were the first encounter with the cadaver, respect for the cadaver, and the presence or absence of humanity in the cadaver. In general the questionnaire showed that the students found the experience to be positive. We believe that the pedagogical activity described here provides an opportunity to reverse the gloomy state of affairs of dehumanized medical care. Group discussions help decrease students' anxiety with the cadaver. This in turn results in a more humane model for the physician-patient relationship and promotes change in the ideology of coldness and distance on the part of the physician. The paradox of medical education--being technical and also having to take into account the complexity of human relationships--can be resolved through activities such as this one.


Subgroup and subtype-specific outcomes in adult medulloblastoma.
Medulloblastoma, a common pediatric malignant central nervous system tumour, represent a small proportion of brain tumours in adults. Previously it has been shown that in adults, Sonic Hedgehog (SHH)-activated tumours predominate, with Wingless-type (WNT) and Group 4 being less common, but molecular risk stratification remains a challenge. We performed an integrated analysis consisting of genome-wide methylation profiling, copy number profiling, somatic nucleotide variants and correlation of clinical variables across a cohort of 191 adult medulloblastoma cases identified through the Medulloblastoma Advanced Genomics International Consortium. We identified 30 WNT, 112 SHH, 6 Group 3, and 41 Group 4 tumours. Patients with SHH tumours were significantly older at diagnosis compared to other subgroups (p < 0.0001). Five-year progression-free survival (PFS) for WNT, SHH, Group 3, and Group 4 tumours was 64.4 (48.0-86.5), 61.9% (51.6-74.2), 80.0% (95% CI 51.6-100.0), and 44.9% (95% CI 28.6-70.7), respectively (p = 0.06). None of the clinical variables (age, sex, metastatic status, extent of resection, chemotherapy, radiotherapy) were associated with subgroup-specific PFS. Survival among patients with SHH tumours was significantly worse for cases with chromosome 3p loss (HR 2.9, 95% CI 1.1-7.6; p = 0.02), chromosome 10q loss (HR 4.6, 95% CI 2.3-9.4; p < 0.0001), chromosome 17p loss (HR 2.3, 95% CI 1.1-4.8; p = 0.02), and PTCH1 mutations (HR 2.6, 95% CI 1.1-6.2; p = 0.04). The prognostic significance of 3p loss and 10q loss persisted in multivariable regression models. For Group 4 tumours, chromosome 8 loss was strongly associated with improved survival, which was validated in a non-overlapping cohort (combined cohort HR 0.2, 95% CI 0.1-0.7; p = 0.007). Unlike in pediatric medulloblastoma, whole chromosome 11 loss in Group 4 and chromosome 14q loss in SHH was not associated with improved survival, where MYCN, GLI2 and MYC amplification were rare. In sum, we report unique subgroup-specific cytogenetic features of adult medulloblastoma, which are distinct from those in younger patients, and correlate with survival disparities. Our findings suggest that clinical trials that incorporate new strategies tailored to high-risk adult medulloblastoma patients are urgently needed.


Tumor-promoting phorbol esters and activated Ras inactivate the tuberous sclerosis tumor suppressor complex via p90 ribosomal S6 kinase.
Tuberous sclerosis complex (TSC) is a genetic disorder caused by mutations in either of the two tumor suppressor genes TSC1 or TSC2, which encode hamartin and tuberin, respectively. Tuberin and hamartin form a complex that inhibits signaling by the mammalian target of rapamycin (mTOR), a critical nutrient sensor and regulator of cell growth and proliferation. Phosphatidylinositol 3-kinase (PI3K) inactivates the tumor suppressor complex and enhances mTOR signaling by means of phosphorylation of tuberin by Akt. Importantly, cellular transformation mediated by phorbol esters and Ras isoforms that poorly activate PI3K promote tumorigenesis in the absence of Akt activation. In this study, we show that phorbol esters and activated Ras also induce the phosphorylation of tuberin and collaborates with the nutrient-sensing pathway to regulate mTOR effectors, such as p70 ribosomal S6 kinase 1 (S6K1). The mitogen-activated protein kinase (MAPK)-activated kinase, p90 ribosomal S6 kinase (RSK) 1, was found to interact with and phosphorylate tuberin at a regulatory site, Ser-1798, located at the evolutionarily conserved C terminus of tuberin. RSK1 phosphorylation of Ser-1798 inhibits the tumor suppressor function of the tuberin/hamartin complex, resulting in increased mTOR signaling to S6K1. Together, our data unveil a regulatory mechanism by which the Ras/MAPK and PI3K pathways converge on the tumor suppressor tuberin to inhibit its function.


Correlation of O6-methylguanine methyltransferase (MGMT) promoter methylation with clinical outcomes in glioblastoma and clinical strategies to modulate MGMT activity.
Resistance to alkylating agents via direct DNA repair by O(6)-methylguanine methyltransferase (MGMT) remains a significant barrier to the successful treatment of patients with malignant glioma. The relative expression of MGMT in the tumor may determine response to alkylating agents, and epigenetic silencing of the MGMT gene by promoter methylation plays an important role in regulating MGMT expression in gliomas. MGMT promoter methylation is correlated with improved progression-free and overall survival in patients treated with alkylating agents. Strategies to overcome MGMT-mediated chemoresistance are being actively investigated. These include treatment with nontoxic pseudosubstrate inhibitors of MGMT, such as O(6)-benzylguanine, or RNA interference-mediated gene silencing of MGMT. However, systemic application of MGMT inhibitors is limited by an increase in hematologic toxicity. Another strategy is to deplete MGMT activity in tumor tissue using a dose-dense temozolomide schedule. These alternative schedules are well tolerated; however, it remains unclear whether they are more effective than the standard dosing regimen or whether they effectively deplete MGMT activity in tumor tissue. Of note, not all patients with glioblastoma having MGMT promoter methylation respond to alkylating agents, and even those who respond will inevitably experience relapse. Herein we review the data supporting MGMT as a major mechanism of chemotherapy resistance in malignant gliomas and describe ongoing studies that are testing resistance-modulating strategies.


The effect of environmental conditions on the rate of RNA degradation in dried blood stains.
The relationship between RNA degradation and the age of a bloodstain has been suggested by the work of several investigators. A prior study from this laboratory described a qPCR assay that was effective at estimating the age of bloodstains stored in an environmentally controlled laboratory for periods of up to one year. In this study, the effect of the environmental conditions on the rate of RNA degradation during storage was analyzed. Bloodstains were prepared on stain cards and stored in one of 9 different environments for periods of up to 24 weeks. At selected times during the storage term, RNA was extracted, reverse transcribed, and the integrity of select transcripts analyzed. Three temperatures (37 °C, 20 °C, and 4 °C) and three relative humidities (rH) (75 %, 35 %, and 10 %) were combined pairwise. The rate of RNA degradation was found to increase 5-10 fold in stains stored at 37 °C versus those stored at 20 °C. The rate of RNA degradation was faster for stains stored at 20 °C compared to 4 °C but differed only 2-4 fold. Multivariate regression analysis suggests elevations in temperature or rH will accelerate RNA degradation and will do so to a similar extent. It is clear from the data that the integrity of the transcriptome in dried bloodstains is better preserved in a cold and dry environment. Investigations are ongoing to develop an approach for the estimation of sample age that incorporates the environmental conditions of a crime scene into the age estimate.


Awareness and attitudes of pre-exposure prophylaxis for HIV prevention among physicians in Guatemala: Implications for country-wide implementation.
HIV continues to be a major health concern with approximately 2.1 million new infections occurring worldwide in 2015. In Central America, Guatemala had the highest incident number of HIV infections (3,700) in 2015. Antiretroviral pre-exposure prophylaxis (PrEP) was recently recommended by the World Health Organization (WHO) as an efficacious intervention to prevent HIV transmission. PrEP implementation efforts are underway in Guatemala and success will require providers that are knowledgeable and willing to prescribe PrEP. We sought to explore current PrEP awareness and prescribing attitudes among Guatemalan physicians in order to inform future PrEP implementation efforts. We conducted a cross-sectional survey of adult internal medicine physicians at the main teaching hospital in Guatemala City in March 2015. The survey included demographics, medical specialty, years of HIV patient care, PrEP awareness, willingness to prescribe PrEP, previous experience with post-exposure prophylaxis, and concerns about PrEP. The primary outcome was willingness to prescribe PrEP, which was assessed using a 5-point Likert scale for different at-risk population scenarios. Univariate and multivariate logistic regression was performed to identify predictors for willingness to prescribe PrEP. Eighty-seven physicians completed the survey; 66% were male, 64% were internal medicine residency trainees, and 10% were infectious disease (ID) specialists. Sixty-nine percent of physicians were PrEP aware, of which 9% had previously prescribed PrEP. Most (87%) of respondents were willing to prescribe PrEP to men who have sex with men (MSM), sex workers, injection drug users, or HIV-uninfected persons having known HIV-positive sexual partners. Concerns regarding PrEP included development of resistance (92%), risk compensation (90%), and cost (64%). Univariate logistic regression showed that younger age, being a resident trainee, and being a non-ID specialist were significant predictors for willingness to prescribe PrEP. In multivariate logistic regression, being a non-ID specialist was a significant predictor. Guatemalan physicians at an urban public hospital were PrEP aware and willing to prescribe, but few have actually done so yet. Future education programs should address the concerns identified, including the low potential for the development of antiretroviral resistance. These findings can aid PrEP implementation efforts in Guatemala.


Short term effectiveness of neural sliders and neural tensioners as an adjunct to static stretching of hamstrings on knee extension angle in healthy individuals: A randomized controlled trial.
To investigate the added benefit of nerve-biased interventions over static stretching in hamstring flexibility and to compare the effectiveness of two types of nerve-biased interventions over a week. Three-arm assessor-blinded randomized controlled trial. University Laboratory. Sixty healthy individuals (mean age = 22 ± 2.4 years) with reduced hamstring flexibility were randomized to three groups who received static stretching and neurodynamic sliders (NS-SS); static stretching with neurodynamic tensioner (NT-SS) and static stretching (SS) alone. Knee extension angle (KEA) in degrees. Baseline characteristics including demographic, anthropomorphic and KEA between groups were comparable. A significant interaction was observed between group (intervention) and time, [F (2,114) = 3.595; p = 0.031]. Post-hoc pairwise comparisons analyses revealed significant differences at post-intervention measurement time point between NS-SS and SS (mean difference: -6.8; 95%CI = -12, -1.5; p = 0.011) and NT-SS and SS (mean difference: -11.6; 95%CI = -16.7, -6.3; p < 0.001). However there was no significant difference between NS-SS and NT-SS groups (mean difference: 4.8; 95%CI = 0.4, 9.9; p = 0.074). Neural sliders and tensioners are both effective in increasing hamstring flexibility as an adjunct to static hamstring stretching when compared to static stretching alone. No neural mobilization technique proved to be superior over another. This clinical trial is registered in Clinical Trials Registry- India (CTRI) with registration number CTRI/2012/05/002619.


Differential effects of salbutamol and montelukast on eosinophil adhesion and superoxide anion generation.
Beta2-agonists, a representative class of bronchodilators used for asthma, have been shown to modulate some functions of eosinophils, including cell adhesion. Similarly, a leukotriene receptor antagonist (LTRA) may be beneficial in controlling inflammation in asthma, as cysteinyl leukotrienes (cysLTs) can cause accumulation or activation of eosinophils. Recent evidence suggests that the addition of an LTRA, but not a long-acting beta2-agonist, to inhaled corticosteroid additionally reduces the number of eosinophils in sputum and blood from patients with asthma. The present study examined whether a beta2-agonist and an LTRA differentially modify eosinophil adhesion and activation induced by cysLTs and other activators. Eosinophils were isolated from blood of healthy donors and then incubated in the presence or absence of salbutamol (albuterol) or montelukast. Eosinophils were then exposed to leukotriene D4 (LTD4) or another activator, and the generation of superoxide anion (O2-) was evaluated by cytochrome C reduction assay. Eosinophil adhesion was examined by an eosinophil peroxidase assay. Montelukast, but not salbutamol (both at 1 microM), inhibited LTD4-induced (100 nM) eosinophil adhesion to recombinant human intercellular adhesion molecule 1. Both drugs similarly and partially inhibited the 100 pM interleukin-5-induced adhesive response of eosinophils to recombinant human intercellular adhesion molecule 1. Montelukast, but not salbutamol, blocked LTD4-induced eosinophil O2- generation of eosinophils. Finally, neither salbutamol nor montelukast modified phorbol myristate acetate (1 ng/ml)-induced O2- generation from eosinophils. These results confirm that LTD4 directly induces activation of eosinophils via the cysLT1 receptor. Furthermore, the results suggest that a beta2-agonist has no effect on eosinophil adhesion and activation induced by cysLTs. These results explain the differential effects of an LTRA and a beta2-agonist in the treatment of eosinophilic inflammation in asthma.


NAT2 genetic polymorphisms and anti-tuberculosis drug-induced hepatotoxicity in Chinese community population.
Anti-tuberculosis drug-induced hepatotoxicity (ATDH) is one of the most prevalent and serious adverse drug reactions in the course of anti-tuberculosis (TB) treatment. Some researchers suggested that determination of N-acetyltransferase 2 (NAT2) genotype may be clinically useful to identify patients at high risk of developing ATDH. To evaluate whether the NAT2 genotype could be as a predictor for ATDH in Chinese community TB population. A total of 4304 community-based TB patients were followed up six to nine months prospectively. A nested case-control study was designed. Each ATDH case was 1:4 matched with controls by age (within 5 years old), gender, treatment history, disease severity and drug dosage. The polymorphisms of NAT2 were determined using polymerase chain reaction with restriction fragment length polymorphism. Conditional Logistic regression model was used to calculate odds ratio (OR) and 95% confidence interval (CI), as well as corresponding P-values. A total of 89 ATDH cases and 356 controls were included in this study. Allele frequency of NAT2*5, NAT2*6 and NAT2*7 in cases and controls were 4.5 and 3.2%, 25.3 and 26.5%, and 13.5 and 13.5%, respectively. Frequencies of genotypes and alleles of NAT2*5, NAT2*6 and NAT2*7 did not differ significantly between cases and controls. The OR of intermediate acetylator and slow acetylator compared with rapid acetylator was 1.040 (95%CI 0.616-1.758) and 0.990 (95%CI 0.509-1.925), respectively. The NAT2 haplotype distribution in cases was similar to controls. In conclusion, we did not find significant association between NAT2 genotype and ATDH in community-based Chinese population. It may be deficient to take NAT2 genotype as a predictor for ATDH in Chinese community TB patients.


Effect of growth rate on plasmid maintenance by Escherichia coli HB101(pAT153).
The effects of changing the composition of the growth medium, the dilution rate and the source of the bacterial host on maintenance of the plasmid pAT153 in Escherichia coli HB101 have been studied. In a medium supplemented with Casamino acids, the plasmid was maintained longer during phosphate-limited growth at a dilution rate of 0.3 h-1 than at 0.15 h-1. In contrast, phosphate-limited growth was not achieved when the Casamino acids were replaced by proline, leucine and thiamin to satisfy the auxotrophic requirements of the host. Although 100% of the bacteria were still ampicillin resistant after 72 generations of growth at a dilution rate of 0.15 h-1, the original plasmid had almost totally been replaced by a structurally modified plasmid which lacked a functional tet gene. Further experiments confirmed that neither the host nor the plasmid was retained unchanged in the minimal medium. The changes were highly reproducible and reflected periodic selection of sub-populations which were either plasmid-free or carried a structurally modified plasmid, which had reverted to Leu+ or Pro+, or had acquired other chromosomal mutations which gave them a selective advantage. We conclude that in complex media the plasmid is maintained longer by E. coli HB101 at a high than at a low growth rate and that different results reported from different laboratories are largely due to differences in analytical techniques and the growth medium rather than to differences in the bacterial host or the plasmid used. A fermenter-adapted strain was isolated which reproducibly maintained the plasmid longer during phosphate-limited continuous growth than the original strain which had been cultured on laboratory media.


Grain processing and nutrition.
Whole grains provide a wide range of nutrients and phytochemicals that optimize health. Epidemiologic studies support the protectiveness of whole grain consumption for cardiovascular disease and cancer. Dietary guidance endorses increased whole grains in our diet. A crucial question remaining is the effect of processing of whole grains on their content of nutrients and phytochemicals. Although processing is often considered to be a negative attribute in nutrition, and some forms of processing reduce nutritional value, many factors support the importance of processing of grains to enhance grain consumption. First, whole grains as harvested are generally not consumed directly by humans but require some processing prior to consumption. While refining, that is, removal of the bran and the germ, reduces the nutrient content of grain, milling of grains otherwise concentrates desirable grain components and removes poorly digested compounds and contaminants. Cooking of grains generally increases digestibility of nutrients and phytochemicals. Studies in both animal models and humans support the notion that processed grains are often nutritionally superior to unprocessed grains, probably because of enhanced nutrient bioavailability in processed grains. Processing of grains also provides shelf-stable products that are convenient and good tasting for consumers.


[Correlation between clinical symptoms and radiologic findings before and after pneumatic balloon dilatation for achalasia].
We investigated the risk factors for short-term recurrence and analyzed the correlation between subjective clinical symtoms and objective radiological findings in patients with achalasia undergoing pneumatic balloon dilatation. Twenty patients who were treated by pneumatic balloon dilatation were enrolled. We compared prospectively various indices before and after the treatment as follows: 1) Eckardt symptom score and dysphagia grade, 2) The ratio of the maximal width in mid-esophageal lumen to the minimal width in distal esophagus around lower esophageal sphincter, and 3) the percentage of maximum activity retained in the esophagus at 30 seconds and T in esophageal scan two days after the treatment. 1) Clinical indices and radiologic indices significantly improved after pneumatic dilatation. 2) There was no significant correlation between the clinical indices and the radiologic indices before and after the treatment. 3) The difference percentage of clinical indices did not show significant correlation with the difference percentage of the radiologic indices. 4) Compared to the group above 20% in the difference percentage of 30 second residual fraction, the one below 20% had a four-fold risk in short-term recurrence. Clinical symptoms and radiologic indices significantly improve after pneumatic dilatation but have no significant correlation to each other. The group below 20% in the difference percentage of 30 second residual fraction has a high risk of recurrence and may need careful examination and early repeated pneumatic dilation.


Putative vascular endothelial cell chemotactic factors: comparison in a standardized migration assay.
While a number of chemoattractants of vascular endothelial cells have now been identified in vitro, differences in methodology preclude comparisons of substances evaluated in different assays. Here, we report a standardized chemotactic assay in which the migration of calf pulmonary artery endothelial cells in a 48-well microchemotaxis chamber was determined. Nonstimulated (control) migration was remarkably constant (mean +/- SD, 96 +/- 14) from plate to plate, thus allowing the indexing of relative migration of stimulated cells to that of nonstimulated cells in the control wells of that plate. Based on the relative migrations observed in response to each of the substances evaluated, those proving to be stimulatory of migration were placed in rank order by potency. The growth factors epidermal growth factor, transforming growth factor-alpha, and basic fibroblast growth factor (followed by pentosan polysulfate, plasmin, fibronectin, fibrinogen, granulocyte-macrophage colony stimulating factor heparin, adenosine, and MgSO4) were the most potent. Only the platelet factors platelet-derived growth factor-BB and platelet activating factor proved inhibitory of migration. Combining fibrinogen with other chemoattractants produced either stimulation or inhibition in comparison to the migration observed with fibrinogen alone, suggesting that more than one signal transduction mechanism was, in all likelihood, invoked by the various agents. This assay will allow the rapid screening and rank ordering of additional putative chemoattractants, will facilitate the study of the biochemical mechanisms involved in endothelial cell migration, and will permit the evaluation of pharmacologic agents capable of modulating stimulated or unstimulated migration.


Melatonin and agomelatine for preventing seasonal affective disorder.
Seasonal affective disorder (SAD) is a seasonal pattern of recurrent major depressive episodes that most commonly starts in autumn or winter and remits in spring. The prevalence of SAD depends on latitude and ranges from 1.5% to 9%. The predictable seasonal aspect of SAD provides a promising opportunity for prevention in people who have a history of SAD. This is one of four reviews on the efficacy and safety of interventions to prevent SAD; we focus on agomelatine and melatonin as preventive interventions. To assess the efficacy and safety of agomelatine and melatonin (in comparison with each other, placebo, second-generation antidepressants, light therapy, psychological therapy or lifestyle interventions) in preventing SAD and improving person-centred outcomes among adults with a history of SAD. We searched Ovid MEDLINE (1950- ), Embase (1974- ), PsycINFO (1967- ) and the Cochrane Central Register of Controlled Trials (CENTRAL) to 19 June 2018. An earlier search of these databases was conducted via the Cochrane Common Mental Disorders Controlled Trial Register (CCMD-CTR) (all years to 11 August 2015). Furthermore, we searched the Cumulative Index to Nursing and Allied Health Literature, Web of Science, the Cochrane Library, the Allied and Complementary Medicine Database and international trial registers (to 19 June 2018). We also conducted a grey literature search and handsearched the reference lists of included studies and pertinent review articles. To examine efficacy, we included randomised controlled trials (RCTs) on adults with a history of winter-type SAD who were free of symptoms at the beginning of the study. For adverse events, we intended also to include non-randomised studies. We planned to include studies that compared agomelatine versus melatonin, or agomelatine or melatonin versus placebo, any second-generation antidepressant, light therapy, psychological therapies or lifestyle changes. We also intended to compare melatonin or agomelatine in combination with any of the comparator interventions mentioned above versus the same comparator intervention as monotherapy. Two review authors screened abstracts and full-text publications, abstracted data and assessed risk of bias of included studies independently. We intended to pool data in a meta-analysis using a random-effects model, but included only one study. We identified 3745 citations through electronic searches and reviews of reference lists after deduplication of search results. We excluded 3619 records during title and abstract review and assessed 126 full-text papers for inclusion in the review. Only one study, providing data of 225 participants, met our eligibility criteria and compared agomelatine (25 mg/day) with placebo. We rated it as having high risk of attrition bias because nearly half of the participants left the study before completion. We rated the certainty of the evidence as very low for all outcomes, because of high risk of bias, indirectness, and imprecision.The main analysis based on data of 199 participants rendered an indeterminate result with wide confidence intervals (CIs) that may encompass both a relevant reduction as well as a relevant increase of SAD incidence by agomelatine (risk ratio (RR) 0.83, 95% CI 0.51 to 1.34; 199 participants; very low-certainty evidence). Also the severity of SAD may be similar in both groups at the end of the study with a mean SIGH-SAD (Structured Interview Guide for the Hamilton Depression Rating Scale, Seasonal Affective Disorders) score of 8.3 (standard deviation (SD) 9.4) in the agomelatine group and 10.1 (SD 10.6) in the placebo group (mean difference (MD) -1.80, 95% CI -4.58 to 0.98; 199 participants; very low-certainty evidence). The incidence of adverse events and serious adverse events may be similar in both groups. In the agomelatine group, 64 out of 112 participants experienced at least one adverse event, while 61 out of 113 did in the placebo group (RR 1.06, 95% CI 0.84 to 1.34; 225 participants; very low-certainty evidence). Three out of 112 patients experienced serious adverse events in the agomelatine group, compared to 4 out of 113 in the placebo group (RR 0.76, 95% CI 0.17 to 3.30; 225 participants; very low-certainty evidence).No data on quality of life or interpersonal functioning were reported. We did not identify any studies on melatonin. Given the uncertain evidence on agomelatine and the absence of studies on melatonin, no conclusion about efficacy and safety of agomelatine and melatonin for prevention of SAD can currently be drawn. The decision for or against initiating preventive treatment of SAD and the treatment selected should consider patient preferences and reflect on the evidence base of all available treatment options.


Evidence that release of adenosine triphosphate from endothelial cells during increased shear stress is vesicular.
In response to increased shear stress, vascular endothelial cells release adenosine triphosphate (ATP) by an unknown mechanism. We have investigated this mechanism using different approaches. First, we discovered that quinacrine, used to locate intracellular stores of ATP bound to peptides, displayed a granular fluorescence, typical of vesicular storage. Second, we found that two inhibitors of vesicular transport (monensin and N-ethylmaleimide) produced a highly significant reduction in the release of ATP from vascular endothelial cells in response to increased shear stress. Preliminary experiments using inhibitors of the cystic fibrosis transmembrane regulator, the sulfonylurea receptor, and the multidrug resistance protein showed no involvement of these ATP-binding cassette transporter proteins (previously characterized in endothelial cells) in the mechanism of release of ATP. We suggest, therefore, that the release of ATP from vascular endothelial cells, like that of nerve cells, is probably by vesicular exocytosis.


Phenotypic Plasticity Promotes Balanced Polymorphism in Periodic Environments by a Genomic Storage Effect.
Phenotypic plasticity is known to evolve in perturbed habitats, where it alleviates the deleterious effects of selection. But the effects of plasticity on levels of genetic polymorphism, an important precursor to adaptation in temporally varying environments, are unclear. Here we develop a haploid, two-locus population-genetic model to describe the interplay between a plasticity modifier locus and a target locus subject to periodically varying selection. We find that the interplay between these two loci can produce a "genomic storage effect" that promotes balanced polymorphism over a large range of parameters, in the absence of all other conditions known to maintain genetic variation. The genomic storage effect arises as recombination allows alleles at the two loci to escape more harmful genetic backgrounds and associate in haplotypes that persist until environmental conditions change. Using both Monte Carlo simulations and analytical approximations we quantify the strength of the genomic storage effect across a range of selection pressures, recombination rates, plasticity modifier effect sizes, and environmental periods.


Predicting Islet Cell Autoimmunity and Type 1 Diabetes: An 8-Year TEDDY Study Progress Report.
Assessment of the predictive power of The Environmental Determinants of Diabetes in the Young (TEDDY)-identified risk factors for islet autoimmunity (IA), the type of autoantibody appearing first, and type 1 diabetes (T1D). A total of 7,777 children were followed from birth to a median of 9.1 years of age for the development of islet autoantibodies and progression to T1D. Time-dependent sensitivity, specificity, and receiver operating characteristic (ROC) curves were calculated to provide estimates of their individual and collective ability to predict IA and T1D. HLA genotype (DR3/4 vs. others) was the best predictor for IA (Youden's index J = 0.117) and single nucleotide polymorphism rs2476601, in PTPN22, was the best predictor for insulin autoantibodies (IAA) appearing first (IAA-first) (J = 0.123). For GAD autoantibodies (GADA)-first, weight at 1 year was the best predictor (J = 0.114). In a multivariate model, the area under the ROC curve (AUC) was 0.678 (95% CI 0.655, 0.701), 0.707 (95% CI 0.676, 0.739), and 0.686 (95% CI 0.651, 0.722) for IA, IAA-first, and GADA-first, respectively, at 6 years. The AUC of the prediction model for T1D at 3 years after the appearance of multiple autoantibodies reached 0.706 (95% CI 0.649, 0.762). Prediction modeling statistics are valuable tools, when applied in a time-until-event setting, to evaluate the ability of risk factors to discriminate between those who will and those who will not get disease. Although significantly associated with IA and T1D, the TEDDY risk factors individually contribute little to prediction. However, in combination, these factors increased IA and T1D prediction substantially.


UK Biobank's cardiovascular magnetic resonance protocol.
UK Biobank's ambitious aim is to perform cardiovascular magnetic resonance (CMR) in 100,000 people previously recruited into this prospective cohort study of half a million 40-69 year-olds. We describe the CMR protocol applied in UK Biobank's pilot phase, which will be extended into the main phase with three centres using the same equipment and protocols. The CMR protocol includes white blood CMR (sagittal anatomy, coronary and transverse anatomy), cine CMR (long axis cines, short axis cines of the ventricles, coronal LVOT cine), strain CMR (tagging), flow CMR (aortic valve flow) and parametric CMR (native T1 map). This report will serve as a reference to researchers intending to use the UK Biobank resource or to replicate the UK Biobank cardiovascular magnetic resonance protocol in different settings.


Crystal structures of the TRIC trimeric intracellular cation channel orthologues.
Ca2+ release from the sarcoplasmic reticulum (SR) and endoplasmic reticulum (ER) is crucial for muscle contraction, cell growth, apoptosis, learning and memory. The trimeric intracellular cation (TRIC) channels were recently identified as cation channels balancing the SR and ER membrane potentials, and are implicated in Ca2+ signaling and homeostasis. Here we present the crystal structures of prokaryotic TRIC channels in the closed state and structure-based functional analyses of prokaryotic and eukaryotic TRIC channels. Each trimer subunit consists of seven transmembrane (TM) helices with two inverted repeated regions. The electrophysiological, biochemical and biophysical analyses revealed that TRIC channels possess an ion-conducting pore within each subunit, and that the trimer formation contributes to the stability of the protein. The symmetrically related TM2 and TM5 helices are kinked at the conserved glycine clusters, and these kinks are important for the channel activity. Furthermore, the kinks of the TM2 and TM5 helices generate lateral fenestrations at each subunit interface. Unexpectedly, these lateral fenestrations are occupied with lipid molecules. This study provides the structural and functional framework for the molecular mechanism of this ion channel superfamily.


Phylogeny of rock-inhabiting fungi related to Dothideomycetes.
The class Dothideomycetes (along with Eurotiomycetes) includes numerous rock-inhabiting fungi (RIF), a group of ascomycetes that tolerates surprisingly well harsh conditions prevailing on rock surfaces. Despite their convergent morphology and physiology, RIF are phylogenetically highly diverse in Dothideomycetes. However, the positions of main groups of RIF in this class remain unclear due to the lack of a strong phylogenetic framework. Moreover, connections between rock-dwelling habit and other lifestyles found in Dothideomycetes such as plant pathogens, saprobes and lichen-forming fungi are still unexplored. Based on multigene phylogenetic analyses, we report that RIF belong to Capnodiales (particularly to the family Teratosphaeriaceae s.l.), Dothideales, Pleosporales, and Myriangiales, as well as some uncharacterised groups with affinities to Dothideomycetes. Moreover, one lineage consisting exclusively of RIF proved to be closely related to Arthoniomycetes, the sister class of Dothideomycetes. The broad phylogenetic amplitude of RIF in Dothideomycetes suggests that total species richness in this class remains underestimated. Composition of some RIF-rich lineages suggests that rock surfaces are reservoirs for plant-associated fungi or saprobes, although other data also agree with rocks as a primary substrate for ancient fungal lineages. According to the current sampling, long distance dispersal seems to be common for RIF. Dothideomycetes lineages comprising lichens also include RIF, suggesting a possible link between rock-dwelling habit and lichenisation.


Single attosecond pulse generation using two-color polarized time-gating technique.
It is proposed that single attosecond pulses be generated via high-order harmonic generation by using a two-color pump pulse with time dependent ellipticity. The two-color pump pulse is created by the fundamental field and its second harmonic: the fundamental field is left-circularly polarized and the second harmonic is right-circularly polarized. Numerical simulations show that single attosecond pulses can be produced in the cut-off region by using the synthesis of 20 fs left-hand and right-hand circularly polarized pulses with a pulse delay of 20 fs. The attosecond pulses produced this way are much stronger than that produced by a few-cycle linear polarized pulse of comparable intensity.


Impact of dye-protein interaction and silver nanoparticles on rose bengal photophysical behavior and protein photocrosslinking.
The role of recombinant Type-I human collagen in the free form or forming AgNP@collagen on the photophysical and photochemical behavior of rose Bengal was analyzed. The formation of dye aggregates on the protein surface was experimentally observed and corroborated by docking calculations. The formation of such aggregates is believed to change the main oxidative mechanism from Type-II (singlet oxygen) to Type-I (free radical) photosensitization. Remarkably, the presence of AgNP in the form of AgNP@collagen altered the dynamics of dye triplet deactivation, effectively preventing the dye degradation and reducing the extent of protein crosslinked. Both crosslinked rHC and AgNP@collagen were able to support fibroblasts proliferation, but only the material containing silver was resistant to S. epidermidis infection.


Cultural responses to climate change during the late Holocene.
Modern complex societies exhibit marked resilience to interannual-to- decadal droughts, but cultural responses to multidecadal-to-multicentury droughts can only be addressed by integrating detailed archaeological and paleoclimatic records. Four case studies drawn from New and Old World civilizations document societal responses to prolonged drought, including population dislocations, urban abandonment, and state collapse. Further study of past cultural adaptations to persistent climate change may provide valuable perspective on possible responses of modern societies to future climate change.


Measurements and modeling of transient blood flow perturbations induced by brief somatosensory stimulation.
Proper interpretation of BOLD fMRI and other common functional imaging methods requires an understanding of neurovascular coupling. We used laser speckle-contrast optical imaging to measure blood-flow responses in rat somatosensory cortex elicited by brief (2 s) forepaw stimulation. Results show a large increase in local blood flow speed followed by an undershoot and possible late-time oscillations. The blood flow measurements were modeled using the impulse response of a simple linear network, a four-element windkessel. This model yielded excellent fits to the detailed time courses of activated regions. The four-element windkessel model thus provides a simple explanation and interpretation of the transient blood-flow response, both its initial peak and its late-time behavior.


Blastomycosis in Namibia--report of a case successfully treated with itraconazole.
The clinical, histological, mycological, radiological and scintigraphic features of a 42-year-old Namibian male with blastomycosis are described. This appears to be the first documented incidence of blastomycosis in Namibia. Leucocyte myeloperoxidase deficiency was evident. Treatment with itraconazole led to dramatic resolution of lesions. A reactive xanthogranulomatous response was present in a healed clavicular lesion.


Beneficial Phytochemicals with Anti-Tumor Potential Revealed through Metabolic Profiling of New Red Pigmented Lettuces (Lactuca sativa L.).
The present study aimed to compare polyphenols among red lettuce cultivars and identify suitable cultivars for the development and utilization of healthy vegetables. Polyphenols, mineral elements, and antioxidant activity were analyzed in the leaves of six red pigmented lettuce (Lactuca sativa L.) cultivars; thereafter, we assessed the anti-tumor effects of cultivar B-2, which displayed the highest antioxidant activity. Quadrupole-Orbitrap mass spectrometry analysis revealed four classes of polyphenols in these cultivars. The composition and contents of these metabolites varied significantly among cultivars and primarily depended on leaf color. The B-2 cultivar had the highest antioxidant potential than others because it contained the highest levels of polyphenols, especially anthocyanin, flavone, and phenolic acid; furthermore, this cultivar displayed anti-tumor effects against the human lung adenocarcinoma cell line A549, human hepatoma cell line Bel7402, human cancer colorectal adenoma cell line HCT-8, and HT-29 human colon cancer cell line. Hence, the new red-leaf lettuce cultivar B-2 has a distinct metabolite profile, with high potential for development and utilization of natural phytochemical and mineral resources in lettuces and can be used as a nutrient-dense food product.


Identification of charged residues in an N-terminal portion of the hormone-binding domain of the human estrogen receptor important in transcriptional activity of the receptor.
We have shown that charged amino acids near C530 of the human estrogen receptor (ER) are involved in receptor discrimination between estrogen and antiestrogen. We now examine the role of charged residues, adjacent to the three other cysteines (381, 417, and 447) in the hormone-binding domain of the human ER, in the hormone-binding, DNA-binding, and transcription activation abilities of the receptor. Mutation of the one charged amino acid nearest to C381 gave a mutant receptor (E380Q) requiring two to three times less estradiol (E2) than wild type (WT) ER to achieve maximal activity and having activity in the absence of added estrogen that was 6-fold higher than that of WT receptor. The enhanced ability of this mutant to bind to estrogen response element DNA in the absence and presence of estrogen may, at least in part, explain its elevated, seemingly constitutive trans-activation activity and its increased sensitivity to estrogen. While more sensitive to E2, this E380Q mutant was less sensitive than WT ER to antiestrogen for suppression of transcriptional activity. Mutation of all three charged residues nearest to C381 (the triple mutant D374N, E380Q, and E385Q) resulted in a greatly reduced potency of the receptor in trans-activation with no change in estrogen-binding affinity. When K449 (near C447), highly conserved among steroid receptors, was mutated to Q, 400-fold more E2 was required for maximal reporter gene trans-activation due to an unstable, temperature-sensitive hormone-receptor complex. In contrast, the mutant K416Q (near C417) was unaltered in E2-binding or receptor transcriptional activity. These studies reveal a region in the N-terminal portion of the hormone-binding domain (ca. amino acids 374-385) where alterations in charged residues result in either increases or decreases in receptor transcriptional activity with no change in receptor affinity for hormone. Our findings suggest that this region may be important in DNA binding and protein-protein interactions that modulate transcriptional activity of the ER. In addition, the region near C447, which is well conserved among steroid receptors, appears to be important in maintaining the receptor in a conformation that is stable at physiological (37 C) temperatures. To our knowledge, this is the first report of an ER (E380Q) with a sensitivity to E2 for trans-activation greater than that of WT receptor and having high trans-activation activity in the absence of added hormone.


Selective C-O bond formation via a photocatalytic radical coupling strategy: access to perfluoroalkoxylated (ORF) arenes and heteroarenes.
Development of an efficient process that employs commercially available and cost effective reagents for the synthesis of perfluoroalkoxylated aromatic compounds (Ar-ORF) remains a daunting challenge in organic synthesis. Herein, we report the first catalytic protocol using readily available perfluoroalkyl iodides (RFI) and N-(hetero)aryl-N-hydroxylamides to access a wide range of perfluoroalkoxylated (hetero)arenes. Mild reaction conditions allow for selective O-RF bond formation over a broad substrate scope and are tolerant of a wide variety of functional groups. Mechanistic studies suggest the formation and recombination of persistent N-hydroxyl radicals and transient RF radicals under photocatalytic reaction conditions to generate N-ORF compounds that rearrange to afford the desired products.


Differential responses of the dorsomedial prefrontal cortex and right posterior superior temporal sulcus to spontaneous mentalizing.
Previous research suggests a role of the dorsomedial prefrontal cortex (dmPFC) in metacognitive representation of social information, while the right posterior superior temporal sulcus (pSTS) has been linked to social perception. This study targeted these functional roles in the context of spontaneous mentalizing. An animated shapes task was presented to 46 subjects during functional magnetic resonance imaging. Stimuli consisted of video clips depicting animated shapes whose movement patterns prompt spontaneous mentalizing or simple intention attribution. Based on their differential response during spontaneous mentalizing, both regions were characterized with respect to their task-dependent connectivity profiles and their associations with autistic traits. Functional network analyses revealed highly localized coupling of the right pSTS with visual areas in the lateral occipital cortex, while the dmPFC showed extensive coupling with instances of large-scale control networks and temporal areas including the right pSTS. Autistic traits were related to mentalizing-specific activation of the dmPFC and to the strength of connectivity between the dmPFC and posterior temporal regions. These results are in good agreement with the hypothesized roles of the dmPFC and right pSTS for metacognitive representation and perception-based processing of social information, respectively, and further inform their implication in social behavior linked to autism. Hum Brain Mapp 38:3791-3803, 2017. © 2017 Wiley Periodicals, Inc.


What functional activities are important to patients with knee replacements?
There is interest in quantifying the patient's function and mobility after joint replacement. The current study identified activities important to patients having total knee replacement and the prevalence of limitations to participation in these activities. A Total Knee Function Questionnaire consisting of 55 questions addressing the patient's participation in various activities was developed, validated, and mailed to 367 patients at least 1 year after knee replacement. Patients were asked the frequency with which they did each activity, the activity's importance to them, and the extent to which their participation was limited by their knee replacement. The questionnaire was returned by 176 patients, 40% men and 60% women, with an average age of 70.5 years. The most prevalent activities were stretching exercises (73%), leg strengthening exercises (70%), kneeling (58%), and gardening (57%). The activities most important to the patients were stretching exercises (56%), kneeling (52%), and gardening (50%); those most difficult were squatting (75%), kneeling (72%), and gardening (54%). The current study showed a high correlation between the importance of activities and frequency of patient participation confirming that knee replacement successfully restores a significant degree of function. However, after knee replacement, improvements in knee function still are needed to allow patients to do all activities that they consider important.


ACE2 and TMPRSS2 variation in savanna monkeys (Chlorocebus spp.): Potential risk for zoonotic/anthroponotic transmission of SARS-CoV-2 and a potential model for functional studies.
The COVID-19 pandemic, caused by the coronavirus SARS-CoV-2, has devastated health infrastructure around the world. Both ACE2 (an entry receptor) and TMPRSS2 (used by the virus for spike protein priming) are key proteins to SARS-CoV-2 cell entry, enabling progression to COVID-19 in humans. Comparative genomic research into critical ACE2 binding sites, associated with the spike receptor binding domain, has suggested that African and Asian primates may also be susceptible to disease from SARS-CoV-2 infection. Savanna monkeys (Chlorocebus spp.) are a widespread non-human primate with well-established potential as a bi-directional zoonotic/anthroponotic agent due to high levels of human interaction throughout their range in sub-Saharan Africa and the Caribbean. To characterize potential functional variation in savanna monkey ACE2 and TMPRSS2, we inspected recently published genomic data from 245 savanna monkeys, including 163 wild monkeys from Africa and the Caribbean and 82 captive monkeys from the Vervet Research Colony (VRC). We found several missense variants. One missense variant in ACE2 (X:14,077,550; Asp30Gly), common in Ch. sabaeus, causes a change in amino acid residue that has been inferred to reduce binding efficiency of SARS-CoV-2, suggesting potentially reduced susceptibility. The remaining populations appear as susceptible as humans, based on these criteria for receptor usage. All missense variants observed in wild Ch. sabaeus populations are also present in the VRC, along with two splice acceptor variants (at X:14,065,076) not observed in the wild sample that are potentially disruptive to ACE2 function. The presence of these variants in the VRC suggests a promising model for SARS-CoV-2 infection and vaccine and therapy development. In keeping with a One Health approach, characterizing actual susceptibility and potential for bi-directional zoonotic/anthroponotic transfer in savanna monkey populations may be an important consideration for controlling COVID-19 epidemics in communities with frequent human/non-human primate interactions that, in many cases, may have limited health infrastructure.


Glial progenitor cell-based treatment and modeling of neurological disease.
The diseases of myelin are among the most prevalent and disabling conditions in neurology. These diseases include both the vascular and inflammatory demyelinating disorders of adulthood, as well as the childhood leukodystrophies and cerebral palsy. These fundamentally glial disorders may be amenable to treatment by glial progenitor cells (GPCs), which give rise to astroglia and myelin-producing oligodendrocytes. Given the development of new methods for generating and isolating human GPCs, the myelin disorders may now be compelling targets for cell-based therapy. In addition, the efficient engraftment and expansion of human GPCs in murine hosts has led to the development of human glial chimeric mouse brains, which provides new opportunities for studying the species-specific roles of human glia in cognition, as well as in disease pathogenesis.


Clinical potential of mucins in diagnosis, prognosis, and therapy of ovarian cancer.
Knowledge of mucins and their multiple roles in various normal and pathological processes has improved greatly in the past two decades. Mucins belong to a family of glycoproteins characterised by densely O-glycosylated repetitive domains and expressed by various surface epithelial cells. Altered expression of mucins is present in various diseases, including cancer. Ovarian cancer is the sixth most common cancer worldwide and the seventh leading cause of cancer-related deaths in women. The most common ovarian cancer is epithelial ovarian carcinoma, which is characterised by few early symptoms, widespread peritoneal dissemination, and ascites at advanced stages that result in poor prognosis. After diagnosis, 5 year survival is only 35-45%. Therefore, improved strategies for early diagnosis and treatment are needed. Because of the surface epithelial origin of epithelial ovarian cancer, mucins are obvious biomolecules for investigation as markers for early diagnosis and as therapeutic targets. We discuss the potential role and clinical usefulness of mucins in early diagnosis, prognosis, and treatment of ovarian cancer.


Trends and cyclical variation in the incidence of childhood type 1 diabetes in 26 European centres in the 25 year period 1989-2013: a multicentre prospective registration study.
Against a background of a near-universally increasing incidence of childhood type 1 diabetes, recent reports from some countries suggest a slowing in this increase. Occasional reports also describe cyclical variations in incidence, with periodicities of between 4 and 6 years. Age/sex-standardised incidence rates for the 0- to 14-year-old age group are reported for 26 European centres (representing 22 countries) that have registered newly diagnosed individuals in geographically defined regions for up to 25 years during the period 1989-2013. Poisson regression was used to estimate rates of increase and test for cyclical patterns. Joinpoint regression software was used to fit segmented log-linear relationships to incidence trends. Significant increases in incidence were noted in all but two small centres, with a maximum rate of increase of 6.6% per annum in a Polish centre. Several centres in high-incidence countries showed reducing rates of increase in more recent years. Despite this, a pooled analysis across all centres revealed a 3.4% (95% CI 2.8%, 3.9%) per annum increase in incidence rate, although there was some suggestion of a reduced rate of increase in the 2004-2008 period. Rates of increase were similar in boys and girls in the 0- to 4-year-old age group (3.7% and 3.7% per annum, respectively) and in the 5- to 9-year-old age group (3.4% and 3.7% per annum, respectively), but were higher in boys than girls in the 10- to 14-year-old age group (3.3% and 2.6% per annum, respectively). Significant 4 year periodicity was detected in four centres, with three centres showing that the most recent peak in fitted rates occurred in 2012. Despite reductions in the rate of increase in some high-risk countries, the pooled estimate across centres continues to show a 3.4% increase per annum in incidence rate, suggesting a doubling in incidence rate within approximately 20 years in Europe. Although four centres showed support for a cyclical pattern of incidence with a 4 year periodicity, no plausible explanation for this can be given.


Investigating the prediction value of multiparametric magnetic resonance imaging at 3 T in response to neoadjuvant chemotherapy in breast cancer.
To explore the predictive value of parameters derived from diffusion-weighted imaging (DWI) and contrast-enhanced (CE)-MRI at different time-points during neoadjuvant chemotherapy (NACT) in breast cancer. Institutional review board approval and written, informed consent from 42 breast cancer patients were obtained. The patients were investigated before and at three different time-points during neoadjuvant chemotherapy (NACT) using tumour diameter and volume from CE-MRI and ADC values obtained from drawn 2D and segmented 3D regions of interest. Prediction of pathologic complete response (pCR) was evaluated using the area under the curve (AUC) of receiver operating characteristic analysis. There was no significant difference between pathologic complete response and non-pCR in baseline size measures (p > 0.39). Diameter change was significantly different in pCR (p < 0.02) before the mid-therapy point. The best predictor was lesion diameter change observed before mid-therapy (AUC = 0.93). Segmented volume was not able to differentiate between pCR and non-pCR at any time-point. The ADC values from 3D-ROI were not significantly different from 2D data (p = 0.06). The best AUC (0.79) for pCR prediction using DWI was median ADC measured before mid-therapy of NACT. The results of this study should be considered in NACT monitoring planning, especially in MRI protocol designing and time point selection. • Mid-therapy diameter changes are the best predictors of pCR in neoadjuvant chemotherapy. • Volumetric measures are not strictly superior in therapy monitoring to lesion diameter. • Size measures perform as a better predictor than ADC values.


Formative Evaluation of a Peer Video-Based Coaching Initiative.
Few opportunities exist for surgeons to receive technical skills feedback after training. Surgeons at hospitals within the Illinois Surgical Quality Improvement Collaborative were invited to participate in a peer-to-peer video-based coaching initiative focused on improving technical skills in laparoscopic right colectomy. We present a formative qualitative evaluation of a video-based coaching initiative. Concurrent with the implementation of our video-based coaching initiative, we conducted two focus groups and 15 individual semistructured interviews with participants; all interviews were audio-recorded and transcribed. A subset of surgeons participated in a group video-review session, which was observed by qualitative researchers. Transcripts and notes were analyzed using an organizational behavior framework adapted from executive coaching. Participation in the initiative was primarily motivated by the opportunity to learn from others and improve skills. Surgeons highlighted the value of self-video and peer-video assessment not only to learn new techniques but also for self-reflection and benchmarking. Barriers to participation included logistics (e.g. using the laparoscopic recording devices, coordinating schedules for peer coaching), time commitment, and a surgical culture that assumes the intent of coaching is to address deficiencies. Video-based peer-coaching provides a platform for surgeons to reflect, benchmark against peers, and receive personalized feedback; however, more work is needed to increase participation and sustain involvement over time. There is an opportunity to decrease logistical barriers and increase acceptability of coaching by integrating video-based coaching into existing surgical conferences and established continuous professional development efforts.


A highly efficient Cu catalyst system for the radical reactions of α-bromocarbonyls.
In this communication, we established highly efficient Cu-catalyzed ARGET-ATRS (atom-transfer radical substitution) of alpha-bromocarbonyls with styrenes to produce tert-alkylated styrenes. The maximum TON was up to 12 000. Hünig's base was very important to regenerate active CuI. Moreover, a Cu-catalyzed C-C cleavage reaction via SH2' and intermolecular C-H cyclization of α-bromoimide was found.


MAO inhibitors and their wider applications: a patent review.
Monoamine oxidase (MAO) inhibitors, after the initial 'golden age', are currently used as third-line antidepressants (selective MAO-A inhibitors) or clinically enrolled as co-adjuvants for neurodegenerative diseases (selective MAO-B inhibitors). However, the research within this field is always increasing due to their pivotal role in modulating synaptic functions and monoamines metabolism. In this paper, MAO inhibitors (2015-2017) are disclosed ordering all the patents according to their chemical scaffold. Structure-activity relationships (SARs) are extrapolated for the most investigated chemotypes (coumarins, pyrazole/oxazepinones, (hetero)arylamides). 108 Compounds are divided into two main groups: newly synthesized molecules and naturally-occurring metabolites. Finally, new therapeutic options are outlined to ensure a more complete view on the potential of these inhibitors. New proposed MAO inhibitors are endowed with a marked isoform selectivity, with innovative therapeutic potential toward other targets (gliomas, inflammation, muscle dystrophies, migraine, chronic pain, pseudobulbar affect), and with a promising ability to address multi-faceted pathologies such as Alzheimer's disease. The increasing number of patents is analyzed collecting data from 2002 to 2017.


Opportunity for verbalization does not improve visual change detection performance: A state-trace analysis.
Evidence suggests that there is a tendency to verbally recode visually-presented information, and that in some cases verbal recoding can boost memory performance. According to multi-component models of working memory, memory performance is increased because task-relevant information is simultaneously maintained in two codes. The possibility of dual encoding is problematic if the goal is to measure capacity for visual information exclusively. To counteract this possibility, articulatory suppression is frequently used with visual change detection tasks specifically to prevent verbalization of visual stimuli. But is this precaution always necessary? There is little reason to believe that concurrent articulation affects performance in typical visual change detection tasks, suggesting that verbal recoding might not be likely to occur in this paradigm, and if not, precautionary articulatory suppression would not always be necessary. We present evidence confirming that articulatory suppression has no discernible effect on performance in a typical visual change-detection task in which abstract patterns are briefly presented. A comprehensive analysis using both descriptive statistics and Bayesian state-trace analysis revealed no evidence for any complex relationship between articulatory suppression and performance that would be consistent with a verbal recoding explanation. Instead, the evidence favors the simpler explanation that verbal strategies were either not deployed in the task or, if they were, were not effective in improving performance, and thus have no influence on visual working memory as measured during visual change detection. We conclude that in visual change detection experiments in which abstract visual stimuli are briefly presented, pre-cautionary articulatory suppression is unnecessary.


Changing Avatars, Changing Selves? The Influence of Social and Contextual Expectations on Digital Rendition of Identity.
Avatar creation is an interesting topic for both video game and social network studies. Research has shown that the creation of avatars is influenced by individual, contextual, and cultural features. Avatars are used to represent aspects of users' personality, but multiple avatars are used in different virtual contexts, as self-presentation strategies may vary according to the different "audiences" to be met online (say: friends, or strangers). Moreover, avatar creation is also influenced by cultural variables, such as gender, as avatars embody stereotypical aspects of being a woman or a man. This research tested whether avatars, as digital self-representations, may change depending on the above-mentioned variables. Ninety-four participants created two avatars to be used in different contexts (video game and job-themed social network). Moreover, two groups of participants were told that they would have met friends or total strangers within the two virtual contexts. Results showed that avatars changed from the game to the job context. Changes involved avatars' transient features (Clothes) more than physical (Body) and symbolic (Accessories) ones, and females changed accessories more than males. Moreover, females who expected to meet friends changed their avatars' bodies significantly more than males in both virtual contexts. The findings are discussed based on literature about computer-mediated communication and online self-disclosure. In conclusion, possible implications of the results for avatar-based interventions and the field of video games and social network design are reviewed.


Functional Subclone Profiling for Prediction of Treatment-Induced Intratumor Population Shifts and Discovery of Rational Drug Combinations in Human Glioblastoma.
Investigation of clonal heterogeneity may be key to understanding mechanisms of therapeutic failure in human cancer. However, little is known on the consequences of therapeutic intervention on the clonal composition of solid tumors. Here, we used 33 single cell-derived subclones generated from five clinical glioblastoma specimens for exploring intra- and interindividual spectra of drug resistance profiles in vitro In a personalized setting, we explored whether differences in pharmacologic sensitivity among subclones could be employed to predict drug-dependent changes to the clonal composition of tumors. Subclones from individual tumors exhibited a remarkable heterogeneity of drug resistance to a library of potential antiglioblastoma compounds. A more comprehensive intratumoral analysis revealed that stable genetic and phenotypic characteristics of coexisting subclones could be correlated with distinct drug sensitivity profiles. The data obtained from differential drug response analysis could be employed to predict clonal population shifts within the naïve parental tumor in vitro and in orthotopic xenografts. Furthermore, the value of pharmacologic profiles could be shown for establishing rational strategies for individualized secondary lines of treatment. Our data provide a previously unrecognized strategy for revealing functional consequences of intratumor heterogeneity by enabling predictive modeling of treatment-related subclone dynamics in human glioblastoma. Clin Cancer Res; 23(2); 562-74. ©2016 AACR.


Risk factors for thyroid cancer: a prospective cohort study.
Given the higher incidence rate of thyroid cancer among women compared to men and evidence that smoking and alcohol consumption may be inversely related to thyroid cancer risk, we examined thyroid cancer risk in association with menstrual, reproductive and hormonal factors, and cigarette and alcohol consumption, in a prospective cohort study of 89,835 Canadian women aged 40-59 at recruitment who were enrolled in the National Breast Screening Study (NBSS). Linkages to national cancer and mortality databases yielded data on cancer incidence and deaths from all causes, respectively, with follow-up ending between 1998 and 2000. Cox proportional hazards models (using age as the time scale) were used to estimate hazard ratios and 95% confidence intervals for the association between each of the potential risk factors and risk of thyroid cancer overall and by the main histologic subtypes. During a mean of 15.9 years of follow-up, we observed 169 incident thyroid cancer cases. There was no evidence of altered overall thyroid cancer risk with any of the menstrual, reproductive, or hormonal factors. There was evidence of a decreased risk of papillary thyroid cancer among women with 5 or more live births (vs. nulliparous). Age at which smoking commenced, duration of smoking, number of cigarettes smoked per day, pack-years of smoking and alcohol consumption were not associated with altered thyroid cancer risk. The present study provides little support for associations with hormonal factors, smoking, or alcohol consumption, but there is a need for additional prospective data.


An Independent Filter for Gene Set Testing Based on Spectral Enrichment.
Gene set testing has become an indispensable tool for the analysis of high-dimensional genomic data. An important motivation for testing gene sets, rather than individual genomic variables, is to improve statistical power by reducing the number of tested hypotheses. Given the dramatic growth in common gene set collections, however, testing is often performed with nearly as many gene sets as underlying genomic variables. To address the challenge to statistical power posed by large gene set collections, we have developed spectral gene set filtering (SGSF), a novel technique for independent filtering of gene set collections prior to gene set testing. The SGSF method uses as a filter statistic the p-value measuring the statistical significance of the association between each gene set and the sample principal components (PCs), taking into account the significance of the associated eigenvalues. Because this filter statistic is independent of standard gene set test statistics under the null hypothesis but dependent under the alternative, the proportion of enriched gene sets is increased without impacting the type I error rate. As shown using simulated and real gene expression data, the SGSF algorithm accurately filters gene sets unrelated to the experimental outcome resulting in significantly increased gene set testing power.


[The presence of crystals of sodium polystyrene sulfonate in the colonic wall: innocent bystander or pathogenic factor?].
Hyperkalemia is a frequent electrolyte disturbance in patients on dialysis or non-dialysis CKD patients, including those using renin-angiotensin system inhibitor drugs. Sodium polystyrene sulfonate (SPS; Kayexalate) is a resin widely used for hyperkalemia treatment. Unfortunately, its use entails some serious unwanted gastrointestinal side effects. We report the case of a 64-year-old male diabetic patient, suffering from ESRD on hemodialysis, who was treated with 30 g of Kayexalate twice a week (long interdialytic interval). This is a quite common case in the clinical practice. The patient experienced an episode of rectal bleeding followed by the diagnosis of non-specific colitis through colonoscopy. Histological examination, showed the presence of crystals of Kayexalate in the colonic mucosa leading to the suspect of iatrogenic intestinal damage caused by Kayexalate administration. Treatment with SPS was stopped. Nevertheless crystals remain evident in the intestinal mucosa in a colonoscopy performed 14 months later due to a new episode of rectal bleeding. Two years after the first episode the patient died because of intestinal infarction. The review of the literature highlights the risk of serious side effects such as necrotizing colitis with perforation both for the drug in sodium phase and in calcium phase. New intestinal potassium-binger agents, apparently without intestinal severe side effects, are under clinical evaluation. This case does not assess if the crystals deposited in the colonic mucosa are inert or have contributed to the final event, but it shows that Kayexalate is a drug with potential harmful effect even when used orally, at very low dosage and without sorbitol. In our opinion, the SPS should be prescribed carefully, especially as chronic administration, and the prescription should be limited to real and pressing requirements.


Challenging assumptions about women's empowerment: social and economic resources and domestic violence among young married women in urban South India.
Although considerable research has documented the widespread prevalence of spousal violence in India, little is known about specific risk or protective factors. This study examines the relationships between factors that are often considered to be social and economic resources for women and recent occurrence of domestic violence. Data were collected from 744 young married women in slum areas of Bangalore, India. Unadjusted and adjusted multivariable logistic regression models were used to determine factors associated with having been hit, kicked or beaten by one's husband in the past 6 months. Over half (56%) of the study participants reported having ever experienced physical domestic violence; about a quarter (27%) reported violence in the past 6 months. In a full multivariable model, women in 'love' marriages (OR=1.7, 95% CI 1.1-2.5) and those whose families were asked for additional dowry after marriage (OR=2.3, 95% CI 1.5-3.4) were more likely to report domestic violence. Women who participated in social groups (OR=1.6, 95% CI 1.0-2.4) and vocational training (OR=3.1, 95% CI 1.7-5.8) were also at higher risk. Efforts to help women empower themselves through vocational training, employment opportunities and social groups need to consider the potential unintended consequences for these women, such as an increased risk of domestic violence. The study findings suggest that the effectiveness of anti-dowry laws may be limited without additional strategies that mobilize women, families and communities to challenge the widespread acceptance of dowry and to promote gender equity. Longitudinal studies are needed to elucidate the complex causal relationships between 'love' marriages and domestic violence.


PIP(2) activates KCNQ channels, and its hydrolysis underlies receptor-mediated inhibition of M currents.
KCNQ channels belong to a family of potassium ion channels with crucial roles in physiology and disease. Heteromers of KCNQ2/3 subunits constitute the neuronal M channels. Inhibition of M currents, by pathways that stimulate phospholipase C activity, controls excitability throughout the nervous system. Here we show that a common feature of all KCNQ channels is their activation by the signaling membrane phospholipid phosphatidylinositol-bis-phosphate (PIP(2)). We show that wortmannin, at concentrations that prevent recovery from receptor-mediated inhibition of M currents, blocks PIP(2) replenishment to the cell surface. Moreover, we identify a C-terminal histidine residue, immediately proximal to the plasma membrane, mutation of which renders M channels less sensitive to PIP(2) and more sensitive to receptor-mediated inhibition. Finally, native or recombinant channels inhibited by muscarinic agonists can be activated by PIP(2). Our data strongly suggest that PIP(2) acts as a membrane-diffusible second messenger to regulate directly the activity of KCNQ currents.


An unusual case of complete ptosis and failure of elevation due to severe facial trauma.
The authors describe the case of 49-year-old female teacher who had sustained severe facial lacerations following a minor fall on the kerb. The severe shearing force by which the flap was ripped off the forehead caused complete ptosis and complete failure of elevation of the left eye, which was presumed to be due to mechanical damage to the superior rectus and levator complex. The management by a multidisciplinary approach and clinical course of the patient are described with documentary photographs. This presentation is meant to highlight an unusual case of severe facial trauma resulting from a minor injury, and its successful management with gratifying results for both patient and the surgeon.


All optical discrete Fourier transform processor for 100 Gbps OFDM transmission.
Optical orthogonal frequency division multiplex (OFDM) symbol generation by all-optical discrete Fourier transform (DFT) is proposed and investigated for 100-Gbps transmission performance. We discuss a design example for a 4x25Gbps OFDM transmission system and its performance comparison with that for a 100-Gbps single-channel return-to-zero data transmission in an optically amplified system.


[Qualitative research in Spain: from political life to mistreatment of the sense].
A current of sociological thought came into being in Spain in the sixties consisting of what is known by the ill-defined term of qualitative methodology in our country. A blatant paradox, as the freedom with which this theoretical and methodological building would be erected was born precisely out of a lack of political freedom and freedom of thought of those dreadful years. Countering the official body of knowledge and also removed from all "protest" orthodoxy, a vivid, problematical reflection of the society's true situation conceived as critical theory took shape. It is in no way owing, as regards its assumptions, its findings or its formulations, to either English-U.S., sociology, which was predominant at the time, or to that which would later progressively makes it way to us. Taking exception to data and the imaginary all-powerful importance thereof, this methodology propounded a radical turnabout of the perspective of this research to focus on language, understood as the social discourse, in the powerful sense of the word, and not as a mere set of statements, also moving away from the more or less subjectivist conceptions of the meaning. Opposing the body of knowledge of this discipline, it construed research as a cross-roads, undertaking an endless task, as it is impossible to complete from a logical point of view. It then propounded listening to the sense, which is never the same as the meaning, and includes the analysis of the wording used for a full understanding thereof.... This is a totally autochthonous current perfectly well-founded at its epistemological, methodological and technical levels, the continuing survival today of which is more than uncertain, as it dissolves into the body of university knowledge, into the ongoing flow of the quotes of authors, currents and disciplines. It is corrupted in its commercial use, where its discontinuance now seems assured in benefit of the marketing discourse, and it is running the risk of becoming completely useless in social areas of study (such as Health), where poorer English-U.S. perspectives are coming into play without apparently meeting with the least critical opposition.


Multislice helical CT: image temporal resolution.
A multislice helical computed tomography (CT) halfscan (HS) reconstruction algorithm is proposed for cardiac applications. The imaging performances (in terms of the temporal resolution, z-axis resolution, image noise, and image artifacts) of the HS algorithm are compared to the existing algorithms using theoretical models and clinical data. A theoretical model of the temporal resolution performance (in terms of the temporal sensitivity profile) is established for helical CT, in general, i.e., for any number of detector rows and any reconstruction algorithm used. It is concluded that the HS reconstruction results in improved image temporal resolution than the corresponding 180 degrees LI (linear interpolation) reconstruction and is more immune to the inconsistent data problem induced by cardiac motions. The temporal resolution of multislice helical CT with the HS algorithm is comparable to that of single-slice helical CT with the HS algorithm. In practice, the 180 degrees LI and HS-LI algorithms can be used in parallel to generate two image sets from the same scan acquisition, one (180 degrees LI) for improved z-resolution and noises, and the other (HS-LI) for improved image temporal resolution.


Variability of the Rh system in a central Pyrenean population (Aran Valley).
This work describes the results of a survey on the Rhesus system carried out in the autochthonous population of Aran Valley, a small and rather isolated region on the Northern side of the Central Pyrenees. Also, a comparison is made with other geographically and historically related populations in order to discuss the data in terms of the historical origin of this population. The data obtained shows a good agreement between observed and expected values in Hardy-Weinberg equilibrium. The Aranese population also reveals some peculiarities concerning some haplotypes. The comparison with European and non European Mediterranean populations shows a clear genetic distance from Basque populations, and a relative proximity with presumably Celtic ones.


Eruptive vellus hair cysts: report of a pediatric case with partial response to calcipotriene therapy.
Eruptive vellus hair cysts (EVHCs) are characterized by asymptomatic, follicular, comedonelike papules usually located on the anterior chest and abdomen. We present a pediatric case of EVHC associated with attention deficit hyperactivity disorder that partially responded to calcipotriene cream within 2 months. Our aim is to refamiliarize clinicians with a common albeit frequently unrecognized disorder of vellus hair follicles.


Constipation in the elderly in a Japanese long-term medical facility: An ultrasonographic investigation.
This study aims to assess the fecal retention in elderly patients using colonic ultrasonography (US) in Japanese long-term care facility and determine the correlation between nutrition management methods and the fecal retention by US. This cross-sectional, single-center study was conducted in a long-term care facility in Japan. Patients with chronic constipation fulfilled the Rome III criteria for the diagnosis of functional constipation. US was performed on constipation patients with 4-day fecal retention before starting the standard management of constipation. After patients had defecated, nurses checked the outside of feces using King's Stool Chart and Bristol Stool Chart. All of 32 patients underwent the management of suppository laxative, the daily life independence level in grade C. In all cases, the King's Stool Chart did not detect > 200 g of fecal matter; the Bristol Stool Chart revealed type 5-7 in 56.2% of patients. The total parenteral nutrition and tube feeding did not completely detect type 1-2 in 0%. While the fecal retention groups comprised 15.6%, the non-fecal retention groups comprised 84.4%. The total parenteral nutrition did not completely detect the fecal retention in 0%. In the non-fecal retention groups, the King's Stool Chart indicated < 100 g in 81.8%, and the Bristol Stool Chart indicated type 5-7 in 100%. In conclusion, fecal properties of elderly constipation patients with the long-term parenteral nutrition should be assessed in follow-up examination by US, which is possible for personalized medical care by US, to avoid the administered regular management of constipation.


Associations between health literacy and preventive health behaviors among older adults: findings from the health and retirement study.
While the association between inadequate health literacy and adverse health outcomes has been well documented, less is known about the impact of health literacy on health perceptions, such as perceptions of control over health, and preventive health behaviors. We identified a subsample of participants (N = 707) from the Health and Retirement Study (HRS), a nationally representative sample of older adults, who participated in health literacy testing. Self-reported health literacy was measured with a literacy screening question, and objective health literacy with a summed score of items from the Test of Functional Health Literacy. We compared answers on these items to those related to participation in health behaviors such as cancer screening, exercise, and tobacco use, as well as self-referencing health beliefs. In logistic regression models adjusted for gender, education, race, and age, participants with adequate self-reported health literacy (compared to poorer levels of health literacy) had greater odds of participation in mammography within the last 2 years (Odds ratio [OR] = 2.215, p = 0.01) and participation in moderate exercise two or more times per week (OR = 1.512, p = 0.03). Participants with adequate objective health literacy had reduced odds of participation in monthly breast self-exams (OR = 0.369, p = 0.004) and reduced odds of current tobacco use (OR = 0.456, p = 0.03). In adjusted linear regression analyses, self-reported health literacy made a small but significant contribution to explaining perceived control of health (β 0.151, p = <0.001) and perceived social standing (β 0.112, p = 0.002). In a subsample of older adult participants of the HRS, measures of health literacy were positively related to several health promoting behaviors and health-related beliefs and non-use of breast self-exams, a screening behavior of questionable benefit. These relationships varied however, between self-reported and objectively-measured health literacy. Further investigation into the specific mechanisms that lead higher literacy people to pursue health promoting actions appears clearly warranted.


Associations between Performance on an Abbreviated CogState Battery, Other Measures of Cognitive Function, and Biomarkers in People at Risk for Alzheimer's Disease.
It is not known whether computerized cognitive assessments, like the CogState battery, are sensitive to preclinical cognitive changes or pathology in people at risk for Alzheimer's disease(AD). In 469 late middle-aged participants from the Wisconsin Registry for Alzheimer's Prevention(mean age 63.8±7 years at testing; 67% female; 39% APOE4+), we examined relationships between a CogState abbreviated battery(CAB) of seven tests and demographic characteristics, traditional paper-based neuropsychological tests as well as a composite cognitive impairment index, cognitive impairment status(determined by consensus review), and biomarkers for amyloid and tau(CSF phosphorylated-tau/Aβ42 and global PET-PiB burden) and neural injury(CSF neurofilament light protein). CSF and PET-PiB were collected in n = 71 and n = 91 participants, respectively, approximately four years prior to CAB testing. For comparison, we examined three traditional tests of delayed memory in parallel. Similar to studies in older samples, the CAB was less influenced by demographic factors than traditional tests. CAB tests were generally correlated with most paper-based cognitive tests examined and mapped onto the same cognitive domains. Greater composite cognitive impairment index was associated with worse performance on all CAB tests. Cognitively impaired participants performed significantly worse compared to normal controls on all but one CAB test. Poorer One Card Learning test performance was associated with higher levels of CSF phosphorylated-tau/Aβ42. These results support the use of the CogState battery as measures of early cognitive impairment in studies of people at risk for AD.


Changes in Neurofilament and Microtubule Distribution following Focal Axon Compression.
Although a number of cytoskeletal derangements have been described in the setting of traumatic axonal injury (TAI), little is known of early structural changes that may serve to initiate a cascade of further axonal degeneration. Recent work by the authors has examined conformational changes in cytoskeletal constituents of neuronal axons undergoing traumatic axonal injury (TAI) following focal compression through confocal imaging data taken in vitro and in situ. The present study uses electron microscopy to understand and quantify in vitro alterations in the ultrastructural composition of microtubules and neurofilaments within neuronal axons of rats following focal compression. Standard transmission electron microscopy processing methods are used to identify microtubules, while neurofilament identification is performed using antibody labeling through gold nanoparticles. The number, density, and spacing of microtubules and neurofilaments are quantified for specimens in sham Control and Crushed groups with fixation at <1 min following load. Our results indicate that the axon caliber dependency known to exist for microtubule and neurofilament metrics extends to axons undergoing TAI, with the exception of neurofilament spacing, which appears to remain constant across all Crushed axon diameters. Confidence interval comparisons between Control and Crushed cytoskeletal measures suggests early changes in the neurofilament spatial distributions within axons undergoing TAI may precede microtubule changes in response to applied loads. This may serve as a trigger for further secondary damage to the axon, representing a key insight into the temporal aspects of cytoskeletal degeneration at the component level, and suggests the rapid removal of neurofilament sidearms as one possible mechanism.


Dietary intake of nutrients and its correlation with fatigue in multiple sclerosis patients.
The role of nutrition in the progression of multiple sclerosis (MS) and related complications such as fatigue has been reported by several studies. The aim of this study is the assessment of nutritional status and its relationship with fatigue in multiple sclerosis patients. This is a cross-sectional study, in which 101 relapsing-remitting MS patients were enrolled. The fatigue status was determined using the validated Persian version of of the Modified Fatigue Impact Scale (MFIS). Dietary intake was assessed using a 3-day food record questionnaire and compared to dietary reference intake (DRI) values. Association between variables was determined using Pearson Correlation Coefficient. In the preset study, 25 men and 76 women (total = 101) were enrolled. Analysis of dietary intake showed that daily intake of vitamin D, folate, calcium, and magnesium were significantly lower than DRI in all of patients. In men, zinc intake was significantly lower than DRI; while, in women, iron was significantly below the DRI level. After adjusting for energy, MFIS and its physical subscale were highly correlated with intake of folate and magnesium. Our findings support that lower magnesium and folate diets are correlated with higher fatigue scores in MS patients.


How effective and safe is medical cannabis as a treatment of mental disorders? A systematic review.
We conducted a review of systematic reviews (SRs) and randomized-controlled trials (RCTs) to analyze efficacy and safety of cannabis-based medication in patients with mental disorders. Five data bases were systematically searched (2006-August 2018); 4 SRs (of 11 RCTs) and 14 RCTs (1629 participants) were included. Diagnoses were: dementia, cannabis and opioid dependence, psychoses/schizophrenia, general social anxiety, posttraumatic stress disorder, anorexia nervosa, attention-deficit hyperactivity disorder, and Tourette`s disorder. Outcome variables were too heterogeneous to conduct a meta-analysis. A narrative synthesis method was applied. The study quality was assessed using the risk-of-bias tool and SIGN-checklists. THC- and CBD-based medicines, given as adjunct to pharmaco- and psychotherapy, were associated with improvements of several symptoms of mental disorders, but not with remission. Side effects occurred, but severe adverse effects were mentioned in single cases only. In order to provide reliable treatment recommendations, more and larger RCTs with follow-up assessments, consistent outcome measures and active comparisons are needed.


Parasite viability during treatment of severe falciparum malaria: differential effects of artemether and quinine.
The effect of artemether (AR) and quinine (QN) on parasite viability ex vivo was compared in children being treated for severe Plasmodium falciparum malaria. Parasitized blood taken at intervals during treatment was cultured in vitro, and parasite development was assessed microscopically. Parasite viability (defined as the proportion of circulating rings developing to early schizonts) was 56.8% in the AR group (n = 7) 6 hr after the start of treatment, compared with 93.3% for QN (n = 6; P = 0.015). Even after 24 hr of QN treatment, parasite viability was not significantly reduced in five patients. These ex vivo findings, which confirm previous observations of the stage-specific effects of these drugs against P. falciparum, suggest that AR may be superior to QN in the treatment of severe malaria.


Validation of non-rigid registration between functional and anatomical magnetic resonance brain images.
This paper presents a set of validation procedures for nonrigid registration of functional EPI to anatomical MRI brain images. Although various registration techniques have been developed and validated for high-resolution anatomical MRI images, due to a lack of quantitative and qualitative validation procedures, the use of nonrigid registration between functional EPI and anatomical MRI images has not yet been deployed in neuroimaging studies. In this paper, the performance of a robust formulation of a nonrigid registration technique is evaluated in a quantitative manner based on simulated data and is further evaluated in a quantitative and qualitative manner based on in vivo data as compared to the commonly used rigid and affine registration techniques in the neuroimaging software packages. The nonrigid registration technique is formulated as a second-order constrained optimization problem using a free-form deformation model and mutual information similarity measure. Bound constraints, resolution level and cross-validation issues have been discussed to show the degree of accuracy and effectiveness of the nonrigid registration technique. The analyses performed reveal that the nonrigid approach provides a more accurate registration, in particular when the functional regions of interest lie in regions distorted by susceptibility artifacts.


Serum lipoprotein binding by Treponema pallidum: possible role for proteoglycans.
Acquisition by the syphilis spirochaete, Treponema pallidum, of radioiodinated total human plasma lipoprotein and lipoprotein subfractions was examined. Time dependent and saturation binding kinetics were observed for total lipoproteins and subfractions, including high density lipoproteins, low density lipoproteins (LDL), and very low density lipoproteins. All subfractions competed equally well in binding iodinated total lipoproteins and individual subfractions, but apoproteins common to all subfractions were ineffective in inhibiting lipoprotein acquisition. The interaction of LDL with T pallidum was studied further and, interestingly, the presence of 17% sulphated dextran sulphate (DS) in the reaction mixture containing treponemes and LDL resulted in up to 172 times more LDL being bound by live treponemes. Biological variability was observed in the extent of increased LDL bound in the presence of 17% sulphated DS by preparations of T pallidum isolated from different infected rabbits. Saturation kinetics of iodinated LDL acquisition was obtained in the presence of 17% sulphated DS but not 1% sulphated DS. Other proteoglycan molecules, such as chondroitin sulphate, hyaluronic acid and heparin, and fibronectin, the extracellular matrix protein targeted by treponemes in parasitism of host cells and tissues neither diminished nor enhanced LDL binding by live treponemes. Only 5% and 10% of associated radioactivity was released from treponemal surfaces after T pallidum was incubated with iodinated LDL and 17% sulphated-DS for 15 and 30 minutes, respectively. These data show binding and possible internalisation of host lipoproteins by T pallidum, which may be mediated by sulphated proteoglycan. Sulphated proteoglycans accumulate during T pallidum infections of host cells.


A Milk and Ochre Paint Mixture Used 49,000 Years Ago at Sibudu, South Africa.
Gas chromatography/mass spectrometry, proteomic and scanning electron microscopy with energy-dispersive X-ray spectroscopy (SEM/EDS) analyses of residue on a stone flake from a 49,000 year-old layer of Sibudu (South Africa) indicate a mixture of ochre and casein from milk, likely obtained by killing a lactating wild bovid. Ochre powder production and use are documented in Middle Stone Age South African sites but until now there has been no evidence of the use of milk as a binder. Our analyses show that this ochre-based mixture was neither a hafting adhesive nor a residue left after treating animal skins, but a liquid mixture consisting of a powdered pigment mixed with milk; in other words, a paint medium that could have been applied to a surface or to human skin. The significance of our finds also lies in the fact that it establishes the antiquity of the use of milk as a binder well before the introduction of domestic cattle in South Africa in the first millennium AD.


Structural characterization of an integral membrane protein in its natural lipid environment by oxidative methionine labeling and mass spectrometry.
Membrane proteins represent formidable challenges for many analytical techniques. Studies on these systems are often carried out after surfactant solubilization. Unfortunately, such a non-natural protein environment can affect conformation and stability, and it offers only partial protection against aggregation. This work employs bacteriorhodopsin (BR) as a model system for in situ structural studies on a membrane protein in its natural lipid bilayer. BR-containing purple membrane suspensions were exposed to hydroxyl radicals, generated by nanosecond laser photolysis of dilute aqueous H(2)O(2). The experiments rely on the premise that oxidative labeling occurs mainly at solvent-exposed side chains, whereas sites that are sterically protected will react to a much lesser extent. Following .OH exposure, the protein was analyzed by tryptic peptide mapping and electrospray tandem mass spectrometry. Oxidative labeling of BR was found to occur only at its nine Met residues. This is in contrast to the behavior of previously studied water-soluble proteins, which generally undergo modifications at many different types of residues. In those earlier experiments the high reactivity of Met has hampered its use as a structural probe. In contrast, the Met oxidation pattern observed here is in excellent agreement with the native BR structure. Extensive labeling is seen for Met32, 68, and 163, all of which are located in solvent-exposed loops. The remaining six Met residues are deeply buried and show severalfold less oxidation. Our results demonstrate the usefulness of Met oxidative labeling for structural studies on membrane proteins, especially when considering that many of these species are methionine-rich. The introduction of additional Met residues as conformational probes, as well as in vivo structural investigations, represents exciting future extensions of the methodology described here.


Retrograde angioplasty for basilar artery stenosis: bypassing bilateral vertebral artery occlusions.
Basilar artery angioplasty with or without stenting is an emerging and promising treatment for vertebrobasilar insufficiency that is refractory to medical therapy. The usual approach is via a transfemoral route, with access directly through the vertebral artery (VA). An approach from the anterior circulation via the posterior communicating artery has been reported for optimal stent positioning and deployment across basilar apex aneurysms. No similar technique has been reported for treatment of midbasilar stenosis. The authors report a case of severe symptomatic basilar stenosis in which both VAs were occluded. The only option was to perform retrograde basilar angioplasty via the posterior communicating artery. This useful technique should be part of the armamentarium for the percutaneous treatment of symptomatic vertebrobasilar insufficiency for the occasional patient in whom occlusion or tortuosity precludes direct access to the VA.