The role of gastric pepsin in the inflammatory cascade of pediatric otitis media.
Otitis media is characterized as an ongoing inflammation with accumulation of an effusion in the middle ear cleft. The molecular mechanisms underlying the pathogenesis, particularly the inflammatory response, remain largely unknown. We hypothesize that aspiration of gastric contents into the nasopharynx may be responsible for the initiation of the inflammatory process or aggravate a preexisting condition. To investigate the correlation of gastric pepsin A with inflammatory cytokines, bacterial infection, and clinical outcomes. Prospective study of 129 pediatric patients undergoing myringotomy with tube placement for otitis media at a tertiary care pediatric hospital. Ear samples were tested for pepsin A; cytokines interleukin (IL)-6, IL-8, and tumor necrosis factor; and bacterial culture inoculation. Data were analyzed by descriptive statistics and regression analysis to identify risk factors for the presence of pepsin A and to correlate pepsin A levels with cytokine levels, infection status, and clinical outcomes. Of the 129 patients, 199 ear samples were obtained; 82 samples (41%) and 64 patients (50%) were positive for pepsin A as measured by immunoassay. Pepsin A positivity correlated with age younger than 3.0 years (mean [SD], 2.3 [2.1] years in the positive group vs 3.3 [3.0] years in the negative group) and with all 3 cytokine levels (mean [SD] tumor necrosis factor, 29.5 [45.9] pg/mL in the positive group vs 13.2 [21.6] pg/mL in the negative group; IL-6, 6791.7 [9389.1] pg/mL in the positive group vs 2849.9 [4066.3] pg/mL in the negative group; and IL-8, 6828.2 [8122.3] pg/mL in the positive group vs 2925.1 [3364.5] pg/mL in the negative group [all P < .05]); however, logistic regression analysis showed that only IL-8 (odds ratio, 3.96; 95% CI, 1.3-12.0; P = .02) and age (odds ratio, 3.83; 95% CI, 1.2-12.7; P = .03) were significant independent variables. No statistically significant association was found with other parameters. Multiple linear regressions revealed that the levels of pepsin A were correlated with IL-8 levels (R2 = 0.248; P < .001) and the need for second or third tubes 6 to 12 months after the first (R2 = 0.102; P = .006). The presence of pepsin A in the middle ear was not associated with increased bacterial infection. Interleukin 8 was independent and significantly associated with both pepsin A levels and bacterial infection (R2 = 0.144 and 0.263, respectively; P = .001 for both). Extraesophageal reflux as indicated by the presence of pepsin A is closely involved in the middle ear inflammatory process and may worsen the disease in some children; however, a proof of cause and effect between extraesophageal reflux and middle ear inflammation requires further investigation.


Effect of load positioning on the kinematics and kinetics of weighted vertical jumps.
One of the most popular exercises for developing lower-body muscular power is the weighted vertical jump. The present study sought to examine the effect of altering the position of the external load on the kinematics and kinetics of the movement. Twenty-nine resistance-trained rugby union athletes performed maximal effort jumps with 0, 20, 40, and 60% of their squat 1 repetition maximum (1RM) with the load positioned (a) on the posterior aspect of the shoulder using a straight barbell and (b) at arms' length using a hexagonal barbell. Kinematic and kinetic variables were calculated through integration of the vertical ground reaction force data using a forward dynamics approach. Performance of the hexagonal barbell jump resulted in significantly (p < 0.05) greater values for jump height, peak force, peak power, and peak rate of force development compared with the straight barbell jump. Significantly (p < 0.05) greater peak power was produced during the unloaded jump compared with all trials where the external load was positioned on the shoulder. In contrast, significantly (p < 0.05) greater peak power was produced when using the hexagonal barbell combined with a load of 20% 1RM compared with all other conditions investigated. The results suggest that weighted vertical jumps should be performed with the external load positioned at arms' length rather than on the shoulder when attempting to improve lower-body muscular performance.


Evidence of general economic principles of bargaining and trade from 2,000 classroom experiments.
Standardized classroom experiments provide evidence about how well scientific results reproduce when nearly identical methods are used. We use a sample of around 20,000 observations to test reproducibility of behaviour in trading and ultimatum bargaining. Double-auction results are highly reproducible and are close to equilibrium predictions about prices and quantities from economic theory. Our sample also shows robust correlations between individual surplus and trading order, and autocorrelation of successive price changes, which test different theories of price dynamics. In ultimatum bargaining, the large dataset provides sufficient power to identify that equal-split offers are accepted more often and more quickly than slightly unequal offers. Our results imply a general consistency of results across a variety of different countries and cultures in two of the most commonly used designs in experimental economics.


Vietnamese Adult-Child and Spousal Caregivers of Older Adults in Houston, Texas: Results from the Vietnamese Aging and Care Survey (VACS).
Vietnamese are the largest Asian ethnic group in Houston, Texas; however, research on this population is scarce. To address this dearth of knowledge, we developed the Vietnamese Aging and Care Survey. The objective of the study was to explore the sociodemographic and health characteristics of Vietnamese adults aged 65 years and older (n = 132) and their family caregivers (n = 64). Adult-child caregivers (n = 41) were aged between 21 and 65 years old. The majority were married, working, female, and in good to excellent health. Spousal caregivers (n = 23) were between 57 and 82 years old, retired, female, and in fair to good health. Adult children received more caregiving-related help from others compared to spousal caregivers; however, they felt more caregiver burden, had more perceived stress, and were in challenging relationships with care recipients. Differences in life stages of adult-child versus spousal caregivers may contribute to these results. Implications are discussed.


A deiminated viral peptide to detect antibodies in rheumatoid arthritis.
The data presented suggest that a deiminated viral peptide is specifically recognized by antibodies contained in rheumatoid arthritis (RA) sera. Antipeptide antibodies are not associated with the presence or severity of specific manifestations of RA, but are more frequent in subjects with erosive arthritis. Taking into account the association with rheumatoid factor and with erosive arthritis, we can conclude that antipeptide antibodies are markers of severe forms of RA. Our data also show familial aggregation of anticitrullinated peptide antibodies.


A 192Arg variant of the human paraoxonase (HUMPONA) gene polymorphism is associated with an increased risk for coronary artery disease in the Japanese.
Recent reports have suggested that polymorphisms in the human paraoxonase (HUMPONA) gene may be a genetic risk factor for coronary artery disease (CAD) in white populations. However, this association has not yet been confirmed in other ethnic populations. We studied 75 Japanese patients with CAD, whose coronary lesions were confirmed by angiography, and 115 Japanese control subjects with no history of CAD and a normal resting electrocardiogram. The assays for genotyping the two polymorphisms in the HUMPONA gene (192Arg/Gln and 55Leu/Met) were based on changes in restriction enzyme digestion patterns. For codon 192, the frequencies of the Arg-coding allele (B allele) in both patients and control subjects were much higher than those from published results of whites (.26 to .31), and the difference between patients (.74) and control subjects (.59) was statistically significant (P = .002). The patient group had a higher proportion of Arg/Arg (B/B) homozygotes (52.0% vs 32.2%, P = .006). For codon 55, the frequencies of the Leu-coding allele in control subjects and patients were much higher (.91 and .93, respectively) than those published results for whites, but there was no difference between Japanese control subjects and Japanese patients. When subjects with the 55Leu/Leu genotype only were analyzed, 192Arg/Arg homozygotes were still significantly more frequent in the patients than in the control subjects (55.4% vs 37.2%, P = .024), and the frequency of the 192Arg allele was also higher in patients than control subjects (P = .013). Logistic regression analysis including conventional coronary risk factors revealed that 192Arg is an independent risk factor for CAD. Thus, in the Japanese, the association of CAD with the 192Arg variant of HUMPONA (B-type enzyme) is similar to that reported for whites, although the allele frequencies for 192Arg and 55Leu are much higher in the former than the latter population.


Defining HIV risk and determining responsibility in postsocialist Poland.
Drawing on 15 months of ethnographic research on HIV prevention programs in Poland, I explore the consequences of the shift from models of HIV prevention that emphasize "risk groups" and AIDS blame, to models that focus on "risky behaviors" and universal risk. The centrality of choice making and individual risk management in these models suggests objective risk assessment free from moralizing arguments. The Polish national prevention strategy shifted to focus on choice making, address all risk groups, and include concrete prevention strategies. This shift created a backlash that resulted in the reassertion of moral arguments about risk and risk groups that positioned those most vulnerable to HIV outside the purview of prevention efforts. AIDS organizations working with marginalized, "morally problematic" populations used the label "at risk" to legitimize claims to resources. They enacted a model of risk reduction in which the relevant actor is the individual buffeted by social forces; behavior change, and therefore HIV risk reduction, is a long process because of myriad forms of vulnerability clients face. Despite efforts to reconceptualize risk, organizations positioned the individual as the locus of HIV prevention interventions, rather than attempting to address the social context that shapes risk.


Integrating racial/ethnic equity into policy assessments to improve child health.
The US child population is rapidly becoming more racially and ethnically diverse, yet there are persistent racial/ethnic gaps in child health. Improving and expanding policies to reduce these gaps is increasingly a mandate of government agencies. Identifying effective policies requires a rigorous approach, yet there is a lack of information about which policies improve equity. This article introduces the Policy Equity Assessment, a framework that combines policy assessment and rigorous equity methods to both synthesize existing research and identify and conduct new analyses of policies' ability to reduce racial/ethnic inequities. We applied the Policy Equity Assessment to three policies: Head Start, the Family and Medical Leave Act, and a federal housing assistance program known as Section 8. Our results show racial/ethnic inequities in access to benefits and substantial data and evidence gaps regarding the impact of policies in improving racial/ethnic equity. These results should motivate policy makers to strengthen equity analysis.


Source strengths, transport pathways and delivery mechanisms of nutrients, suspended solids and coliforms within a small agricultural headwater catchment.
Analysis of water samples and accompanying flow data collected (on ~100 occasions) from well defined land drain outlets located in a small catchment in NE Scotland were made over a five year period. The complex relationship between individual sources that can exist even within a small (200 ha) agriculturally managed headwater catchment was clearly evident. On average ~60% of the measured flow from the catchment outlet was accounted for, with ~50% originating from field drains and 10% from the farmyard. Certain field drains stopped flowing during the summer. Flow from the farmyard was continuous, and because livestock were present all year round also represented a renewable source of potential contaminants. The majority of nitrate and suspended sediment originated directly from field drainage. The variability in nitrate concentration between individual field drains was large and probably reflected differences in soil drainage properties. Farmyard drainage contributed a large proportion of the ammonium, phosphate and Faecal Indicator Organisms (FIO) measured as a flux from the catchment. On numerous sampling occasions the combined flux from individual sources was greater than the corresponding loss measured at the catchment outlet. This was attributed to result from the temporary storage/retention mechanisms (sedimentation, transformation or biological uptake/exchange) that can operate within the stream channel. Despite many fields being grazed and/or receiving regular applications of slurry/manure, the majority ~60% of the total flux of FIO still originated from the 'farmyard', with significant contributions from the field drains only occurring during the autumn. The presence of field drinkers and secure well maintained fencing denying cattle access to the open drainage channel (often a recommended best management practice) may well have contributed to this observation. Benefits to water quality that might arise from riparian management, such as buffer strips in this particular situation may be limited due to the dominant contribution originating from land drains and farmyard.


The value of value of information: best informing research design and prioritization using current methods.
Value of information (VOI) methods have been proposed as a systematic approach to inform optimal research design and prioritization. Four related questions arise that VOI methods could address. (i) Is further research for a health technology assessment (HTA) potentially worthwhile? (ii) Is the cost of a given research design less than its expected value? (iii) What is the optimal research design for an HTA? (iv) How can research funding be best prioritized across alternative HTAs? Following Occam's razor, we consider the usefulness of VOI methods in informing questions 1-4 relative to their simplicity of use. Expected value of perfect information (EVPI) with current information, while simple to calculate, is shown to provide neither a necessary nor a sufficient condition to address question 1, given that what EVPI needs to exceed varies with the cost of research design, which can vary from very large down to negligible. Hence, for any given HTA, EVPI does not discriminate, as it can be large and further research not worthwhile or small and further research worthwhile. In contrast, each of questions 1-4 are shown to be fully addressed (necessary and sufficient) where VOI methods are applied to maximize expected value of sample information (EVSI) minus expected costs across designs. In comparing complexity in use of VOI methods, applying the central limit theorem (CLT) simplifies analysis to enable easy estimation of EVSI and optimal overall research design, and has been shown to outperform bootstrapping, particularly with small samples. Consequently, VOI methods applying the CLT to inform optimal overall research design satisfy Occam's razor in both improving decision making and reducing complexity. Furthermore, they enable consideration of relevant decision contexts, including option value and opportunity cost of delay, time, imperfect implementation and optimal design across jurisdictions. More complex VOI methods such as bootstrapping of the expected value of partial EVPI may have potential value in refining overall research design. However, Occam's razor must be seriously considered in application of these VOI methods, given their increased complexity and current limitations in informing decision making, with restriction to EVPI rather than EVSI and not allowing for important decision-making contexts. Initial use of CLT methods to focus these more complex partial VOI methods towards where they may be useful in refining optimal overall trial design is suggested. Integrating CLT methods with such partial VOI methods to allow estimation of partial EVSI is suggested in future research to add value to the current VOI toolkit.


Erlotinib alone or with bevacizumab as first-line therapy in patients with advanced non-squamous non-small-cell lung cancer harbouring EGFR mutations (JO25567): an open-label, randomised, multicentre, phase 2 study.
With use of EGFR tyrosine-kinase inhibitor monotherapy for patients with activating EGFR mutation-positive non-small-cell lung cancer (NSCLC), median progression-free survival has been extended to about 12 months. Nevertheless, new strategies are needed to further extend progression-free survival and overall survival with acceptable toxicity and tolerability for this population. We aimed to compare the efficacy and safety of the combination of erlotinib and bevacizumab compared with erlotinib alone in patients with non-squamous NSCLC with activating EGFR mutation-positive disease. In this open-label, randomised, multicentre, phase 2 study, patients from 30 centres across Japan with stage IIIB/IV or recurrent non-squamous NSCLC with activating EGFR mutations, Eastern Cooperative Oncology Group performance status 0 or 1, and no previous chemotherapy for advanced disease received erlotinib 150 mg/day plus bevacizumab 15 mg/kg every 3 weeks or erlotinib 150 mg/day monotherapy as a first-line therapy until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival, as determined by an independent review committee. Randomisation was done with a dynamic allocation method, and the analysis used a modified intention-to-treat approach, including all patients who received at least one dose of study treatment and had tumour assessment at least once after randomisation. This study is registered with the Japan Pharmaceutical Information Center, number JapicCTI-111390. Between Feb 21, 2011, and March 5, 2012, 154 patients were enrolled. 77 were randomly assigned to receive erlotinib and bevacizumab and 77 to erlotinib alone, of whom 75 patients in the erlotinib plus bevacizumab group and 77 in the erlotinib alone group were included in the efficacy analyses. Median progression-free survival was 16·0 months (95% CI 13·9-18·1) with erlotinib plus bevacizumab and 9·7 months (5·7-11·1) with erlotinib alone (hazard ratio 0·54, 95% CI 0·36-0·79; log-rank test p=0·0015). The most common grade 3 or worse adverse events were rash (19 [25%] patients in the erlotinib plus bevacizumab group vs 15 [19%] patients in the erlotinib alone group), hypertension (45 [60%] vs eight [10%]), and proteinuria (six [8%] vs none). Serious adverse events occurred at a similar frequency in both groups (18 [24%] patients in the erlotinib plus bevacizumab group and 19 [25%] patients in the erlotinib alone group). Erlotinib plus bevacizumab combination could be a new first-line regimen in EGFR mutation-positive NSCLC. Further investigation of the regimen is warranted. Chugai Pharmaceutical Co Ltd.


Molecular analysis of the plasmid-encoded hemolysin of Escherichia coli O157:H7 strain EDL 933.
In this study, we determined the nucleotide sequence of the 5.4-kb SalI restriction fragment of the recombinant plasmid pEO40-1, cloned from the large plasmid of enterohemorrhagic Escherichia coli (EHEC) O157:H7 strain EDL 933. This revealed two open reading frames which shared approximately 60% homology to the hlyC and hlyA genes of the E. coli alpha-hemolysin (alpha-hly) operon. We termed these genes EHEC-hlyA and EHEC-hlyC to distinguish them from the alpha-hly genes. Preliminary sequence analysis indicated that another open reading frame homolog to the hlyB gene is located close to the 3' end of EHEC-hlyA. The predicted molecular masses of the EHEC-hlyA and EHEC-hlyC gene products were 107 and 19.9 kDa, respectively. The EHEC hemolysin protein (EHEC-Hly) was not secreted into the culture supernatant by the strain EDL 933. However, hemolytic activity was found in the broth culture supernatant after transforming EDL 933 with the recombinant plasmid pRSC6 carrying the hlyB and hlyD genes from the E. coli alpha-hemolysin operon. The EHEC hemolysin was precipitated and used as an antigen for immunoblot analysis. This demonstrated that 19 of 20 reconvalescent-phase serum samples from patients with hemolytic uremic syndrome reacted specifically with the antigen; conversely, only 1 of 20 control serum samples demonstrated reactivity. To investigate the prevalence of EHEC hemolysin genes in diarrheagenic E. coli, a PCR was developed to specifically detect EHEC-hlyA. All Shiga-like toxin-producing O157 strains and 12 of 25 Shiga-like toxin-producing non-O157 strains were PCR positive; strains of other categories of diarrheagenic E. coli were PCR negative. All PCR-positive strains hybridized with the CVD 419 probe. We found the CVD 419 probe to be identical to the 3.4-kb HindIII fragment of plasmid pEO40 carrying most of the EHEC-hlyA gene and a part of the putative EHEC-hlyB gene. In this study, the newly discovered EHEC hemolysin was shown to be responsible for the enterohemolytic phenotype and demonstrated to be related but not identical to alpha-hemolysin. The EHEC hemolysin appears to have clinical importance because it occurs in all O157 strains tested and is reactive to sera of patients with hemolytic uremic syndrome.


Pediatric Cogan Syndrome Masquerading as IgA vasculitis.
Pediatric Cogan Syndrome is a rare and underrecognized autoimmune vasculitis characterized by ocular inflammation and sensorineural hearing loss. Its etiopathogenesis, diagnosis and management are not well defined. We report a 12-year-old girl who initially presented with symptoms of IgA vasculitis formerly called Henoch Schoenlein Purpura (HSP) and eventually developed anterior uveitis and bilateral sensorineural hearing loss leading to the diagnosis of atypical Cogan Syndrome. The workup for infectious etiologies and other systemic rheumatologic disorders was negative. The management was multidisciplinary involving Rheumatology, Ophthalmology, Otorhinolaryngology and Audiology. The anterior uveitis responded well to systemic glucocorticoids and Methotrexate, but the hearing loss was grossly progressive warranting a cochlear implant. We are not aware of Pediatric Cogan Syndrome being reported as a mimicker of IgA vasculitis previously in the literature. It is an important finding as IgA vasculitis is prevalent in the pediatric age group and new-onset ocular or vestibular symptoms after IgA vasculitis should alert the clinician to the possibility of Cogan Syndrome. In the absence of well-defined diagnostic criteria, it is crucial to recognize the clinical symptoms of Pediatric Cogan Syndrome for early diagnosis and treatment since the delay in diagnosis can lead to permanent disability.


Assessment of novel digital and smartphone goniometers for measurement of canine stifle joint angles.
OBJECTIVE To evaluate accuracy and reliability of 3 novel goniometers for measurement of canine stifle joint angles and compare the results with those obtained with a universal goniometer (UG). SAMPLE 8 pelvic limbs from 4 canine cadavers. PROCEDURES Each limb was secured to a wooden platform at 3 arbitrarily selected fixed stifle joint angles. Goniometry was performed with 2 smartphone-based applications (novel goniometers A and B), a digital goniometer (novel goniometer C), and a UG; 3 evaluators performed measurements in triplicate for each angle with each device. Results were compared with stifle joint angle measurements on radiographs (used as a gold standard). Accuracy was determined by calculation of bias and total error, coefficients of variation were calculated to estimate reliability, and strength of linear association between radiographic and goniometer measurements was assessed by calculation of correlation coefficients. RESULTS Mean coefficient of variation was lowest for the UG (4.88%), followed by novel goniometers B (7.37%), A (7.57%), and C (12.71%). Correlation with radiographic measurements was highest for the UG (r = 0.97), followed by novel goniometers B (0.93), A (0.90), and C (0.78). Constant bias was present for all devices except novel goniometer B. The UG and novel goniometer A had positive constant bias; novel goniometer C had negative constant bias. Total error at 50° and 100° angles was > 5% for all devices. CONCLUSIONS AND CLINICAL RELEVANCE None of the devices accurately represented radiographically measured stifle joint angles. Additional veterinary studies are indicated prior to the use of novel goniometers in dogs.


An adverse lipid profile and increased levels of adiposity significantly predict clinical course after a first demyelinating event.
To investigate the prospective associations between adiposity and lipid-related variables and conversion to multiple sclerosis (MS), time to subsequent relapse and progression in disability. A cohort of 279 participants with a first clinical diagnosis of central nervous system demyelination was prospectively followed to 5-year review. Height, weight, waist and hip circumference were measured, and serum samples taken for measurement of lipids and apolipoproteins. Survival analysis was used for conversion to MS and time to relapse, and linear regression for annualised change in disability (Expanded Disability Status Scale). Higher body mass index (BMI; adjusted HR (aHR): 1.22 (1.04 to 1.44) per 5 kg/m2 increase), hip circumference (aHR: 1.32 (1.12 to 1.56) per 10 cm increase) and triglyceride levels (aHR: 1.20 (1.03 to 1.40) per unit increase) were associated with increased risk of subsequent relapse, while adiposity and lipid-related measures were not associated with conversion to MS. In addition, higher BMI (β: 0.04 (0.01 to 0.07) per 5 kg/m2 increase), hip circumference (β: 0.04 (0.02 to 0.08) per 10 cm increase), waist circumference (β: 0.04 (0.02 to 0.07) per 10 cm increase), total cholesterol to high-density lipoprotein ratio (TC/HDL ratio; β: 0.05 (0.001 to 0.10) and non-HDL; β: 0.04 (0.001 to 0.08) at study entry) were associated with a higher subsequent annual change in disability. Higher levels of adiposity, non-HDL and TC/HDL ratio were prospectively associated with a higher rate of disability progression, and higher adiposity and triglycerides were associated with relapse but not with conversion to MS. Improving the lipid profile and losing weight into the healthy range could reduce the accumulation of disability.


Rare coexistence of gouty and septic arthritis: a report of 14 cases.
To analyse the characteristic features of patients with coexistence of gouty arthritis and pyarthrosis at our university hospital in southern Taiwan, an area with high prevalence of hyperuricemia and gout. A retrospective chart review was performed for patients who had concomitant gouty and septic arthritis from July 1998 to June 2008. Clinical and laboratory data of these patients were analysed. Furthermore, a comparison was made with published cases in English literature. Fourteen cases with coexistence of gouty arthritis and pyarthrosis have been identified during the past 10 years. There were 13 male and 1 female, all of Han Chinese in ethnicity, with ages ranging from 45 to 85 and an average of 63.7 years. At disease presentation, there were 11 oligoarticular cases (78.6%), 2 monoarticular cases (14.3%) and 1 polyarticular case (7.1%). Ankle and knee joints were most commonly involved. Bacteriological analyses demonstrated gram-positive cocci in 12 cases, of these 10 were oxacillin-sensitive Staphylococcus aureus (71.4%). Multiple tophi deposition was noted in 13 patients (92.9%) and among them 11 patients (84.6%) had associated chronic kidney disease. Different clinical presentations and bacteriological characteristics have been identified in the present series. While the mechanisms responsible for such a coexistence remain to be elucidated, these cases underline the importance of thorough evaluation of the aspirated synovial fluid. Our report adds a novel insight into the understanding of the clinical and microbiological manifestations of such a rare concurrence of gouty and septic arthritis.


Culture modulates implicit ownership-induced self-bias in memory.
The relation of incoming stimuli to the self implicitly determines the allocation of cognitive resources. Cultural variations in the self-concept shape cognition, but the extent is unclear because the majority of studies sample only Western participants. We report cultural differences (Asian versus Western) in ownership-induced self-bias in recognition memory for objects. In two experiments, participants allocated a series of images depicting household objects to self-owned or other-owned virtual baskets based on colour cues before completing a surprise recognition memory test for the objects. The 'other' was either a stranger or a close other. In both experiments, Western participants showed greater recognition memory accuracy for self-owned compared with other-owned objects, consistent with an independent self-construal. In Experiment 1, which required minimal attention to the owned objects, Asian participants showed no such ownership-related bias in recognition accuracy. In Experiment 2, which required attention to owned objects to move them along the screen, Asian participants again showed no overall memory advantage for self-owned items and actually exhibited higher recognition accuracy for mother-owned than self-owned objects, reversing the pattern observed for Westerners. This is consistent with an interdependent self-construal which is sensitive to the particular relationship between the self and other. Overall, our results suggest that the self acts as an organising principle for allocating cognitive resources, but that the way it is constructed depends upon cultural experience. Additionally, the manifestation of these cultural differences in self-representation depends on the allocation of attentional resources to self- and other-associated stimuli.


Cardiovascular effects of 1-nitro-2-phenylethane, the main constituent of the essential oil of Aniba canelilla, in spontaneously hypertensive rats.
This study investigated the cardiovascular responses to the essential oil of Aniba canelilla (EOAC) and its main constituent 1-nitro-2-phenylethane (NP) in spontaneously hypertensive rats (SHRs). In anesthetized SHRs, intravenous (i.v.) bolus injections of EOAC (1-20 mg/kg) or NP (1-10 mg/kg) elicited dose-dependent hypotensive and bradycardiac effects, which were characterized in two periods (phases 1 and 2). The first rapid component (phase 1) evoked by EOAC and NP both at 10 mg/kg was absent after left ventricle injection, fully abolished by bilateral vagotomy and perineural treatment of both cervical vagus nerves with capsaicin (250 μg/mL) while remained unaltered by i.v. pretreatment with capsazepine (1 mg/kg) or ondansetron (30 μg/kg). In conscious SHRs, NP (5 and 10 mg/kg, i.v.) evoked rapid hypotensive and bradycardiac effects (phase 1) that were fully abolished by methylatropine (1 mg/kg, i.v.) pretreatment. In rat endothelium-containing mesenteric preparations, increasing concentrations (0.1-1000 μg/mL) of EOAC and NP relaxed the phenylephrine-induced contraction in a concentration-dependent manner. It is concluded that NP induces a vago-vagal bradycardiac and depressor reflex (phase 1) that apparently results from the stimulation of vagal pulmonary rather than cardiac C-fiber afferents. This effect does not appear to involve activation of either vanilloid TPRV(1) or 5-HT(3) receptors located on vagal sensory nerves. The phase 2 hypotensive response to i.v. NP seems to result, at least in part, from its direct vasodilatory effect on the peripheral smooth muscle. All in vivo and in vitro effects of EOAC are mostly attributed to the actions of its main constituent NP.


The Facilitative Effect of Transcranial Direct Current Stimulation on Visuospatial Working Memory in Patients with Diabetic Polyneuropathy: A Pre-post Sham-Controlled Study.
Diabetes mellitus can lead to diabetic polyneuropathy (DPN) and cognitive deficits that manifest as peripheral and central neuropathy, respectively. In this study we investigated the relationship between visuospatial working memory (VSWM) capacity and DPN severity, and attempted to improve VSWM in DPN patients via the use of transcranial direct current stimulation (tDCS). Sixteen DPN patients and 16 age- and education-matched healthy control subjects received Wechsler Adult Intelligence Scale-Fourth Edition (WAIS-IV) and Montreal Cognitive Assessment (MOCA) for baseline cognitive assessment. A forward- and backward-recall computerized Corsi block tapping task (CBT), both with and without a concurrent motor interference task was used to measure VSWM capacity. Each DPN patient underwent a pre-treatment CBT, followed by tDCS or sham treatment, then a post-treatment CBT on two separate days. We found that although patients with severe DPN (Dyck's grade 2a or 2b) showed comparable general intelligence scores on WAIS-IV as their age- and education-matched healthy counterparts, they nonetheless showed mild cognitive impairment (MCI) on MOCA and working memory deficit on digit-span test of WAIS-IV. Furthermore, patients' peripheral nerve conduction velocity (NCV) was positively correlated with their VSWM span in the most difficult CBT condition that involved backward-recall with motor interference such that patients with worse NCV also had lower VSWM span. Most importantly, anodal tDCS over the right DLPFC was able to improve low-performing patients' VSWM span to be on par with the high-performers, thereby eliminating the correlation between NCV and VSWM. In summary, these findings suggest that (1) MCI and severe peripheral neuropathy can coexist with unequal severity in diabetic patients, (2) the positive correlation of VSWM and NCV suggests a link between peripheral and central neuropathies, and (3) anodal tDCS over the right DLPFC can improve DPN patients' VSWM, particularly for the low-performing patients.


Expanding landscapes of the diversified mcr-1-bearing plasmid reservoirs.
Polymyxin is a cationic polypeptide antibiotic that can disrupt bacterial cell membrane by interacting with its lipopolysaccharide molecules and is used as a last resort drug against lethal infections by the carbapenem-resistant superbugs (like NDM-1). However, global discovery of the MCR-1 colistin resistance dramatically challenges the newly renewed interest in colistin for clinical use. The mcr-1-harboring plasmids were acquired from swine and human Escherichia coli isolated in China, from 2015 to 2016, and subjected to Illumina PacBio RSII and Hi-Seq2000 for full genome sequencing. PCR was applied to close the gap of the assembled contigs. Ori-Finder was employed to predict the replication origin (oriC) in plasmids. The phenotype of MCR-1-producing isolates was evaluated on the LBA plates with various level of colistin. Genetic deletion was used to test the requirement of the initial "ATG" codon for the MCR-1 function. Here, we report full genomes of over 10 mcr-1-harboring plasmids with diversified replication incompatibilities. A novel hybrid IncI2/IncFIB plasmid pGD17-2 was discovered and characterized from a swine isolate with colistin resistance. Intriguingly, co-occurrence of two unique mcr-1-bearing plasmids (pGD65-3, IncI2, and pGD65-5, IncX4) was detected in a single isolate GD65, which might accelerate dissemination of the mcr-1 under environmental selection pressure. Genetic analyses of these plasmids mapped mobile elements in the context of antibiotic resistance and determined two insertion sequences (ISEcp1 and ISApl1) that are responsible for the mobilization of mcr-1. Gene deletion also proved that the first ATG codon is redundant in the mcr-1 gene. Collectively, our results extend landscapes of the diversified mcr-1-bearing plasmid reservoirs.


Safety, Immunogenicity and Efficacy of Prime-Boost Vaccination with ChAd63 and MVA Encoding ME-TRAP against Plasmodium falciparum Infection in Adults in Senegal.
Malaria transmission is in decline in some parts of Africa, partly due to the scaling up of control measures. If the goal of elimination is to be achieved, additional control measures including an effective and durable vaccine will be required. Studies utilising the prime-boost approach to deliver viral vectors encoding the pre-erythrocytic antigen ME-TRAP (multiple epitope thrombospondin-related adhesion protein) have shown promising safety, immunogenicity and efficacy in sporozoite challenge studies. More recently, a study in Kenyan adults, similar to that reported here, showed substantial efficacy against P. falciparum infection. One hundred and twenty healthy male volunteers, living in a malaria endemic area of Senegal were randomised to receive either the Chimpanzee adenovirus (ChAd63) ME-TRAP as prime vaccination, followed eight weeks later by modified vaccinia Ankara (MVA) also encoding ME-TRAP as booster, or two doses of anti-rabies vaccine as a comparator. Prior to follow-up, antimalarials were administered to clear parasitaemia and then participants were monitored by PCR for malaria infection for eight weeks. The primary endpoint was time-to-infection with P. falciparum malaria, determined by two consecutive positive PCR results. Secondary endpoints included adverse event reporting, measures of cellular and humoral immunogenicity and a meta-analysis of combined vaccine efficacy with the parallel study in Kenyan adults.We show that this pre-erythrocytic malaria vaccine is safe and induces significant immunogenicity, with a peak T-cell response at seven days after boosting of 932 Spot Forming Cells (SFC)/106 Peripheral Blood Mononuclear Cells(PBMC) compared to 57 SFC/ 106 PBMCs in the control group. However, a vaccine efficacy was not observed: 12 of 57 ME-TRAP vaccinees became PCR positive during the intensive monitoring period as compared to 13 of the 58 controls (P = 0.80). This trial confirms that vaccine efficacy against malaria infection in adults may be rapidly assessed using this efficient and cost-effective clinical trial design. Further efficacy evaluation of this vectored candidate vaccine approach in other malaria transmission settings and age-de-escalation into the main target age groups for a malaria vaccine is in progress.


Attenuation of early phase inflammation by cannabidiol prevents pain and nerve damage in rat osteoarthritis.
Osteoarthritis (OA) is a multifactorial joint disease, which includes joint degeneration, intermittent inflammation, and peripheral neuropathy. Cannabidiol (CBD) is a noneuphoria producing constituent of cannabis that has the potential to relieve pain. The aim of this study was to determine whether CBD is anti-nociceptive in OA, and whether inhibition of inflammation by CBD could prevent the development of OA pain and joint neuropathy. Osteoarthritis was induced in male Wistar rats (150-175 g) by intra-articular injection of sodium monoiodoacetate (MIA; 3 mg). On day 14 (end-stage OA), joint afferent mechanosensitivity was assessed using in vivo electrophysiology, whereas pain behaviour was measured by von Frey hair algesiometry and dynamic incapacitance. To investigate acute joint inflammation, blood flow and leukocyte trafficking were measured on day 1 after MIA. Joint nerve myelination was calculated by G-ratio analysis. The therapeutic and prophylactic effects of peripheral CBD (100-300 μg) were assessed. In end-stage OA, CBD dose-dependently decreased joint afferent firing rate, and increased withdrawal threshold and weight bearing (P < 0.0001; n = 8). Acute, transient joint inflammation was reduced by local CBD treatment (P < 0.0001; n = 6). Prophylactic administration of CBD prevented the development of MIA-induced joint pain at later time points (P < 0.0001; n = 8), and was also found to be neuroprotective (P < 0.05; n = 6-8). The data presented here indicate that local administration of CBD blocked OA pain. Prophylactic CBD treatment prevented the later development of pain and nerve damage in these OA joints. These findings suggest that CBD may be a safe, useful therapeutic for treating OA joint neuropathic pain.


Clinical phenotypes of psychosis in the Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP).
Developing categorical diagnoses that have biological meaning within the clinical phenotype of psychosis (schizophrenia, schizoaffective disorder, and bipolar I disorder with psychosis) is as important for developing targeted treatments as for nosological goals. The Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) was formed to examine a broad array of intermediate phenotypes across psychotic disorders and to test the hypothesis that intermediate phenotype characteristics are homogeneous within phenomenologically derived DSM-IV diagnoses. The consortium recruited 933 stable probands with schizophrenia, schizoaffective disorder, or psychotic bipolar I disorder, 1,055 of their first-degree relatives, and 459 healthy comparison subjects for clinical characterization and dense phenotyping. Clinical, psychosocial, and family characteristics were contrasted. All proband groups showed lower psychosocial functioning than the relatives or comparison group. On average, schizophrenia probands showed more symptoms and lower psychosocial functioning than probands with psychotic bipolar disorder, but there was considerable overlap in clinical manifestations. The characteristics of schizoaffective disorder were more often similar to schizophrenia than to psychotic bipolar disorder. The rates of lifetime suicide attempts were high across all proband groups, with the highest reported frequencies in the schizoaffective and bipolar groups. Proband family lineages included both families with "pure" psychosis diagnoses and families with mixed schizophrenia-bipolar diagnoses. Symptoms, psychosocial functioning, and familial lineage overlap across the three DSM-IV psychosis diagnoses used in B-SNIP. The comingling of psychosis diagnoses within families suggests overlapping genetic determinants across psychoses. These data provide scant evidence for distinct phenotypic clustering around traditional phenomenological diagnoses.


Limited male incubation ability and the evolution of egg size in shorebirds.
In bird species where males incubate but are smaller than females, egg size may be constrained by male body size, and hence ability to incubate the eggs. Using data from 71 such shorebird species, we show that egg size decreases as the degree of female-biased sexual size dimorphism increases, after controlling for female body mass. Relative egg size was not related to mean clutch size. However, when controlling for mating system, the relationship between female-biased sexual size dimorphism and relative egg size was only significant in polyandrous species. The relatively small eggs of socially polyandrous shorebirds have previously been explained as an energy-saving strategy associated with the production of multiple clutches. Our findings suggest that egg size evolution is better explained by male incubation limitation in these birds.


Interplay of Staphylococcal and Host Proteases Promotes Skin Barrier Disruption in Netherton Syndrome.
Netherton syndrome (NS) is a monogenic skin disease resulting from loss of function of lymphoepithelial Kazal-type-related protease inhibitor (LEKTI-1). In this study we examine if bacteria residing on the skin are influenced by the loss of LEKTI-1 and if interaction between this human gene and resident bacteria contributes to skin disease. Shotgun sequencing of the skin microbiome demonstrates that lesional skin of NS subjects is dominated by Staphylococcus aureus (S. aureus) and Staphylococcus epidermidis (S. epidermidis). Isolates of either species from NS subjects are able to induce skin inflammation and barrier damage on mice. These microbes promote skin inflammation in the setting of LEKTI-1 deficiency due to excess proteolytic activity promoted by S. aureus phenol-soluble modulin α as well as increased bacterial proteases staphopain A and B from S. aureus or EcpA from S. epidermidis. These findings demonstrate the critical need for maintaining homeostasis of host and microbial proteases to prevent a human skin disease.


From microscopic to macroscopic descriptions of cell migration on growing domains.
Cell migration and growth are essential components of the development of multicellular organisms. The role of various cues in directing cell migration is widespread, in particular, the role of signals in the environment in the control of cell motility and directional guidance. In many cases, especially in developmental biology, growth of the domain also plays a large role in the distribution of cells and, in some cases, cell or signal distribution may actually drive domain growth. There is an almost ubiquitous use of partial differential equations (PDEs) for modelling the time evolution of cellular density and environmental cues. In the last 20 years, a lot of attention has been devoted to connecting macroscopic PDEs with more detailed microscopic models of cellular motility, including models of directional sensing and signal transduction pathways. However, domain growth is largely omitted in the literature. In this paper, individual-based models describing cell movement and domain growth are studied, and correspondence with a macroscopic-level PDE describing the evolution of cell density is demonstrated. The individual-based models are formulated in terms of random walkers on a lattice. Domain growth provides an extra mathematical challenge by making the lattice size variable over time. A reaction-diffusion master equation formalism is generalised to the case of growing lattices and used in the derivation of the macroscopic PDEs.


Genetic diversity shaped by historical and recent factors in the live-bearing twoline skiffia Neotoca bilineata.
The endangered twoline skiffia Neotoca bilineata, a viviparous fish of the subfamily Goodeinae, endemic to central Mexico (inhabiting two basins, Cuitzeo and Lerma-Santiago) was evaluated using genetic and habitat information. The genetic variation of all remaining populations of the species was analysed using both mitochondrial and microsatellite markers and their habitat conditions were assessed using a water quality index (I(WQ)). An 80% local extinction was found across the distribution of N. bilineata. The species was found in three of the 16 historical localities plus one previously unreported site. Most areas inhabited by the remaining populations had I(WQ) scores unsuitable for the conservation of freshwater biodiversity. Populations showed low but significant genetic differentiation with both markers (mtDNA φ(ST) = 0.076, P < 0.001; microsatellite F(ST) = 0.314, P < 0.001). Borbollon, in the Cuitzeo Basin, showed the highest level of differentiation and was identified as a single genetic unit by Bayesian assignment methods. Rio Grande de Morelia and Salamanca populations showed the highest genetic diversity and also a high migration rate facilitated by an artificial channel that connected the two basins. Overall, high genetic diversity values were observed compared with other freshwater fishes (average N(a) = 16 alleles and loci and mean ±S.D. H(o) = 0.63 ± 0.10 and nucleotide diversity π = 0.006). This suggests that the observed genetic diversity has not diminished as rapidly as the species' habitat destruction. No evidence of correlation between habitat conditions and genetic diversity was found. The current pattern of genetic diversity may be the result of both historical factors and recent modifications of the hydrological system. The main threat to the species may be the rapid habitat deterioration and associated demographic stochasticity rather than genetic factors.


Targeting Lysine Deacetylases (KDACs) in Parasites.
Due to an increasing problem of drug resistance among almost all parasites species ranging from protists to worms, there is an urgent need to explore new drug targets and their inhibitors to provide new and effective parasitic therapeutics. In this regard, there is growing interest in exploring known drug leads of human epigenetic enzymes as potential starting points to develop novel treatments for parasitic diseases. This approach of repurposing (starting with validated targets and inhibitors) is quite attractive since it has the potential to reduce the expense of drug development and accelerate the process of developing novel drug candidates for parasite control. Lysine deacetylases (KDACs) are among the most studied epigenetic drug targets of humans, and a broad range of small-molecule inhibitors for these enzymes have been reported. In this work, we identify the KDAC protein families in representative species across important classes of parasites, screen a compound library of 23 hydroxamate- or benzamide-based small molecules KDAC inhibitors, and report their activities against a range of parasitic species, including the pathogen of malaria (Plasmodium falciparum), kinetoplastids (Trypanosoma brucei and Leishmania donovani), and nematodes (Brugia malayi, Dirofilaria immitis and Haemonchus contortus). Compound activity against parasites is compared to that observed against the mammalian cell line (L929 mouse fibroblast) in order to determine potential parasite-versus-host selectivity). The compounds showed nanomolar to sub-nanomolar potency against various parasites, and some selectivity was observed within the small panel of compounds tested. The possible binding modes of the active compounds at the different protein target sites within different species were explored by docking to homology models to help guide the discovery of more selective, parasite-specific inhibitors. This current work supports previous studies that explored the use of KDAC inhibitors in targeting Plasmodium to develop new anti-malarial treatments, and also pioneers experiments with these KDAC inhibitors as potential new anthelminthics. The selectivity observed begins to address the challenges of targeting specific parasitic diseases while limiting host toxicity.


The Academic RVU: Ten Years Developing a Metric for and Financially Incenting Academic Productivity at Oregon Health & Science University.
Established metrics reward academic faculty for clinical productivity. Few data have analyzed a bonus model to measure and reward academic productivity. This study's objective was to describe development and use of a departmental academic bonus system for incenting faculty scholarly and educational productivity. This cross-sectional study analyzed a departmental bonus system among emergency medicine academic faculty at Oregon Health & Science University, including growth from 2005 to 2015. All faculty members with a primary appointment were eligible for participation. Each activity was awarded points based on a predetermined education or scholarly point scale. Faculty members accumulated points based on their activity (numerator), and the cumulative points of all faculty were the denominator. Variables were individual faculty member (deidentified), academic year, bonus system points, bonus amounts awarded, and measures of academic productivity. Data were analyzed using descriptive statistics, including measures of variance. The total annual financial bonus pool ranged from $211,622 to $274,706. The median annual per faculty academic bonus remained fairly constant over time ($3,980 in 2005-2006 vs. $4,293 in 2014-2015), with most change at the upper quartile of academic bonus (max bonus $16,920 in 2005-2006 vs. $39,207 in 2014-2015). Bonuses rose linearly among faculty in the bottom three quartiles of academic productivity, but increased exponentially in the 75th to 100th percentile. Faculty academic productivity can be measured and financially rewarded according to an objective academic bonus system. The "academic point" used to measure productivity functions as an "academic relative value unit."


Opening doors and building capacity: employing a community-based approach to surveying.
Although many community-based initiatives employ community residents to undertake door-to-door surveys as a form of community mobilization or for purposes of needs assessment or evaluation, very little has been published on the strengths and weaknesses of this approach. This article discusses our experience in undertaking such a survey in collaboration with a coalition of community-based organizations (CBOs) in the South Bronx, New York. Although resource constraints limited the already-strained capacity of the CBOs to provide supervision, the CBOs and community surveyors helped us gain access to neighborhood buildings and to individuals who might otherwise have been inaccessible. The survey process also contributed to the coalition's community outreach efforts and helped to link the CBO leadership and staff more closely to the coalition and its mission. Many of the surveyors enhanced their knowledge and skills in ways that have since benefited them or the coalition directly. The participating CBOs continue to be deeply engaged in the coalition's work, and many of the surveyors are active as community health advocates and have taken leadership roles within the coalition.


[Pharmacology of tramadol].
(+/-)-Tramadol is a synthetic 4-phenyl-piperidine analogue of codeine. It is a central analgesic with a low affinity for opioid receptors. Its selectivity for mu receptors has recently been demonstrated, and the M1 metabolite of tramadol, produced by liver O-demethylation, shows a higher affinity for opioid receptors than the parent drug. The rate of production of this M1 derivative (O-demethyl tramadol), is influenced by a polymorphic isoenzyme of the debrisoquine-type, cytochrome P450 2D6 (CYP2D6). Nevertheless, this affinity for mu receptors of the CNS remains low, being 6000 times lower than that of morphine. Moreover, and in contrast to other opioids, the analgesic action of tramadol is only partially inhibited by the opioid antagonist naloxone, which suggests the existence of another mechanism of action. This was demonstrated by the discovery of a monoaminergic activity that inhibits noradrenaline (norepinephrine) and serotonin (5-hydroxytryptamine; 5-HT) reuptake, making a significant contribution to the analgesic action by blocking nociceptive impulses at the spinal level. (+/-)-Tramadol is a racemic mixture of 2 enantiomers, each one displaying differing affinities for various receptors. (+/-)-Tramadol is a selective agonist of mu receptors and preferentially inhibits serotonin reuptake, whereas (-)-tramadol mainly inhibits noradrenaline reuptake. The action of these 2 enantiomers is both complementary and synergistic and results in the analgesic effect of (+/-)-tramadol. After oral administration, tramadol demonstrates 68% bioavailability, with peak serum concentrations reached within 2 hours. The elimination kinetics can be described as 2-compartmental, with a half-life of 5.1 hours for tramadol and 9 hours for the M1 derivative after a single oral dose of 100mg. This explains the approximately 2-fold accumulation of the parent drug and its M1 derivative that is observed during multiple dose treatment with tramadol. The recommended daily dose of tramadol is between 50 and 100mg every 4 to 6 hours, with a maximum dose of 400 mg/day; the duration of the analgesic effect after a single oral dose of tramadol 100mg is about 6 hours. Adverse effects, and nausea in particular, are dose-dependent and therefore considerably more likely to appear if the loading dose is high. The reduction of this dose during the first days of treatment is an important factor in improving tolerability. Other adverse effects are generally similar to those of opioids, although they are usually less severe, and can include respiratory depression, dysphoria and constipation. Tramadol can be administered concomitantly with other analgesics, particularly those with peripheral action, while drugs that depress CNS function may enhance the sedative effect of tramadol. Tramadol should not be administered to patients receiving monoamine oxidase inhibitors, and administration with tricyclic antidepressant drugs should also be avoided. Tramadol has pharmacodynamic and pharmacokinetic properties that are highly unlikely to lead to dependence. This was confirmed by various controlled studies and postmarketing surveillance studies, which reported an extremely small number of patients developing tolerance or instances of tramadol abuse. Tramadol is a central acting analgesic which has been shown to be effective and well tolerated, and likely to be of value for treating several pain conditions (step II of the World Health Organization ladder) where treatment with strong opioids is not required.


Tropomodulin assembles early in myofibrillogenesis in chick skeletal muscle: evidence that thin filaments rearrange to form striated myofibrils.
Actin filament lengths in muscle and nonmuscle cells are believed to depend on the regulated activity of capping proteins at both the fast growing (barbed) and slow growing (pointed) filament ends. In striated muscle, the pointed end capping protein, tropomodulin, has been shown to maintain the lengths of thin filaments in mature myofibrils. To determine whether tropomodulin might also be involved in thin filament assembly, we investigated the assembly of tropomodulin into myofibrils during differentiation of primary cultures of chick skeletal muscle cells. Our results show that tropomodulin is expressed early in differentiation and is associated with the earliest premyofibrils which contain overlapping and misaligned actin filaments. In addition, tropomodulin can be found in actin filament bundles at the distal tips of growing myotubes, where sarcomeric alpha-actinin is not always detected, suggesting that tropomodulin caps actin filament pointed ends even before the filaments are cross-linked into Z bodies by alpha-actinin. Tropomodulin staining exhibits an irregular punctate pattern along the length of premyofibrils that demonstrate a smooth phalloidin staining pattern for F-actin. Strikingly, the tropomodulin dots often appear to be located between the closely spaced, dot-like Z bodies that are stained for (&agr;)-actinin. Thus, in the earliest premyofibrils, the pointed ends of the thin filaments are clustered and partially aligned with respect to the Z bodies (the location of the barbed filament ends). At later stages of differentiation, the tropomodulin dots become aligned into regular periodic striations concurrently with the appearance of striated phalloidin staining for F-actin and alignment of Z bodies into Z lines. Tropomodulin, together with the barbed end capping protein, CapZ, may function from the earliest stages of myofibrillogenesis to restrict the lengths of newly assembled thin filaments by capping their ends; thus, transitions from nonstriated to striated myofibrils in skeletal muscle are likely due principally to filament rearrangements rather than to filament polymerization or depolymerization. Rearrangements of actin filaments capped at their pointed and barbed ends may be a general mechanism by which cells restructure their actin cytoskeletal networks during cell growth and differentiation.


Distribution of glutamate decarboxylase-containing neurons in rabbit medulla oblongata with attention to intramedullary and spinal projections.
Functional studies in the rabbit suggest that GABA is an important inhibitory neurotransmitter in the control of cardiovascular, respiratory and neuroendocrine functions by the medulla oblongata. The present work was undertaken to provide a description of the distribution in the rabbit medulla of neurons containing glutamate decarboxylase, an enzyme present in GABA-synthesizing neurons. Combined retrograde axonal transport and immunohistochemical studies were carried out to determine intramedullary and spinal projections of immunopositive neurons located in regions particularly relevant to the interpretation of functional studies. Neurons containing glutamate decarboxylase, putatively GABA-containing neurons, were found in all nuclei of the rabbit medulla with the exception of somatic cranial nerve nuclei and the lateral reticular nucleus. The immunopositive cells were distributed throughout individual nuclei and their morphological appearance was similar to that of neighbouring immunonegative neurons in the nucleus. An exception was encountered in the dorsal motor nucleus of the vagus where the glutamate decarboxylase-containing neurons belong to a population of small neurons easily distinguished from the larger vagal preganglionic cells. Many immunopositive cells in the raphe nuclei, in the medial reticular formation and in the vestibular nuclei have axonal projections to the spinal cord and presumably represent sources of inhibitory bulbospinal control. Within the medulla there were glutamate decarboxylase-containing neurons in the nucleus tractus solitarius with projections to caudal but not to rostral regions of the ventrolateral medulla. These neurons could provide a GABAergic input to respiratory, cardiovascular and neuroendocrine neurons in the caudal ventrolateral medulla. Immunopositive cells projecting from the caudal to the rostral ventrolateral medulla could form part of the population of inhibitory vasomotor neurons known to be present in the caudal ventrolateral medulla. Some glutamate decarboxylase-containing neurons just medial to the nucleus ambiguous in the rostral medulla, in the region containing the Botzinger group, project to the caudal ventrolateral medulla and could therefore provide an inhibitory input to caudal respiratory cells.


IgE antibody responses to platinum group metals: a large scale refinery survey.
All 306 South African platinum refinery workers (116 white, 190 coloured) accepted for employment on grounds of absence of evidence of atopy were investigated using the skin prick test and RAST to detect sensitivity to platinum, palladium, and rhodium salts. RAST studies were made for these, together with HSA and DNP-HSA RAST. Of the 306 workers, 38 had a positive skin prick test to the platinum halide salts; of these, one gave a positive reaction to the palladium salt and six to the rhodium salt. There were no isolated positives to the rhodium and palladium halide salts. Total IgE levels were raised in 24 of the 38 (63%) platinum salt prick test positive workers compared with only 43 of the 268 (16%) prick test negative group (p less than 0.001). Positive RASTs were obtained in 62% of those with positive skin tests to the platinum salts. Four of the six giving positive rhodium salt skin tests gave a positive RAST to rhodium salt. Of these, two gave positive RASTS to HSA and all four to DNP-HSA. The palladium salt RAST was negative in the single skin test reactor. In the platinum salt skin test positive group a raised HSA RAST was obtained in 10.5% compared with only 2.5% in the skin negative group. Twenty one per cent of the platinum salt skin positive group had a raised RAST score to DNP-HSA with only 3.5% (4/116) in the skin test negative group, of whom three also had a raised HSA RAST. The latter findings are suggestive of IgE antibody production to new antigenic determinants in HSA produced by conjugation with the platinum salts.


Reading and reading-related skills in adults with dyslexia from different orthographic systems: a review and meta-analysis.
An individual diagnosed with dyslexia in childhood typically remains dyslexic throughout his/her life. However, the cognitive profile of adults with dyslexia has been less explored than that of children. This meta-analytic study is intended to clarify three questions: (1) To what extent, and in what manner, do adults with reading difficulties (dyslexia) differ from typical adult readers in measures of reading and writing competence and related cognitive skills?; (2) To what extent do speed measures pose a greater challenge than accuracy measures in an adult population that has already had years of print exposure?; and (3) To what extent does orthographic transparency modulate the reading profile of adults with dyslexia? A total of 178 studies comparing adults with dyslexia and matched controls were reviewed. The results showed that adults with dyslexia exhibited poor performance on almost all reading and writing tasks expressed by very large effect sizes (range 1.735 ≤ d ≤ 2.034), except for reading comprehension (d = 0.729). Deficits in reading- and writing-related variables are also present but with a lower expression (range 0.591 ≤ d ≤ 1.295). These difficulties are exacerbated for speed measures, especially for word and pseudoword reading, phonological awareness and orthographic knowledge. Orthographic transparency proved to be a significant moderator of dyslexic deficits in word and pseudoword reading, reading comprehension, spelling and phonological awareness, with the expression of the deficits being weaker on transparent-as opposed to intermediate and opaque-orthographies. Overall, the meta-analysis shows that reading and writing difficulties persist in adulthood and are more pronounced in speed measures. Moreover, symptoms are more severe for reading and writing than they are for measures tapping into the cognitive processes underlying reading skills. Orthographic transparency has a significant effect on the manifestation of dyslexia, with dyslexia symptoms being less marked on transparent orthographies. In addition, phonological awareness seems to be a minor problem in adulthood, especially for transparent orthographies.


Genoarchitecture of the extended amygdala in zebra finch, and expression of FoxP2 in cell corridors of different genetic profile.
We used a battery of genes encoding transcription factors (Pax6, Islet1, Nkx2.1, Lhx6, Lhx5, Lhx9, FoxP2) and neuropeptides to study the extended amygdala in developing zebra finches. We identified different components of the central extended amygdala comparable to those found in mice and chickens, including the intercalated amygdalar cells, the central amygdala, and the lateral bed nucleus of the stria terminalis. Many cells likely originate in the dorsal striatal domain, ventral striatal domain, or the pallidal domain, as is the case in mice and chickens. Moreover, a cell subpopulation of the central extended amygdala appears to originate in the prethalamic eminence. As a general principle, these different cells with specific genetic profiles and embryonic origin form separate or partially intermingled cell corridors along the extended amygdala, which may be involved in different functional pathways. In addition, we identified the medial amygdala of the zebra finch. Like in the chickens and mice, it is located in the subpallium and is rich in cells of pallido-preoptic origin, containing minor subpopulations of immigrant cells from the ventral pallium, alar hypothalamus and prethalamic eminence. We also proposed that the medial bed nucleus of the stria terminalis is composed of several parallel cell corridors with different genetic profile and embryonic origin: preoptic, pallidal, hypothalamic, and prethalamic. Several of these cell corridors with distinct origin express FoxP2, a transcription factor implicated in synaptic plasticity. Our results pave the way for studies using zebra finches to understand the neural basis of social behavior, in which the extended amygdala is involved.


Bone marrow examination findings at Aga Khan University Hospital, Nairobi.
To establish the bone marrow examination findings and determine the indication for bone marrow examination. A retrospective audit. Aga Khan University Hospital, Nairobi. All bone marrow aspirates done at Aga Khan University for the period comprising February 2003 to February 2006 were retrieved and analysed. A total of 356 patient's case histories including bone marrow examination results were analysed. Ages of the patients ranged from 18 months to 91 years. Males were 180 (50.6%) and females were 176 (49.4%). Nutritional anaemia as a group was the most common haematological disorder found on bone marrow examination in our patients with megaloblastic anaemia predominating. Acute myeloid leukaemia was the most common malignant haematological disorder. The most common indication for bone marrow examination was anaemia followed by diagnostic work up of fever of unknown origin. Nutritional anaemia predominated as the commonest benign haematological finding on bone marrow examination while acute myeloid leukaemia was the most frequent haematological malignancy. Most bone marrow examinations were performed on patients with anaemia.


Permissive glycan support of photoreceptor outer segment assembly occurs via a non-metabolic mechanism.
We have previously demonstrated that in RPE-deprived retinas, lactose, galactose, and structurally related glycans support the proper assembly of nascent photoreceptor outer segment membranes. Other glycans such as mannose and glucose have no effect on this process. While the ability to support outer segment assembly is highly specific, all of the permissive glycans we have tested are able to enter metabolic pathways within the retinal cells, thus the mechanism by which the glycans are functioning is still ambiguous. The present study was undertaken to determine if permissive glycan-mediated support of photoreceptor outer segment assembly occurred via a non-metabolic mechanism and if the phenomenon was reversible. The RPE was removed from isolated Xenopus laevis embryonic eyes that were allowed to complete differentiation in (1) Niu-Twitty medium, (2) Niu-Twitty supplemented with 5x10-3 M lactose or mannose, (3) Niu-Twitty supplemented with lactose and 3H-galactose, (4) Niu-Twitty medium supplemented with isopropyl beta-D-thiogalactopyranoside (IPTG) at concentrations spanning five orders of magnitude, or (5) Niu-Twitty medium containing lactose or IPTG to which 3H-leucine was added for 2 days followed by an additional 2 days in Niu-Twitty alone. Control RPE-deprived and RPE-supported retinas were included for comparison. Under all experimental conditions, retinal photoreceptors were evaluated to determine the level of organized folding of outer segment membranes. Outer segment membranes of RPE-deprived retinas exposed to lactose were significantly more organized than both control RPE-deprived retinas and those exposed to mannose. In eyes exposed to the radiolabeled metabolizable glycan, the majority of the sugar was incorporated into Müller cells. IPTG, a non-metabolizable form of galactose, promoted the formation of organized outer segment assembly similar to lactose although at a 100 fold reduced concentration compared to metabolizable permissive glycans. Both IPTG and lactose supported outer segment assembly in a step-wise fashion with maximal support at 5x10(-5) M and 5x10(-3) M, respectively. Removal of the permissive glycans resulted in loss of support of outer segment assembly. The ability of both lactose and IPTG to support outer segment assembly in the absence of the RPE is dose-dependent and the effect of these sugars upon membrane folding is reversible. Moreover, this effect is supported by a non-metabolic mechanism and is therefore not accounted for by simple provision of an energy source.


Superior mesenteric venous thrombosis: a retrospective study of thirteen cases.
To analyze the epidemiology, associated risk factors, clinical presentation, diagnostic methods, treatment, and evolution of patients diagnosed with superior mesenteric venous thrombosis (SMVT) at an university hospital in Madrid. Retrospective and descriptive study. We review the medical records of patients with this diagnosis in our hospital from January 1998 to December 2002. Data were processed by using the SPSS vs. 11 software. All thirteen subjects diagnosed with SMVT in that period were included. Associated risk factors included tumoral conditions (5 patients), acute abdominal pathology (2), polyglobulia (1), prothrombin gene mutation (1), and anticardiolipin antibodies (1). No predisposing factor was found in 3 patients. Clinical presentation for all patients was abdominal pain, with nausea and vomiting being the second symptom in frequency (7). The diagnosis was reached by abdominal CT (9), arteriography (2), ultrasounds (1), and histology after intestinal resection (1). Treatment with only anticoagulation was initiated in 4 patients, whereas anticoagulation and surgery were performed in 5 cases. In 4 subjects no specific treatment was prescribed and only palliative measures were established due to a baseline end-stage condition. Five patients died, and four of them had a neoplasic condition as associated risk factor. Mortality in our series was 38.5%. SMVT is a very rare disease that is often associated with neoplasic pathology, which influences its high mortality. Due to non specific symptoms, imaging is essential for the diagnosis and the detection of associated risk factors. In our series, computed tomography imaging was the most profitable test.


Branch Thinning and the Large-Scale, Self-Similar Structure of Trees.
Branch formation in trees has an inherent tendency toward exponential growth, but exponential growth in the number of branches cannot continue indefinitely. It has been suggested that trees balance this tendency toward expansion by also losing branches grown in previous growth cycles. Here, we present a model for branch formation and branch loss during ontogeny that builds on the phenomenological assumption of a branch carrying capacity. The model allows us to derive approximate analytical expressions for the number of tips on a branch, the distribution of growth modules within a branch, and the rate and size distribution of tree wood litter produced. Although limited availability of data makes empirical corroboration challenging, we show that our model can fit field observations of red maple (Acer rubrum) and note that the age distribution of discarded branches predicted by our model is qualitatively similar to an empirically observed distribution of dead and abscised branches of balsam poplar (Populus balsamifera). By showing how a simple phenomenological assumption-that the number of branches a tree can maintain is limited-leads directly to predictions on branching structure and the rate and size distribution of branch loss, these results potentially enable more explicit modeling of woody tissues in ecosystems worldwide, with implications for the buildup of flammable fuel, nutrient cycling, and understanding of plant growth.


Coupled and uncoupled dipole models of nonlinear scattering.
Dipole models are one of the simplest numerical models to understand nonlinear scattering. Existing dipole model for second harmonic generation, third harmonic generation and coherent anti-Stokes Raman scattering assume that the dipoles which make up a scatterer do not interact with one another. Thus, this dipole model can be called the uncoupled dipole model. This dipole model is not sufficient to describe the effects of refractive index of a scatterer or to describe scattering at the edges of a scatterer. Taking into account the interaction between dipoles overcomes these short comings of the uncoupled dipole model. Coupled dipole model has been primarily used for linear scattering studies but it can be extended to predict nonlinear scattering. The coupled and uncoupled dipole models have been compared to highlight their differences. Results of nonlinear scattering predicted by coupled dipole model agree well with previously reported experimental results.


No association between gallstones and gastroesophageal reflux disease.
Gallstones and hiatal hernia reportedly have been linked to similar dietary factors prevalent in western countries, and patients with cholelithiasis or previous cholecystectomy have been reported to have more duodenogastric reflux than healthy controls. Nonetheless, the contribution of duodenogastric reflux to the development of gastroesophageal reflux disease (GERD) remains controversial. The present study was aimed to assess the association between gallstone disease and GERD. Outpatients from general medical clinics who underwent upper GI endoscopy and abdominal ultrasonography were recruited into a case-control study. A case population of 790 patients with various grades of GERD was compared to a control population of 407 patients without GERD. In a multivariate logistic regression, the presence of GERD served as the outcome variable, whereas the presence of gallstones, hiatal hernia, social habits, and demographic characteristics served as predictor variables. No associations were found between the presence of cholelithiasis or previous cholecystectomy and GERD or between the presence of cholelithiasis or previous cholecystectomy and hiatal hernia. The severity of GERD also remained unaffected by the presence of gallstones. The occurrence of GERD was influenced only by hiatal hernia (odds ratio [OR] = 3.15, 95% CI = 2.44-4.08), alcohol consumption (OR = 1.47, CI = 1.08-1.99), and not by cholelithiasis (OR = 1.02, CI = 0.68-1.51), or cholecystectomy (OR = 0.90, CI = 0.64-1.28). The frequency of GERD among hiatus hernia patients with gallstones (437/592 = 74%) was similar to the frequency of GERD among hiatus hernia patients without gallstones (168/220 = 76%, p = 0.516). Neither cholelithiasis nor cholecystectomy poses a risk for the occurrence of GERD or hiatal hernia. Gallstone disease does not seem to influence the integrity of the esophageal mucosa through GERD.


Convulsant agent pentylenetetrazol does not alter the structural and dynamical properties of dipalmitoylphosphatidylcholine model membranes.
Pentylenetetrazol (PTZ) is an epileptogenic agent, which is widely used in the determination of epilepsy-induced alterations and in the assessment of anticonvulsant agents in epileptic studies. Even though PTZ is suggested to induce repetitive firing of nerve fibers and shorten the refractory, its mechanism of action is only partially understood. In the literature there are discrepancies for its action mechanism. While some studies stated that primary sites of PTZ are membrane proteins, some reports indicated that PTZ acts on membrane lipids. In order to gain new insight for this we tested the possibility of interaction of PTZ with a simplified model system called dipalmitoylphosphatidylcholine (DPPC) multilamellar vesicles (MLVs) at agent concentrations (0-24 mol%) using differential scanning calorimetry (DSC), Fourier transform infrared (FTIR), electron spin resonance (ESR) and steady-state fluorescence spectroscopy. The results showed that PTZ at concentrations used (1-24 mol%), does not cause any significant change in lipid phase behavior, lipid dynamics (fluidity), lipid acyl chain flexibility (order), hydration state of the head group and/or the region near the head group of DPPC MLVs. These results clearly revealed that PTZ does not change the structural and dynamical parameters of neutral DPPC lipid vesicles and does not locate within the bilayer.


Implications of 2D versus 3D surveys to measure the abundance and composition of benthic coral reef communities.
A paramount challenge in coral reef ecology is to estimate the abundance and composition of the communities residing in such complex ecosystems. Traditional 2D projected surface cover estimates neglect the 3D structure of reefs and reef organisms, overlook communities residing in cryptic reef habitats (e.g., overhangs, cavities), and thus may fail to represent biomass estimates needed to assess trophic ecology and reef function. Here, we surveyed the 3D surface cover, biovolume, and biomass (i.e., ash-free dry weight) of all major benthic taxa on 12 coral reef stations on the island of Curaçao (Southern Caribbean) using structure-from-motion photogrammetry, coral point counts, in situ measurements, and elemental analysis. We then compared our 3D benthic community estimates to corresponding estimates of traditional 2D projected surface cover to explore the differences in benthic community composition using different metrics. Overall, 2D cover was dominated (52 ± 2%, mean ± SE) by non-calcifying phototrophs (macroalgae, turf algae, benthic cyanobacterial mats), but their contribution to total reef biomass was minor (3.2 ± 0.6%). In contrast, coral cover (32 ± 2%) more closely resembled coral biomass (27 ± 6%). The relative contribution of erect organisms, such as gorgonians and massive sponges, to 2D cover was twofold and 11-fold lower, respectively, than their contribution to reef biomass. Cryptic surface area (3.3 ± 0.2 m2 m-2 planar reef) comprised half of the total reef substrate, rendering two thirds of coralline algae and almost all encrusting sponges (99.8%) undetected in traditional assessments. Yet, encrusting sponges dominated reef biomass (35 ± 18%). Based on our quantification of exposed and cryptic reef communities using different metrics, we suggest adjustments to current monitoring approaches and highlight ramifications for evaluating the ecological contributions of different taxa to overall reef function. To this end, our metric conversions can complement other benthic assessments to generate non-invasive estimates of the biovolume, biomass, and elemental composition (i.e., standing stocks of organic carbon and nitrogen) of Caribbean coral reef communities. The online version contains supplementary material available at 10.1007/s00338-021-02118-6.


Observations of ozone formation in power plant plumes and implications for ozone control strategies.
Data taken in aircraft transects of emissions plumes from rural U.S. coal-fired power plants were used to confirm and quantify the nonlinear dependence of tropospheric ozone formation on plume NO(x) (NO plus NO(2)) concentration, which is determined by plant NO(x) emission rate and atmospheric dispersion. The ambient availability of reactive volatile organic compounds, principally biogenic isoprene, was also found to modulate ozone production rate and yield in these rural plumes. Differences of a factor of 2 or greater in plume ozone formation rates and yields as a function of NO(x) and volatile organic compound concentrations were consistently observed. These large differences suggest that consideration of power plant NO(x) emission rates and geographic locations in current and future U.S. ozone control strategies could substantially enhance the efficacy of NO(x) reductions from these sources.


Characterization of tryptophan transport in human placental brush-border membrane vesicles.
The characteristics of tryptophan uptake in isolated human placental brush-border membrane vesicles were investigated. Tryptophan uptake in these vesicles was predominantly Na+-independent. Uptake of tryptophan as measured with short incubations occurred exclusively by a carrier-mediated process, but significant binding of this amino acid to the membrane vesicles was observed with longer incubations. The carrier-mediated system obeyed Michaelis-Menten kinetics, with an apparent affinity constant of 12.7 +/- 1.0 microM and a maximal velocity of 91 +/- 5 pmol/15 s per mg of protein. The kinetic constants were similar in the presence and absence of a Na+ gradient. Competition experiments showed that tryptophan uptake was effectively inhibited by many neutral amino acids except proline, hydroxyproline and 2-(methylamino)isobutyric acid. The inhibitory amino acids included aromatic amino acids as well as other system-1-specific amino acids (system 1 refers to the classical L system, according to the most recent nomenclature of amino acid transport systems). The transport system showed very low affinity for D-isomers, was not affected by phloretin or glucose but was inhibited by p-azidophenylalanine and N-ethylmaleimide. The uptake rates were only minimally affected by change in pH over the range 4.5-8.0. Tryptophan uptake markedly responded to trans-stimulation, and the amino acids capable of causing trans-stimulation included all amino acids with system-1-specificity. The patterns of inhibition of uptake of tryptophan and leucine by various amino acids were very similar. We conclude that system t, which is specific for aromatic amino acids, is absent from human placenta and that tryptophan transport in this tissue occurs via system 1, which has very broad specificity.


Higher economic inequality intensifies the financial hardship of people living in poverty by fraying the community buffer.
The current research investigates whether higher economic inequality disproportionately intensifies the financial hardship of low-income individuals. We propose that higher economic inequality increases financial hardship for low-income individuals by reducing their ability to rely on their community as a buffer against financial difficulties. This may occur, in part, because a frayed community buffer reduces low-income individuals' propensity to seek informal financial support from others. We provide empirical support across eight studies (sample size N = 1,029,900) from the United States, Australia and rural Uganda, through correlational and experimental data, as well as an instrumental variable analysis. On average across our studies, a 1 s.d. increase in economic inequality is associated with an increase of financial hardship among low-income individuals of 0.10 s.d. We discuss the implications of these results for policies aimed to help people living in poverty buffer against the adverse effects higher economic inequality imposes on them.


Antibody to native human immunodeficiency virus type 1 envelope glycoproteins induced by IIIB and MN recombinant gp120 vaccines. The NIAID AIDS Vaccine Evaluation Group.
The ability of antibody induced by MN and IIIB recombinant gp120 (rgp120) human immunodeficiency virus type 1 (HIV-1) vaccines the bind to oligomeric native and monomeric recombinant HIV-1 envelope glycoproteins (rgp 120) was measured in 25 uninfected, healthy adult volunteers. A major focus was to evaluate the effect of simultaneous and sequential immunization with vaccines representing different strains of HIV-1 on the ability to broaden cross-reactivity of antibodies against these and other HIV-1 strains. A flow cytometric indirect immunofluorescence assay (FIFA) to detect vaccine-induced antibody to envelope glycoprotein expressed by infected and rgp120-coated target cells was used, MN rgp120 HIV-1 vaccine given alone and coadministered with IIIB rgp120 HIV-1 vaccine elicited antibody which bound to cells infected with HIV-1MN, HIV-IIIB, HIV-1RF, and HIV-1-SF2. The presence of envelope glycoprotein-binding antibody detected by FIFA correlated to a moderate degree with functional antibody against HIV-1MN and HIV-IIIB. Priming immunization with IIIB rgp120 HIV-1 vaccine followed by booster injections of MN rgp120 HIV-1 vaccine resulted in increased cross-reactive antibody binding to these and heterologous clade B HIV-1 strains infecting cells. MN rgp120 HIV-1 vaccine given alone was better able to induce cross-reactive antibody to cells infected with heterologous HIV-1 laboratory strains than was IIIB rgp120 HIV-1 vaccine given alone. The vaccines induced binding antibody to rgp120 possessing the amino acid sequence of a clade E HIV-1 strain as measured by enzyme-linked immunosorbent assay. Levels of antibody binding to cells infected with clade B HIV-1 and cells coated with monomeric rgp120 were greater than that induced by HIV-1IIIB-based gp160 vaccines in previous studies.


Heritabilities of radiologic osteoarthritis in peripheral joints and of disc degeneration of the spine.
To estimate the genetic influence on the occurrence of radiologic osteoarthritis (ROA) in the knees, hips, and hands and disc degeneration of the spine in the general population. A random sample of 1,583 individuals was drawn to estimate the prevalence of ROA and disc degeneration in the general population. Of 118 probands with multiple affected joint sites who were derived from this sample, we were able to recruit 257 siblings. The variance of ROA and disc degeneration within sibling pairs was compared with the variance between sibling pairs. Heritability estimates for ROA in the knees, hips, and hands and for disc degeneration of the spine were calculated. OA was defined according to radiologic criteria, using the Kellgren/Lawrence grading system. We observed that hand ROA and disc degeneration of the spine were statistically significantly more frequent in siblings than in the random sample, whereas the prevalence of knee and of hip ROA was similar and lower, respectively. Heritability estimates for hand ROA and disc degeneration were statistically significant, P = 0.56 (95% confidence interval [95% CI] 0.34-0.76) and P = 0.75 (95% CI 0.30-1.00), respectively. For knee and hip ROA, no evidence of a genetic effect in the general population was found. Finally, the heritability estimate for a score that summed the number of joints affected in the knees, hips, hands, and spine was 0.78 (95% CI 0.52-0.98). All heritability estimates were adjusted for age, sex, body mass index, and bone mineral density. The present study shows that in the general population, there is a strong genetic effect for hand ROA and disc degeneration of the spine. The findings on the total number of joints affected at multiple sites suggest genetic susceptibility to generalized OA.


Space versus phylogeny: disentangling phylogenetic and spatial signals in comparative data.
Variation in traits across species or populations is the outcome of both environmental and historical factors. Trait variation is therefore a function of both the phylogenetic and spatial context of species. Here we introduce a method that, within a single framework, estimates the relative roles of spatial and phylogenetic variations in comparative data. The approach requires traits measured across phylogenetic units, e.g. species, the spatial occurrences of those units and a phylogeny connecting them. The method modifies the expected variance of phylogenetically independent contrasts to include both spatial and phylogenetic effects. We illustrate this approach by analysing cross-species variation in body mass, geographical range size and species-typical environmental temperature in three orders of mammals (carnivores, artiodactyls and primates). These species attributes contain highly disparate levels of phylogenetic and spatial signals, with the strongest phylogenetic autocorrelation in body size and spatial dependence in environmental temperatures and geographical range size showing mixed effects. The proposed method successfully captures these differences and in its simplest form estimates a single parameter that quantifies the relative effects of space and phylogeny. We discuss how the method may be extended to explore a range of models of evolution and spatial dependence.


The clonal and mutational evolution spectrum of primary triple-negative breast cancers.
Primary triple-negative breast cancers (TNBCs), a tumour type defined by lack of oestrogen receptor, progesterone receptor and ERBB2 gene amplification, represent approximately 16% of all breast cancers. Here we show in 104 TNBC cases that at the time of diagnosis these cancers exhibit a wide and continuous spectrum of genomic evolution, with some having only a handful of coding somatic aberrations in a few pathways, whereas others contain hundreds of coding somatic mutations. High-throughput RNA sequencing (RNA-seq) revealed that only approximately 36% of mutations are expressed. Using deep re-sequencing measurements of allelic abundance for 2,414 somatic mutations, we determine for the first time-to our knowledge-in an epithelial tumour subtype, the relative abundance of clonal frequencies among cases representative of the population. We show that TNBCs vary widely in their clonal frequencies at the time of diagnosis, with the basal subtype of TNBC showing more variation than non-basal TNBC. Although p53 (also known as TP53), PIK3CA and PTEN somatic mutations seem to be clonally dominant compared to other genes, in some tumours their clonal frequencies are incompatible with founder status. Mutations in cytoskeletal, cell shape and motility proteins occurred at lower clonal frequencies, suggesting that they occurred later during tumour progression. Taken together, our results show that understanding the biology and therapeutic responses of patients with TNBC will require the determination of individual tumour clonal genotypes.


Tardiness Increases in Winter: Evidence for Annual Rhythms in Humans.
Annual rhythms in humans have been described for a limited number of behavioral and physiological parameters. The aim of this study was to investigate time-of-year variations in late arrivals, sick leaves, dismissals from class (attendance), and grades (performance). Data were collected in Dutch high school students across 4 academic years (indicators of attendance in about 1700 students; grades in about 200 students). Absenteeism showed a seasonal variation, with a peak in winter, which was more strongly associated with photoperiod (number of hours of daylight) compared with other factors assessed (e.g., weather conditions). Grades also varied with time of year, albeit differently across the 4 years. The observed time-of-year variation in the number of sick leaves was in accordance with the literature on the seasonality of infectious diseases (e.g., influenza usually breaks out in winter). The winter peak in late arrivals was unexpected and requires more research. Our findings could be relevant for a seasonal adaptation of school schedules and working environments (e.g., later school and work hours in winter, especially at higher latitudes where seasonal differences in photoperiod are more pronounced).


Increase of the Bacillus thuringiensis secreted toxicity against lepidopteron larvae by homologous expression of the vip3LB gene during sporulation stage.
The Vegetative insecticidal Vip3A proteins display a wide range of insecticidal spectrum against several agricultural insect pests. The fact that the expression of vip3 genes occurs only during the vegetative growth phase of Bacillus thuringiensis is a limiting factor in term of production level. Therefore, extending the synthesis of the Vip proteins to the sporulation phase is a good alternative to reach high levels of toxin synthesis. In this study, we have demonstrated that the maximal production of the secreted Vip3LB (also called Vip3Aa16) during the growth of the wild-type strain B. thuringiensis BUPM 95 is reached at the end of the vegetative growth phase, and that the protein remains relatively stable in the culture supernatant during the late sporulation stages. The vip3LB gene was cloned and expressed under the control of the sporulation dependant promoters BtI and BtII in B. thuringiensis BUPM 106 (Vip3(-)) and BUPM 95 (Vip3(+)) strains. The examination of the culture supernatants during the sporulation phase evidenced the synthesis of Vip3LB and its toxicity against the second-instars larvae of the Lepidopteron insect Spodoptera littoralis for the recombinant BUPM 106. Moreover, there was an increase of the Vip3LB synthesis level and an enhancement of the oral toxicity for the recombinant BUPM 95 resulting from the expression of the vip3LB gene during both the vegetative and sporulation phases and the relative stability of the Vip3LB protein.


Evaluating Response Time in Zanzibar's Malaria Elimination Case-Based Surveillance-Response System.
As countries transition toward malaria elimination, malaria programs rely on surveillance-response systems, which are often supported by web- and mobile phone-based reporting tools. Such surveillance-response systems are interventions for elimination, making it important to determine if they are operating optimally. A metric to measure this by is timeliness. This study used a mixed-methods approach to investigate the response time of Zanzibar's malaria elimination surveillance-response system, Malaria Case Notification (MCN). MCN conducts both passive and reactive case detection, supported by a mobile phone-based reporting tool called Coconut Surveillance. Using data obtained from RTI International and the Zanzibar Malaria Elimination Program (ZAMEP), analysis of summary statistics was conducted to investigate the association of response time with geography, and time series techniques were used to investigate trends in response time and its association with the number of reported cases. Results indicated that response time varied by the district in Zanzibar (0.6-6.05 days) and that it was not associated with calendar time or the number of reported cases. Survey responses and focus groups with a cadre of health workers, district malaria surveillance officers, shed light on operational challenges faced during case investigation, such as incomplete health records and transportation issues, which stem from deficiencies in aspects of ZAMEP's program management. These findings illustrate that timely response for malaria elimination depends on effective program management, despite the automation of web-based or mobile phone-based tools. For surveillance-response systems to work optimally, malaria programs should ensure that optimal management practices are in place.