K-r/K-c but not d(N)/d(S) correlates positively with body mass in birds, raising implications for inferring lineage-specific selection

Background: The ratio of the rates of non-synonymous and synonymous substitution (d(N)/d(S)) is commonly used to estimate selection in coding sequences. It is often suggested that, all else being equal, d(N)/d(S) should be lower in populations with large effective size (Ne) due to increased efficacy of purifying selection. As N-e is difficult to measure directly, life history traits such as body mass, which is typically negatively associated with population size, have commonly been used as proxies in empirical tests of this hypothesis. However, evidence of whether the expected positive correlation between body mass and d(N)/d(S) is consistently observed is conflicting. Results: Employing whole genome sequence data from 48 avian species, we assess the relationship between rates of molecular evolution and life history in birds. We find a negative correlation between dN/dS and body mass, contrary to nearly neutral expectation. This raises the question whether the correlation might be a method artefact. We therefore in turn consider non-stationary base composition, divergence time and saturation as possible explanations, but find no clear patterns. However, in striking contrast to d(N)/d(S), the ratio of radical to conservative amino acid substitutions (K-r/K-c) correlates positively with body mass. Conclusions: Our results in principle accord with the notion that non-synonymous substitutions causing radical amino acid changes are more efficiently removed by selection in large populations, consistent with nearly neutral theory. These findings have implications for the use of d(N)/d(S) and suggest that caution is warranted when drawing conclusions about lineage-specific modes of protein evolution using this metric.

Reference values and factors associated with renal resistive index in a family-based population study.

Increased renal resistive index (RRI) has been recently associated with target organ damage and cardiovascular or renal outcomes in patients with hypertension and diabetes mellitus. However, reference values in the general population and information on familial aggregation are largely lacking. We determined the distribution of RRI, associated factors, and heritability in a population-based study. Families of European ancestry were randomly selected in 3 Swiss cities. Anthropometric parameters and cardiovascular risk factors were assessed. A renal Doppler ultrasound was performed, and RRI was measured in 3 segmental arteries of both kidneys. We used multilevel linear regression analysis to explore the factors associated with RRI, adjusting for center and family relationships. Sex-specific reference values for RRI were generated according to age. Heritability was estimated by variance components using the ASSOC program (SAGE software). Four hundred women (mean age±SD, 44.9±16.7 years) and 326 men (42.1±16.8 years) with normal renal ultrasound had mean RRI of 0.64±0.05 and 0.62±0.05, respectively (P<0.001). In multivariable analyses, RRI was positively associated with female sex, age, systolic blood pressure, and body mass index. We observed an inverse correlation with diastolic blood pressure and heart rate. Age had a nonlinear association with RRI. We found no independent association of RRI with diabetes mellitus, hypertension treatment, smoking, cholesterol levels, or estimated glomerular filtration rate. The adjusted heritability estimate was 42±8% (P<0.001). In a population-based sample with normal renal ultrasound, RRI normal values depend on sex, age, blood pressure, heart rate, and body mass index. The significant heritability of RRI suggests that genes influence this phenotype.

Effect of multidimensional lifestyle intervention on fitness and adiposity in predominantly migrant preschool children (Ballabeina): cluster randomised controlled trial.

OBJECTIVE: To test the effect of a multidimensional lifestyle intervention on aerobic fitness and adiposity in predominantly migrant preschool children. DESIGN: Cluster randomised controlled single blinded trial (Ballabeina study) over one school year; randomisation was performed after stratification for linguistic region. SETTING: 40 preschool classes in areas with a high migrant population in the German and French speaking regions of Switzerland. PARTICIPANTS: 652 of the 727 preschool children had informed consent and were present for baseline measures (mean age 5.1 years (SD 0.7), 72% migrants of multicultural origins). No children withdrew, but 26 moved away. INTERVENTION: The multidimensional culturally tailored lifestyle intervention included a physical activity programme, lessons on nutrition, media use (use of television and computers), and sleep and adaptation of the built environment of the preschool class. It lasted from August 2008 to June 2009. MAIN OUTCOME MEASURES: Primary outcomes were aerobic fitness (20 m shuttle run test) and body mass index (BMI). Secondary outcomes included motor agility, balance, percentage body fat, waist circumference, physical activity, eating habits, media use, sleep, psychological health, and cognitive abilities. RESULTS: Compared with controls, children in the intervention group had an increase in aerobic fitness at the end of the intervention (adjusted mean difference: 0.32 stages (95% confidence interval 0.07 to 0.57; P=0.01) but no difference in BMI (-0.07 kg/m(2), -0.19 to 0.06; P=0.31). Relative to controls, children in the intervention group had beneficial effects in motor agility (-0.54 s, -0.90 to -0.17; P=0.004), percentage body fat (-1.1%, -2.0 to -0.2; P=0.02), and waist circumference (-1.0 cm, -1.6 to -0.4; P=0.001). There were also significant benefits in the intervention group in reported physical activity, media use, and eating habits, but not in the remaining secondary outcomes. CONCLUSIONS: A multidimensional intervention increased aerobic fitness and reduced body fat but not BMI in predominantly migrant preschool children.

Effect of once-yearly zoledronic acid five milligrams on fracture risk and change in femoral neck bone mineral density.

CONTEXT: In the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly - Pivotal Fracture Trial (HORIZON-PFT), zoledronic acid (ZOL) 5 mg significantly reduced fracture risk. OBJECTIVE: The aim of the study was to identify factors associated with greater efficacy during ZOL 5 mg treatment. DESIGN, SETTING, AND PATIENTS: We conducted a subgroup analysis (preplanned and post hoc) of a multicenter, double-blind, placebo-controlled, 36-month trial in 7765 women with postmenopausal osteoporosis. Intervention: A single infusion of ZOL 5 mg or placebo was administered at baseline, 12, and 24 months. MAIN OUTCOME MEASURES: Primary endpoints were new vertebral fracture and hip fracture. Secondary endpoints were nonvertebral fracture and change in femoral neck bone mineral density (BMD). Baseline risk factor subgroups were age, BMD T-score and vertebral fracture status, total hip BMD, race, weight, geographical region, smoking, height loss, history of falls, physical activity, prior bisphosphonates, creatinine clearance, body mass index, and concomitant osteoporosis medications. RESULTS: Greater ZOL induced effects on vertebral fracture risk were seen with younger age (treatment-by-subgroup interaction, P = 0.05), normal creatinine clearance (P = 0.04), and body mass index >or= 25 kg/m(2) (P = 0.02). There were no significant treatment-factor interactions for hip or nonvertebral fracture or for change in BMD. CONCLUSIONS: ZOL appeared more effective in preventing vertebral fracture in younger women, overweight/obese women, and women with normal renal function. ZOL had similar effects irrespective of fracture risk factors or femoral neck BMD.

Quantify this! Report on a round table discussion on quantitative mass spectrometry in proteomics.

Following the success of the first round table in 2001, the Swiss Proteomic Society has organized two additional specific events during its last two meetings: a proteomic application exercise in 2002 and a round table in 2003. Such events have as their main objective to bring together, around a challenging topic in mass spectrometry, two groups of specialists, those who develop and commercialize mass spectrometry equipment and software, and expert MS users for peptidomics and proteomics studies. The first round table (Geneva, 2001) entitled "Challenges in Mass Spectrometry" was supported by brief oral presentations that stressed critical questions in the field of MS development or applications (Stöcklin and Binz, Proteomics 2002, 2, 825-827). Topics such as (i) direct analysis of complex biological samples, (ii) status and perspectives for MS investigations of noncovalent peptide-ligant interactions; (iii) is it more appropriate to have complementary instruments rather than a universal equipment, (iv) standardization and improvement of the MS signals for protein identification, (v) what would be the new generation of equipment and finally (vi) how to keep hardware and software adapted to MS up-to-date and accessible to all. For the SPS'02 meeting (Lausanne, 2002), a full session alternative event "Proteomic Application Exercise" was proposed. Two different samples were prepared and sent to the different participants: 100 micro g of snake venom (a complex mixture of peptides and proteins) and 10-20 micro g of almost pure recombinant polypeptide derived from the shrimp Penaeus vannamei carrying an heterogeneous post-translational modification (PTM). Among the 15 participants that received the samples blind, eight returned results and most of them were asked to present their results emphasizing the strategy, the manpower and the instrumentation used during the congress (Binz et. al., Proteomics 2003, 3, 1562-1566). It appeared that for the snake venom extract, the quality of the results was not particularly dependant on the strategy used, as all approaches allowed Lication of identification of a certain number of protein families. The genus of the snake was identified in most cases, but the species was ambiguous. Surprisingly, the precise identification of the recombinant almost pure polypeptides appeared to be much more complicated than expected as only one group reported the full sequence. Finally the SPS'03 meeting reported here included a round table on the difficult and challenging task of "Quantification by Mass Spectrometry", a discussion sustained by four selected oral presentations on the use of stable isotopes, electrospray ionization versus matrix-assisted laser desorption/ionization approaches to quantify peptides and proteins in biological fluids, the handling of differential two-dimensional liquid chromatography tandem mass spectrometry data resulting from high throughput experiments, and the quantitative analysis of PTMs. During these three events at the SPS meetings, the impressive quality and quantity of exchanges between the developers and providers of mass spectrometry equipment and software, expert users and the audience, were a key element for the success of these fruitful events and will have definitively paved the way for future round tables and challenging exercises at SPS meetings.

The role of teriparatide in sequential and combination therapy of osteoporosis.

Osteoporosis is complicated by the occurrence of fragility fractures. Over past years, various treatment options have become available, mostly potent antiresorptive agents such as bisphosphonates and denosumab. However, antiresorptive therapy cannot fully and rapidly restore bone mass and structure that has been lost because of increased remodelling. Alternatively recombinant human parathyroid hormone (rhPTH) analogues do increase the formation of new bone material. The bone formation stimulated by intermittent PTH analogues not only increases bone mineral density (BMD) and bone mass but also improves the microarchitecture of the skeleton, thereby reducing incidence of vertebral and nonvertebral fractures. Teriparatide, a recombinant human PTH fragment available in Switzerland, is reimbursed as second-line treatment in postmenopausal women and men with increased fracture risk, specifically in patients with incident fractures under antiresorptive therapy or patients with glucocorticoid-induced osteoporosis and intolerance to antiresorptives. This position paper focuses on practical aspects in the management of patients on teriparatide treatment. Potential first-line indications for osteoanabolic treatment as well as the benefits and limitations of sequential and combination therapy with antiresorptive drugs are discussed.

Statewide Transportation Improvement Program 2016-2019: Sorted by MPO and RPA, 2015

Iowa’s Statewide Transportation Improvement Program (STIP) has been developed in conformance with the guidelines prescribed by 23 U.S.C. and 49 U.S.C. The STIP is generated to provide the Federal Highway Administration and Federal Transit Administration a listing of all projects that are candidates for federal aid from the FHWA and FTA for the four federal fiscal years (FFY) 2016-2019. The 2016-2019 STIP was approved by FHWA and FTA on September 29, 2015. Preceding the listings of federal-aid candidates are general comments concerning Iowa’s public participation process for selection of federal-aid projects and the basis for funding the proposed projects. Documents evidencing the Iowa Department of Transportation’s authority to act concerning matters related to transportation, federal-aid expenditures, and approvals of metropolitan planning organizations’ (MPOs) transportation improvements programs (TIPs) have been provided in past STIPs and can be provided again upon request.

Do political factors matter in explaining under- and overweight outcomes in developing countries?

We construct a rich dataset covering 47 developing countries over the years 1990-2007, combining several micro and macro level data sources to explore the link between political factors and body mass index (BMI). We implement a heteroskedastic generalized ordered logit model allowing for different covariate effects across the BMI distribution and accounting for the unequal BMI dispersion by geographical area. We find that systems with democratic qualities are more likely to reduce under-weight, but increase overweight/obesity, whereas effective political competition does entail double-benefits in the form of reducing both under-weight and obesity. Our results are robust to the introduction of country fixed effects.

Closed soilless growing system for producing strawberry bare root transplants and runner tips

The objective of this work was to test a closed soilless growing system for producing bare root transplants and runner tips of two strawberry clones, using two categories of substrates. The system used corrugated roofing panels of fiber-cement, over which a substrate layer was used as a growing bed. The nutrient solution was pumped from a reservoir toward the upper end of the roofing panels and drained back to a reservoir. Plant growth and development were determined for two advanced strawberry clones, grown in sand or in Plantmax organic substrate. Growth of the stock plants and the number and dry mass of bare root transplants were similar in the substrates, but bare roots differed in their crown diameters by substrate. For number of runner tips, no significant differences were found in total, small, and medium categories in the substrates. A mean production of about 590 runner tips per square meter and 145 bare root transplants per square meter was obtained. For both clones, a large number of bare root transplants and runner tips of adequate size were produced in the closed soilless growing system using sand or organic substrate.

Association between the PNPLA3 (rs738409 C>G) variant and hepatocellular carcinoma: Evidence from a meta-analysis of individual participant data.

The incidence of hepatocellular carcinoma (HCC) is increasing in Western countries. Although several clinical factors have been identified, many individuals never develop HCC, suggesting a genetic susceptibility. However, to date, only a few single-nucleotide polymorphisms have been reproducibly shown to be linked to HCC onset. A variant (rs738409 C>G, encoding for p.I148M) in the PNPLA3 gene is associated with liver damage in chronic liver diseases. Interestingly, several studies have reported that the minor rs738409[G] allele is more represented in HCC cases in chronic hepatitis C (CHC) and alcoholic liver disease (ALD). However, a significant association with HCC related to CHC has not been consistently observed, and the strength of the association between rs738409 and HCC remains unclear. We performed a meta-analysis of individual participant data including 2,503 European patients with cirrhosis to assess the association between rs738409 and HCC, particularly in ALD and CHC. We found that rs738409 was strongly associated with overall HCC (odds ratio [OR] per G allele, additive model=1.77; 95% confidence interval [CI]: 1.42-2.19; P=2.78 × 10(-7) ). This association was more pronounced in ALD (OR=2.20; 95% CI: 1.80-2.67; P=4.71 × 10(-15) ) than in CHC patients (OR=1.55; 95% CI: 1.03-2.34; P=3.52 × 10(-2) ). After adjustment for age, sex, and body mass index, the variant remained strongly associated with HCC. Conclusion: Overall, these results suggest that rs738409 exerts a marked influence on hepatocarcinogenesis in patients with cirrhosis of European descent and provide a strong argument for performing further mechanistic studies to better understand the role of PNPLA3 in HCC development.

Avian haemosporidian persistence and co-infection in great tits at the individual level.

BACKGROUND: Many studies have tracked the distribution and persistence of avian haemosporidian communities across space and time at the population level, but few studies have investigated these aspects of infection at the individual level over time. Important aspects of parasite infection at the individual level can be missed if only trends at the population level are studied. This study aimed to determine how persistent Haemosporida are in great tit individuals recaptured over several years, whether parasitaemia differed by parasite lineage (mitochondrial cytochrome b haplotype) and how co-infection (i.e. concurrent infection with multiple genera of parasites) affects parasitaemia and body mass. METHODS: Parasite prevalence was determined by polymerase chain reaction (PCR), quantitative PCR were used to assess parasitaemia and sequencing was employed to determine the identity of the lineages using the MalAvi database. RESULTS: Haemosporidian prevalence was high over sampled years with 98% of 55 recaptured individuals showing infection in at least one year of capture. Eighty-two percent of all positive individuals suffered co-infection, with an overall haemosporidian lineage diversity of seventeen. Plasmodium and Haemoproteus parasites were found to be highly persistent, with lineages from these genera consistently found in individuals across years and with no differences in individual parasitaemia being recorded at subsequent captures. Conversely, Leucocytozoon parasites showed higher turnover with regard to lineage changes or transitions in infection status (infected vs non-infected) across years. Parasitaemia was found to be lineage specific and there was no relationship between Plasmodium parasitaemia or host body condition and the presence of Leucocytozoon parasites. CONCLUSIONS: The findings of this study suggest that different genera of haemosporidian parasites interact differently with their host and other co-infecting parasites, influencing parasite persistence most likely through inter-parasite competition or host-parasite immune interactions. Even-though co-infections do not seem to result in increased virulence (higher parasitaemia or poorer host body condition), further investigation into infection potential of these parasites, both individually and as co-infections, is necessary.

Revisiting spatial distribution and biochemical composition of calcium-containing crystals in human osteoarthritic articular cartilage.

INTRODUCTION: Calcium-containing (CaC) crystals, including basic calcium phosphate (BCP) and calcium pyrophosphate dihydrate (CPP), are associated with destructive forms of osteoarthritis (OA). We assessed their distribution and biochemical and morphologic features in human knee OA cartilage. METHODS: We prospectively included 20 patients who underwent total knee replacement (TKR) for primary OA. CaC crystal characterization and identification involved Fourier-transform infra-red spectrometry and scanning electron microscopy of 8 to 10 cartilage zones of each knee, including medial and lateral femoral condyles and tibial plateaux and the intercondyle zone. Differential expression of genes involved in the mineralization process between cartilage with and without calcification was assessed in samples from 8 different patients by RT-PCR. Immunohistochemistry and histology studies were performed in 6 different patients. RESULTS: Mean (SEM) age and body mass index of patients at the time of TKR was 74.6 (1.7) years and 28.1 (1.6) kg/m², respectively. Preoperative X-rays showed joint calcifications (chondrocalcinosis) in 4 cases only. The medial femoro-tibial compartment was the most severely affected in all cases, and mean (SEM) Kellgren-Lawrence score was 3.8 (0.1). All 20 OA cartilages showed CaC crystals. The mineral content represented 7.7% (8.1%) of the cartilage weight. All patients showed BCP crystals, which were associated with CPP crystals for 8 joints. CaC crystals were present in all knee joint compartments and in a mean of 4.6 (1.7) of the 8 studied areas. Crystal content was similar between superficial and deep layers and between medial and femoral compartments. BCP samples showed spherical structures, typical of biological apatite, and CPP samples showed rod-shaped or cubic structures. The expression of several genes involved in mineralization, including human homolog of progressive ankylosis, plasma-cell-membrane glycoprotein 1 and tissue-nonspecific alkaline phosphatase, was upregulated in OA chondrocytes isolated from CaC crystal-containing cartilages. CONCLUSIONS: CaC crystal deposition is a widespread phenomenon in human OA articular cartilage involving the entire knee cartilage including macroscopically normal and less weight-bearing zones. Cartilage calcification is associated with altered expression of genes involved in the mineralisation process.

Reference values of fat-free and fat masses by bioelectrical impedance analysis in 3393 healthy subjects.

Determination of fat-free mass (FFM) and fat mass (FM) is of considerable interest in the evaluation of nutritional status. In recent years, bioelectrical impedance analysis (BIA) has emerged as a simple, reproducible method used for the evaluation of FFM and FM, but the lack of reference values reduces its utility to evaluate nutritional status. The aim of this study was to determine reference values for FFM, FM, and %FM by BIA in a white population of healthy subjects, to observe the changes in these values with age, and to develop percentile distributions for these parameters. Whole-body resistance of 1838 healthy white men and 1555 women, aged 15-64 y, was determined by using four skin electrodes on the right hand and foot. FFM and FM were calculated according to formulas validated for the subject groups and analyzed for age decades. This is the first study to present BIA-determined age- and sex-specific percentiles for FFM, FM, and %FM for healthy subjects, aged 15-64 y. Mean FM and %FM increased progressively in men and after age 45 y in women. The results suggest that any weight gain noted with age is due to a gain in FM. In conclusion, the data presented as percentiles can serve as reference to evaluate the normality of body composition of healthy and ill subject groups at a given age.

Commentary : beyond vague causal effect estimation of obesity on health outcomes

In the current issue of epidemiology, Danaei and colleagues elegantly estimated both the direct effect and the indirect effect-that is, the effect mediated by blood pressure, cholesterol, glucose, fibrinogen, and high-sensitivity C-reactive protein-of body mass index (BMI) on the risk of coronary heart disease (CHD). they analyzed data from 9 cohort studies including 58,322 patients and 9459 CHD events, with baseline measurements between 1954 and 2001. Using sophisticated and cutting-edge methods for direct and indirect effect estimations, the authors estimated that half of the risk of overweight and obesity would be mediated by blood pressure, cholesterol, and glucose. Few additional percentage points of the risk would be mediated by fibrinogen and hs-CRP. How should we understand these estimates? Can we say that if obese persons reduce their body weight and reach a normal body weight, their excess risk of CHD would be reduced by half through an improvement in these mediators and by half through the reduction in BmI itself? Is that also true if these individuals are prevented from becoming obese in the first place? Can we also conclude that if these mediators are well controlled in obese individuals through other means than a body weight reduction, their excess risk of CHD would be reduced by half? Let us confront these estimates with observations from studies evaluating 2 interventions to reduce body weight, that is, bariatric surgery in patients with severe obesity and intensive lifestyle intervention in overweight patients with diabetes