International variation in GP treatment strategies for subclinical hypothyroidism in older adults: a case-based survey

Background: There is limited evidence about the impact of treatment for subclinical hypothyroidism, especially among older people. Aim: To investigate the variation in GP treatment strategies for older patients with subclinical hypothyroidism depending on country and patient characteristics. Design and setting: Case-based survey of GPs in the Netherlands, Germany, England, Ireland, Switzerland, and New Zealand. Method: The treatment strategy of GPs (treatment yes/no, starting-dose thyroxine) was assessed for eight cases presenting a woman with subclinical hypothyroidism. The cases differed in the patient characteristics of age (70 versus 85 years), vitality status (vital versus vulnerable), and thyroid-stimulating hormone (TSH) concentration (6 versus 15 mU/L). Results: A total of 526 GPs participated (the Netherlands n = 129, Germany n = 61, England n = 22, Ireland n = 21, Switzerland n = 262, New Zealand n = 31; overall response 19%). Across countries, differences in treatment strategy were observed. GPs from the Netherlands (mean treatment percentage 34%), England (40%), and New Zealand (39%) were less inclined to start treatment than GPs in Germany (73%), Ireland (62%), and Switzerland (52%) (P = 0.05). Overall, GPs were less inclined to start treatment in 85-year-old than in 70-year-old females (pooled odds ratio [OR] 0.74 [95% confidence interval [CI] = 0.63 to 0.87]). Females with a TSH of 15 mU/L were more likely to get treated than those with a TSH of 6 mU/L (pooled OR 9.49 [95% CI = 5.81 to 15.5]). Conclusion: GP treatment strategies of older people with subclinical hypothyroidism vary largely by country and patient characteristics. This variation underlines the need for a new generation of international guidelines based on the outcomes of randomised clinical trials set within primary care

Short communication: Immunoglobulin variation in quarter-milked colostrum

Whereas whole first-milked colostrum IgG1 variation is documented, the IgG1 difference between the quarter mammary glands of dairy animals is unknown. First colostrum was quarter-collected from healthy udders of 8 multiparous dairy cows, all within 3h of parturition. Weight of colostrum produced by individual quarters was determined and a sample of each was frozen for subsequent analysis. Immunoglobulin G1 concentration (mg/mL) was measured by ELISA and total mass (g) was calculated. Standard addition method was used to overcome colostrum matrix effects and validate the standard ELISA measures. Analysis of the data showed that cow and quarter (cow) were significantly different in both concentration and total mass per quarter. Analysis of the mean IgG1 concentration of the front and rear quarters showed that this was not different, but the large variation in individual quarters confounds the analysis. This quarter difference finding indicates that each mammary gland develops a different capacity to accumulate precolostrum IgG1, whereas the circulating hormone concentrations that induce colostrogenesis reach the 4 glands similarly. This finding also shows that the variation in quarter colostrum production is a contributor to the vast variation in first milking colostrum IgG1 content. Finally, the data suggests other factors, such as locally acting autocrine or paracrine, epigenetic, or stochasticity, in gene regulation mechanisms may impinge on colostrogenesis capacity.

Variation in treatment strategies of Swiss general practitioners for subclinical hypothyroidism in older adults.

QUESTIONS UNDER STUDY As the best management of subclinical hypothyroidism is controversial, we aimed to assess variations in treatment strategies depending on different Swiss regions, physician and patient characteristics. METHODS We performed a case-based survey among general practitioners (GPs) in different Swiss regions, which consisted of eight hypothetical cases presenting a female patient with subclinical hypothyroidism and nonspecific complaints differing by age, vitality status and thyroid-stimulating hormone (TSH) concentration. RESULTS A total of 262 GPs participated in the survey. There was considerable variation in the levothyroxine starting dose chosen by GPs, ranging from 25 µg to 100 µg. Across the Swiss regions, GPs in the Bern region were significantly more inclined to treat, with a higher probability of initiating treatment (60%, p = 0.01) and higher mean starting doses (45 µg, p <0.01) compared with the French-speaking region (44%, 36 µg); the Zurich region had intermediate values (52%, 39 µg). We found no association between treatment rate and other physician characteristics. GPs were more reluctant to initiate treatment in 85-year-old than in 70-year-old women (odds ratio [OR] 0.77, 95% confidence interval [CI] 0.63-0.94), and more likely to treat women with a TSH of 15 mU/l than those with a TSH of 6mU/l (OR 8.71, 95% CI 6.21-12.20). CONCLUSIONS There are strong variations in treatment strategies for elderly patients with subclinical hypothyroidism across different Swiss regions, including use of higher starting doses than the recommended 25 µg in the Swiss guidelines, which recommend a starting dose of 25 µg. These variations likely reflect the current uncertainty about the benefits of treatment, which arise from the current lack of evidence from adequately powered clinical trials.

Expansion load: recessive mutations and the role of standing genetic variation

Expanding populations incur a mutation burden – the so-called expansion load. Previous studies of expansion load have focused on codominant mutations. An important consequence of this assumption is that expansion load stems exclusively from the accumulation of new mutations occurring in individuals living at the wave front. Using individual-based simulations, we study here the dynamics of standing genetic variation at the front of expansions, and its consequences on mean fitness if mutations are recessive. We find that deleterious genetic diversity is quickly lost at the front of the expansion, but the loss of deleterious mutations at some loci is compensated by an increase of their frequencies at other loci. The frequency of deleterious homozygotes therefore increases along the expansion axis, whereas the average number of deleterious mutations per individual remains nearly constant across the species range. This reveals two important differences to codominant models: (i) mean fitness at the front of the expansion drops much faster if mutations are recessive, and (ii) mutation load can increase during the expansion even if the total number of deleterious mutations per individual remains constant. We use our model to make predictions about the shape of the site frequency spectrum at the front of range expansion, and about correlations between heterozygosity and fitness in different parts of the species range. Importantly, these predictions provide opportunities to empirically validate our theoretical results. We discuss our findings in the light of recent results on the distribution of deleterious genetic variation across human populations and link them to empirical results on the correlation of heterozygosity and fitness found in many natural range expansions.

Animal Guts as Nonideal Chemical Reactors: Partial Mixing and Axial Variation in Absorption Kinetics

Animal guts have been idealized as axially uniform plug-flow reactors (PFRs) without significant axial mixing or as combinations in series of such PFRs with other reactor types. To relax these often unrealistic assumptions and to provide a means for relaxing others, I approximated an animal gut as a series of n continuously stirred tank reactors (CSTRs) and examined its performance as a Function of n. For the digestion problem of hydrolysis and absorption in series, I suggest as a first approximation that a tubular gut of length L and diameter D comprises n=L/D tanks in series. For n greater than or equal to 10, there is little difference between performance of the nCSTR model and an ideal PFR in the coupled tasks of hydrolysis and absorption. Relatively thinner and longer guts, characteristic of animals feeding on poorer forage, prove more efficient in both conversion and absorption by restricting axial mixing, in the same total volume, they also give a higher rate of absorption. I then asked how a fixed number of absorptive sites should be distributed among the n compartments. Absorption rate generally is maximized when absorbers are concentrated in the hindmost few compartments, but high food quality or suboptimal ingestion rates decrease the advantage of highly concentrated absorbers. This modeling approach connects gut function and structure at multiple scales and can be extended to include other nonideal reactor behaviors observed in real animals.

Adiposity and the perilipin gene: The role of single locus and multilocus variation, obesity-related quantitative traits, and disease-related phenotypes in the Atherosclerosis Risk in Communities (ARIC) study

Obesity is a complex multifactorial disease and is a public health priority. Perilipin coats the surface of lipid droplets in adipocytes and is believed to stabilize these lipid bodies by protecting triglyceride from early lipolysis. This research project evaluated the association between genetic variation within the human perilipin (PLIN) gene and obesity-related quantitative traits and disease-related phenotypes in Non-Hispanic White (NHW) and African American (AA) participants from the Atherosclerosis Risk in Communities (ARIC) Study. ^ Multivariate linear regression, multivariate logistic regression, and Cox proportional hazards models evaluated the association between single gene variants (rs2304794, rs894160, rs8179071, and rs2304795) and multilocus variation (rs894160 and rs2304795) within the PLIN gene and both obesity-related quantitative traits (body weight, body mass index [BMI], waist girth, waist-to-hip ratio [WHR], estimated percent body fat, and plasma total triglycerides) and disease-related phenotypes (prevalent obesity, metabolic syndrome [MetS], prevalent coronary heart disease [CHD], and incident CHD). Single variant analyses were stratified by race and gender within race while multilocus analyses were stratified by race. ^ Single variant analyses revealed that rs2304794 and rs894160 were significantly related to plasma triglyceride levels in all NHWs and NHW women. Among AA women, variant rs8179071 was associated with triglyceride levels and rs2304794 was associated with risk-raising waist circumference (>0.8 in women). The multilocus effects of variants rs894160 and rs2304795 were significantly associated with body weight, waist girth, WHR, estimated percent body fat, class II obesity (BMI ≥ 35 kg/m2), class III obesity (BMI ≥ 35 kg/m2), and risk-raising WHR (>0.9 in men and >0.8 in women) in AAs. Variant rs2304795 was significantly related to prevalent MetS among AA males and prevalent CHD in NHW women; multilocus effects of the PLIN gene were associated with prevalent CHD among NHWs. Rs2304794 was associated with incident CHD in the absence of the MetS among AAs. These findings support the hypothesis that variation within the PLIN gene influences obesity-related traits and disease-related phenotypes. ^ Understanding these effects of the PLIN genotype on the development of obesity can potentially lead to tailored health promotion interventions that are more effective. ^

Identification of genetic variation influencing apolipoprotein E levels: Follow-up of genome-wide linkage scans in the GENOA study

Apolipoprotein E (ApoE) plays a major role in the metabolism of high density and low density lipoproteins (HDL and LDL). Its common protein isoforms (E2, E3, E4) are risk factors for coronary artery disease (CAD) and explain between 16 to 23% of the inter-individual variation in plasma apoE levels. Linkage analysis has been completed for plasma apoE levels in the GENOA study (Genetic Epidemiology Network of Atherosclerosis). After stratification of the population by lipoprotein levels and body mass index (BMI) to create more homogeneity with regard to biological context for apoE levels, Hispanic families showed significant linkage on chromosome 17q for two strata (LOD=2.93 at 104 cM for a low cholesterol group, LOD=3.04 at 111 cM for a low cholesterol, high HDLC group). Replication of 17q linkage was observed for apoB and apoE levels in the unstratified Hispanic and African-American populations, and for apoE levels in African-American families. Replication of this 17q linkage in different populations and strata provides strong support for the presence of gene(s) in this region with significant roles in the determination of inter-individual variation in plasma apoE levels. Through a positional and functional candidate gene approach, ten genes were identified in the 17q linked region, and 62 polymorphisms in these genes were genotyped in the GENOA families. Association analysis was performed with FBAT, GEE, and variance-component based tests followed by conditional linkage analysis. Association studies with partial coverage of TagSNPs in the gene coding for apolipoprotein H (APOH) were performed, and significant results were found for 2 SNPs (APOH_20951 and APOH_05407) in the Hispanic low cholesterol strata accounting for 3.49% of the inter-individual variation in plasma apoE levels. Among the other candidate genes, we identified a haplotype block in the ACE1 gene that contains two major haplotypes associated with apoE levels as well as total cholesterol, apoB and LDLC levels in the unstratified Hispanic population. Identifying genes responsible for the remaining 60% of inter-individual variation in plasma apoE level, will yield new insights into the understanding of genetic interactions involved in the lipid metabolism, and a more precise understanding of the risk factors leading to CAD. ^

(Table 1) Variation in chemical composition of Black Sea ctenophores depending on size

Data of chemical analysis of Black Sea ctenophore Mnemiopsis leidyi indicates that their body contains on average 5.28% carbon, 3.48% nitrogen, 0.11% phosphorus, and 0.03% silicon on dry weight. Mean ratios of the main biogenic elements in ctenophores is C:N=1.4, N:P=10.9, and C:P=32.2. Comparing concentration of the main biogenic elements in the surface layer with their concentrations in ctenophores it is concluded that mass development of M. leidyi has negative effect on the hydrochemical structure of the Black Sea.

(Table 1) Biomass and total standing crop of major wet sedge tundra species at five sites at Alexandra Fiord in 1981 and 2005

The global climate is changing rapidly and Arctic regions are showing responses to recent warming. Responses of tundra ecosystems to climate change have been examined primarily through short-term experimental manipulations, with few studies of long-term ambient change. We investigated changes in above- and belowground biomass of wet sedge tundra to the warming climate of the Canadian High Arctic over the past 25 years. Aboveground standing crop was harvested from five sedge meadow sites and belowground biomass was sampled from one of the sites in the early 1980s and in 2005 using the same methods. Aboveground biomass was on average 158% greater in 2005 than in the early 1980s. The belowground biomass was also much greater in 2005: root biomass increased by 67% and rhizome biomass by 139% since the early 1980s. Dominant species from each functional group (graminoids, shrubs and forbs) showed significant increases in aboveground biomass. Responsive species included the dominant sedge species Carex aquatilis stans, C. membranacea, and Eriophorum angustifolium, as well as the dwarf shrub Salix arctica and the forb Polygonum viviparum. However, diversity measures were not different between the sample years. The greater biomass correlated strongly with increased annual and summer temperatures over the same time period, and was significantly greater than the annual variation in biomass measured in 1980-1983. Increased decomposition and mineralization rates, stimulated by warmer soils, were likely a major cause of the elevated productivity, as no differences in the mass of litter were found between sample periods. Our results are corroborated by published short-term experimental studies, conducted in other wet sedge tundra communities which link warming and fertilization with elevated decomposition, mineralization and tundra productivity. We believe that this is the first study to show responses in High Arctic wet sedge tundra to recent climate change.

(Table 1) Sulfur isotopes, total sulfur, and degree of oxidation of basalt samples from DSDP Holes 69-504B and 70-504B

Whole-rock basalt samples from the upper half of Deep Sea Drilling Project Hole 504B have oxygen-isotope compositions typical of mid-ocean-ridge basalts which have experienced a moderate degree of low-temperature alteration by sea water. By contrast, d18O values in the lower half of the hole correspond to basalts which have experienced almost no detectable oxygen-isotope alteration. These observations suggest that the overall water/rock ratio was lower in the lower half of the drilled crust. A correlation between d18O values and 87Sr/86Sr ratios suggests that the water/rock ratio, rather than temperature variation, was the main factor determining basalt d18O values. Hydrogen-isotope data appear to be consistent with a low water/rock ratio in the lower part of the crust.

Selective mortality associated with variation in CO2 tolerance in a marine fish

Predicted future CO2 levels can affect reproduction, growth, and behaviour of many marine organisms. However, the capacity of species to adapt to predicted changes in ocean chemistry is largely unknown. We used a unique field-based experiment to test for differential survival associated with variation in CO2 tolerance in a wild population of coral-reef fishes. Juvenile damselfish exhibited variation in their response to elevated (700 µatm) CO2 when tested in the laboratory and this influenced their behaviour and risk of mortality in the wild. Individuals that were sensitive to elevated CO2 were more active and move further from shelter in natural coral reef habitat and, as a result, mortality from predation was significantly higher compared with individuals from the same treatment that were tolerant of elevated CO2. If individual variation in CO2 tolerance is heritable, this selection of phenotypes tolerant to elevated CO2 could potentially help mitigate the effects of ocean acidification.