Is a specific drinking pattern a consistent feature of the Mediterranean diet in Spain in the XXI century?

Background and aimOver the last 50 years, people in Spain have increasingly been eating their main meal away from home and are shifting from the typical Mediterranean diet (MD). In addition, wine consumption has decreased whereas beer intake has risen. Consequently, it is uncertain if the Mediterranean drinking pattern (MDP; moderate alcohol intake mainly from wine and during meals) is a habitual feature of the MD today.Methods and resultsCross-sectional study conducted from 2008 to 2010 among 8894 individuals representative of the Spanish population aged 18–64 years. Consumption of alcoholic beverages and food was collected with a validated diet history. Accordance with the MD was defined as a score ≥8 on the Mediterranean Diet Adherence Screener (MEDAS) or ≥5 in the Trichopoulou index (after excluding alcohol intake from both indices). Among individuals with MEDAS-based MD accordance, only 17.1% had a MDP. After adjustment for potential confounders, this drinking pattern showed a weak association with higher MD accordance (odds ratio (OR) 1.32; 95% confidence interval (CI) 1.12–1.57). Only 14.7% of those with Trichopoulou-based MD accordance had a MDP; this pattern showed an even weaker association with higher MD accordance (OR 1.17; 95% CI 1.01–1.36). Similar results were obtained when this drinking pattern was redefined to include persons who drank wine with or outside of meals, as well as those who were primarily beer drinkers.ConclusionsThe MDP is not a habitual feature of the MD in the early XXI century in Spain.     

Atenolol as a comparator in outcome trials in hypertension: a correct choice in the past, but not for the future?

OBJECTIVE: Twelve years after the design of the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study, which showed superiority of losartan- vs atenolol-based therapy for cardiovascular outcomes, we reviewed the literature for the effect of beta-blockers compared with initial placebo or no treatment on reduction of cardiovascular events to re-evaluate atenolol as the comparator in the LIFE study. METHODS: A literature search was conducted in September 2006 for randomized, controlled trials comparing beta-blockers with/without diuretics with placebo or no treatment in patients with hypertension and without recent cardiovascular morbidity. We calculated risk reductions for combined cardiovascular events, cardiovascular death, stroke, and coronary heart disease from groups of trials using atenolol first-line and all beta-blockers first-line. RESULTS: Five studies met the criteria. Significant risk reductions for cardiovascular events and stroke occurred in groups receiving treatment with atenolol or all beta-blockers, and for cardiovascular death in the all beta-blocker analysis. In meta-analysis of beta-blocker vs placebo or no treatment trials, risk reductions were 19% for combined cardiovascular events (95% CI 0.73-0.91, p<0.001), 15% for cardiovascular death (0.73-0.99, p = 0.037), 32% for stroke (0.57-0.82, p<0.001), and 10% for coronary heart disease (0.78-1.04, p = 0.146). CONCLUSIONS: Beta-blocker-based antihypertensive therapy significantly reduces cardiovascular risk in hypertension compared with placebo or no treatment. Atenolol was an appropriate comparator in the LIFE study. As the results of the LIFE study and other recent trials demonstrate superiority of newer agents over atenolol, this agent is not an appropriate reference drug for future trials of cardiovascular risk in hypertension.     

Indeterminate colitis: a review of the concept--what's in a name?

The precise diagnosis of colitis cannot always be established with the available diagnostic tools. The subgroup of patients with an uncertain diagnosis has been classified as "indeterminate colitis" (IC). The definition of "indeterminate," however, has changed over the years. Originally, IC was proposed by pathologists for colectomy specimens, usually from patients operated on for severe colitis, showing overlapping features of ulcerative colitis (UC) and Crohn's disease (CD). Later, the same terminology was used for patients showing no clear clinical, endoscopic, histologic, and other features allowing a diagnosis of either UC or CD. Therefore, it is difficult to compare different studies. An International Organization of Inflammatory Bowel Diseases (IOIBD) working party confirmed 1) the ambiguous nature of the term, and 2) proposes an updated classification for the category of patients with an unclear diagnosis. According to this, the term IBD unclassified (IBDU) is confirmed, as suggested by the Montreal Working Party 2005 for patients with clinically chronic colitis, that clearly have IBD but when definitive features of CD or UC are absent. In resected specimens the term "colitis of uncertain type or etiology" (CUTE) is preferred. It is accepted that most of the time this may have a prefix, such as severe, chronic. The classification of IBD varies when based only on biopsies rather than on a colectomy specimen. The vast majority of these have severe colitis. For those that cannot bear to abandon the highly ambiguous term IC, if it is used at all, this is where it can be used parenthetically.     

Is there a role for fibrates in the management of dyslipidemia in the metabolic syndrome?

The outcomes of fibrate trials have varied: positive with gemfibrozil in the primary prevention Helsinki Heart Study and the secondary prevention VA-HIT trial; positive with reservations in the primary prevention WHO trial (clofibrate); and mixed with bezafibrate in the secondary prevention BIP study and with fenofibrate in the combined primary and secondary prevention FIELD study. Overall, the mixed results, combined with potential for adverse effects when given in combination with statins, have limited the use of these fibrates as cardioprotective agents. However, post hoc analyses of several of the fibrate studies have shown that people with features of the metabolic syndrome, particularly overweight people with high plasma triglyceride levels and low levels of HDL cholesterol, derive a disproportionately large reduction in cardiovascular events when treated with these agents. Thus, there is a strong case for the use of a fibrate to reduce the cardiovascular risk in overweight people with high triglyceride and low HDL-C. However, it should be noted that such people also have their cardiovascular risk reduced by statin therapy. It remains to be determined whether the combination of a fibrate plus statin reduces the risk beyond that achieved with a statin alone.     

Does the consent of the patients have a role to play in formulating a treatment policy?

Zambia recently changed its treatment policy for malaria from the failing chloroquine to the more effective artemisinin combination therapy (ACT). A study was conducted to find out if the community accepted the new treatment policy, as a prediction of its success. Following high levels of acceptability, it was not surprising to see high levels of compliance and subsequent reduction in cases of severe malaria and deaths.     

Greenhouse?icehouse transition in the Late Ordovician marks a step change in extinction regime in the marine plankton

Two distinct regimes of extinction dynamic are present in the major marine zooplankton group, the graptolites, during the Ordovician and Silurian periods (486−418 Ma). In conditions of “background” extinction, which dominated in the Ordovician, taxonomic evolutionary rates were relatively low and the probability of extinction was highest among newly evolved species (“background extinction mode”). A sharp change in extinction regime in the Late Ordovician marked the onset of repeated severe spikes in the extinction rate curve; evolutionary turnover increased greatly in the Silurian, and the extinction mode changed to include extinction that was independent of species age (“high-extinction mode”). This change coincides with a change in global climate, from greenhouse to icehouse conditions. During the most extreme episode of extinction, the Late Ordovician Mass Extinction, old species were selectively removed (“mass extinction mode”). Our analysis indicates that selective regimes in the Paleozoic ocean plankton switched rapidly (generally in <0.5 My) from one mode to another in response to environmental change, even when restoration of the full ecosystem was much slower (several million years). The patterns observed are not a simple consequence of geographic range effects or of taxonomic changes from Ordovician to Silurian. Our results suggest that the dominant primary controls on extinction throughout the lifespan of this clade were abiotic (environmental), probably mediated by the microphytoplankton.The importance of the marine plankton in both the carbon cycle and in the food web that supports the diversity of marine life is undisputed. However, the evolutionary dynamics of planktic species and the factors controlling their diversity and evolutionary turnover are still poorly known (1, 2). This is particularly so for the Paleozoic, where problems of preservation and sampling bias, and poor time resolution, have precluded detailed analysis. How does the marine plankton respond to environmental perturbations arising from climate change over geological time? How does background extinction differ from episodic and mass extinction in the pelagic realm? Is the risk of plankton species extinction dependent on the amount of time since the species originated (3)? These questions have important implications for macroevolutionary process, stability of marine ecosystems, and modern biodiversity conservation (3–5). Here, using a new global data set of unparalleled temporal resolution, we attempt to answer these questions.The graptoloid clade (order Graptoloidea) constituted the main component of the early Paleozoic macrozooplankton from the beginning of the Ordovician to the Early Devonian (6). Graptoloids were colonial filter-feeding protochordates, generally ranging from a few millimeteres up to ∼200 mm in maximum dimension, which lived suspended in the water column in a range of depth zones. They have been used extensively for correlation and zonation (7–10), and the stratigraphic distributions of species are well documented. Thus, their observed stratigraphic ranges commonly are inferred to be good approximations of their true ranges in time, and empirical graptoloid range data have been used as examples of, or tests for, macroevolutionary rates (3, 4, 11–13). Like most of the marine macroplankton, their evolutionary dynamics are interpreted to have depended closely on those of the microphytoplankton and bacterioplankton (13–16), the primary producers in the food web and which, in the modern oceans, are sensitive indicators of oceanic circulation, nutrient flux, and global climate (1, 17); in addition, they depended on physical properties of the water mass such as temperature and chemistry.Most previous studies of taxonomic survivorship using the fossil record have been limited by the relatively coarse time resolution of the analyses, generally no better than 7- to 11-My time bins (5, 18–20). We use the constrained optimization (CONOP) global graptolite composite developed by Sadler et al. (10) that has been calibrated directly by radiometric dating and provides the basis for the Ordovician and Silurian global time scales (21). This composite has been constructed from >18,000 local records of the stratigraphic ranges of 2,045 species in 518 published stratigraphic sections distributed globally; it resolves 2,031 discrete temporal levels through the 74-My span of the graptoloid clade, yielding a mean resolution of 37 kya between levels (13). The first- and last-appearance events of all species in all sections have been used to optimally order, and proportionally space in time, the earliest first appearance and latest last appearance of each taxon using a simulated annealing optimization heuristic (10, 22) (see SI Text, Construction of the Global Composite Sequence). The raw extinction and origination rates of the 2,045 graptolite species have been smoothed with a 0.25-My moving window centered at each resolved level, providing, in effect, instantaneous rate curves, each with 2,031 control points. Extinction and origination rates, and the derivative measures such as faunal turnover (origination + extinction), have thus been estimated with a precision that is orders of magnitude better than in most previous studies of global extinction. Uncertainty bounds have been estimated by bootstrapping. Our data set spans the entire lifespan of the graptoloid clade; the uppermost part, in the earliest Devonian, is omitted from further analysis because species diversity is very low and analytical uncertainty becomes unacceptably large. For similar reasons, the basal 4 My of the clade history is not included in the analysis.To test if extinction depends on species age, we use taxon survivorship of birth cohorts (23) (Fig. 1A) and AIC-based model selection (Figs. S1–S6). Birth cohorts are comprised of all species originating in a short interval of time; we use time bins of 0.25 million years, 0.5 million years, and 1 million years. A survivorship curve, produced by plotting the age of species in a cohort against the proportion of species still extant as the cohort decays over time, is exponential when the probability of extinction is uniform through the life of the cohort. In a semilog plot, this results in a linear distribution (3) (Fig. 1A, β = 1). Significant deviations from an exponential relationship indicate age dependency of extinction and yield curves in semilog space that are either convex up or concave up, which are approximated by Weibull distributions with shape parameters (β-values) greater than or less than unity, respectively (24). A concave-upward curve indicates a decreasing extinction probability with species age (Fig. 1A, β < 1). A convex-upward curve indicates increasing extinction probability with taxon age (Fig. 1A, β > 1). To produce Fig. 2C, on which each cohort is represented by a single point plotted at its β-value, we varied the cohort durations and start times in successive iterations using time bin durations of 0.25 million years, 0.5 million years, and 1 million years, and offsets of bin start equal to one-fifth of the bin duration. This produces, in effect, a series of moving windows of different duration and boundary ages, and, for this reason, points shown are not statistically independent of each other. This approach, however, maps out patterns of survivorship that are robust to arbitrary variations in cohort size and start time, and robust results are indicated by clustering of points in the figure. In contrast, isolated points in the plot are idiosyncratic to a particular combination of bin duration and starting time, and are ignored during subsequent interpretation. Gaps in coverage indicate intervals where species richness is low and cohorts fail to meet the qualifying threshold of at least 20 taxa.Open in a separate windowFig. 1.(A) Semilog plot showing idealized taxon survivorship curves for a cohort commencing at 0 My; β = 1, linear survivorship curve indicating exponential decay rate (constant extinction probability); β < 1, decreasing decay rate, extinction probability decreases with taxon age; β > 1, increasing decay rate, extinction probability increases with taxon age). Black dots indicate median cohort age in each curve. (B−D) General age structure curves for all species (B) and for all Ordovician and all Silurian species (C and, detail, D). The life expectancy of a Silurian species is half that of an Ordovician species.Open in a separate windowFig. 2.(A) Graptoloid standing species richness, main families shown. The white line is level-by-level generic richness. (B) Extinction rate (extinctions per lineage-million-years), 0.25-My moving window, centered at each level in the composite. The band represents ±1 SE from bootstrap means (1,000 iterations) of median values for each 0.25-My bin. The main extinction episodes, those exceeding the 75th percentile for each period (dashed lines) are: La2bEE, Lancefieldian 2; Da3EE, Darriwilian 3; Da4EE, Darriwilian 4; EaEE, Eastonian; BoEE, Bolindian; HiEE, Hirnantian; RhuEE, Rhuddanian; AerEE, Aeronian; ShEE, Sheinwoodian; HomEE, Homerian; Lu1EE, Ludfordian (early); Lu2EE, Ludfordian (late); and PriEE, Pridolian. (C) Weibull shape (β) value for each cohort survivorship curve is plotted at the median age, in geological time, of the last appearances of its constituent species. Red points, Weibull model preferred; green points, exponential model preferred; the darker the tone, the greater the AIC weight of the preferred model. Age bands with clusters of green points indicate fields with cohorts in which extinction is not dependent on species age; 498 points are shown.Open in a separate windowFig. S1.Examples of model fits for individual cohorts taken from our data. In all cases, the green curve is the best-fit exponential distribution, the red curve is the best-fit Weibull distribution, and the heavier line indicates the favored fit. “Weight” indicates Akaike weight of the best-fitting model. (A) Cohort for which an exponential fit is favored. (B) Cohort for which there is no preferred fit. (C) Cohort for which a Weibull fit, with shape parameter β > 1, is favored. (D) Cohort for which a Weibull fit, with β < 1, is favored.Open in a separate windowFig. S6.Test of the impact of uneven distribution of first appearances. Time series of fitted Weibull shape parameters (β) for the graptolite data, superimposed on gray-scale map of fitted β from data in which observed durations have been randomized with respect to observed first-appearance ages; density of gray shading is proportional to density of points. Dashed lines are the one-tailed, 95% and 99% quantiles on the distribution of the randomized data; fluctuations in the levels of these lines are a consequence of uneven distribution of first-appearance ages in time. See Fig. 2 for explanation of symbol colors, etc.     

Is there a role for estrogen in follicular maturation in the primate?

The present study focusses attention on the effects of blocking estrogen synthesis, during follicular phase, on follicular maturation in the adult female bonnet monkey (Macaca radiata). Administration of cycling females (n=4) with an aromatase inhibitor CGS 16949A (Al) by Alzet mini-pump (2,5 mg/day) from day 3 of cycle resulted in significant reduction in basal (by 53%) and surge levels of estrogen (by 70%) but this had no effect on follicular maturation, ovulation and luteal function as assessed by serum hormone profiles as well as laparotomy. This lack of need for estrogen for completion of follicular maturation process was confirmed by administering cycling monkeys hFSH (25 IU/day) from day 3 till day 8 of the cycle along with (5 mg Al/day) or without Al (n=3/group). Administration of AI resulted in suppression of FSH induced increase in serum estrogen (by 100%) and elevation in circulating androstenedione. Aromatase inhibitor treatment had no effect on either the number of follicles developed or their size relative to control. Testing the ability of both granulosa and thecal cells, removed on day 9 of treatment cycle, to respond to gonadotropinsin vitro showed no change indicating that cellular development and maturation of follicular cells had occurred normally. It is concluded that follicular maturation in the primate can occur even when increase in estrogen synthesis is blocked.     

Thrombocytopenia and erythrocytosis in mice with a mutation in the gene encoding the hemoglobin β minor chain

Diverse mutations in the genes encoding hemoglobin (Hb) have been characterized in human disease. We describe here a mutation in the mouse Hbb-b2 gene, denoted Plt12, that precisely mimics the human hemoglobin Hotel Dieu variant. The mutation results in increased affinity of Hb for oxygen and Plt12 mutant mice exhibited reduced partial pressure of O(2) in the blood, accompanied by erythrocytosis characterized by elevated erythropoietin levels and splenomegaly with excess erythropoiesis. Most homozygous Hbb-b2(Plt12/Plt12) mice succumbed to early lethality associated with emphysema, cardiac abnormalities, and liver degeneration. Survivors displayed a marked thrombocytopenia without significant deficiencies in the numbers of megakaryocytes or megakaryocyte progenitor cells. The lifespan of platelets in the circulation of Hbb-b2(Plt12/Plt12) mice was normal, and splenectomy did not correct the thrombocytopenia, suggesting that increased sequestration was unlikely to be a major contributor. These data, together with the observation that megakaryocytes in Hbb-b2(Plt12/Plt12) mice appeared smaller and deficient in cytoplasm, support a model in which hypoxia causes thrombocytopenia as a consequence of an inability of megakaryocytes, once formed, to properly mature and produce sufficient platelets. The Plt12 mouse is a model of high O(2)-affinity hemoglobinopathy and provides insights into hematopoiesis under conditions of chronic hypoxia.