Prophylactic effect of recombinant factor VIIa in factor VII deficient patients

Inherited factor VII (FVII) deficiency is a rare autosomal recessive disorder associated with a bleeding tendency. We describe three patients with congenital FVII deficiency who have been treated with activated recombinant factor VII (rVIIa). Two patients had novel mutations and were treated prophylactically with 1.2 mg rVIIa two to three times a week. Patients 1 and 2 had a severe bleeding tendency. The frequency and severity of bleeding decreased by treatment with rVIIa compared with similar treatment with plasma-derived FVII. The third patient with a moderate bleeding phenotype was treated on demand and showed no change in the frequency of bleeding upon treatment with rVIIa or plasma products. The beneficial effect of rVIIa cannot be explained by the rVIIa half-lives. Pharmacokinetical analysis showed rVIIa activity half-lives of 35, 50 and 54 min for patients 1, 2 and 3, respectively. In conclusion, prophylactic treatment of FVII deficient patients with rVIIa appears to be applicable, safe and successful, although the mechanism of action remains to be elucidated.     

Factors associated with preservation of C-peptide levels at the diagnosis of type 1 diabetes

Aims

The level of C-peptide can identify individuals most likely to respond to immune interventions carried out to prevent pancreatic β-cell damage.The aim of the study was to evaluate factors associated with C-peptide levels at type 1 diabetes (T1D) diagnosis.

Characterization of mutations in ATP8B1 associated with hereditary cholestasis

Progressive familial intrahepatic cholestasis (PFIC) and benign recurrent intrahepatic cholestasis (BRIC) are clinically distinct hereditary disorders. PFIC patients suffer from chronic cholestasis and develop liver fibrosis. BRIC patients experience intermittent attacks of cholestasis that resolve spontaneously. Mutations in ATP8B1 (previously FIC1) may result in PFIC or BRIC. We report the genomic organization of ATP8B1 and mutation analyses of 180 families with PFIC or BRIC that identified 54 distinct disease mutations, including 10 mutations predicted to disrupt splicing, 6 nonsense mutations, 11 small insertion or deletion mutations predicted to induce frameshifts, 1 large genomic deletion, 2 small inframe deletions, and 24 missense mutations. Most mutations are rare, occurring in 1-3 families, or are limited to specific populations. Many patients are compound heterozygous for 2 mutations. Mutation type or location correlates overall with clinical severity: missense mutations are more common in BRIC (58% vs. 38% in PFIC), while nonsense, frameshifting, and large deletion mutations are more common in PFIC (41% vs. 16% in BRIC). Some mutations, however, lead to a wide range of phenotypes, from PFIC to BRIC or even no clinical disease. ATP8B1 mutations were detected in 30% and 41%, respectively, of the PFIC and BRIC patients screened.     

Functional trait space and the latitudinal diversity gradient

The processes causing the latitudinal gradient in species richness remain elusive. Ecological theories for the origin of biodiversity gradients, such as competitive exclusion, neutral dynamics, and environmental filtering, make predictions for how functional diversity should vary at the alpha (within local assemblages), beta (among assemblages), and gamma (regional pool) scales. We test these predictions by quantifying hypervolumes constructed from functional traits representing major axes of plant strategy variation (specific leaf area, plant height, and seed mass) in tree assemblages spanning the temperate and tropical New World. Alpha-scale trait volume decreases with absolute latitude and is often lower than sampling expectation, consistent with environmental filtering theory. Beta-scale overlap decays with geographic distance fastest in the temperate zone, again consistent with environmental filtering theory. In contrast, gamma-scale trait space shows a hump-shaped relationship with absolute latitude, consistent with no theory. Furthermore, the overall temperate trait hypervolume was larger than the overall tropical hypervolume, indicating that the temperate zone permits a wider range of trait combinations or that niche packing is stronger in the tropical zone. Although there are limitations in the data, our analyses suggest that multiple processes have shaped trait diversity in trees, reflecting no consistent support for any one theory.Species richness increases toward the equator (1, 2) in major clades of both extant and extinct species of plants and animals (3, 4). The generality of the pattern hints at a correspondingly general explanation, yet the latitudinal gradient in species richness remains one of ecology’s greatest unsolved puzzles. Long-running debates over the causes of the latitudinal gradient of species richness have focused on ecological, evolutionary, and geographic explanations (5–10). Although there has been some progress (11), it is also increasingly clear that there are numerous obstacles to understanding the primary drivers of the latitudinal gradient, including an ever-increasing number of hypotheses (12, 13), challenges in clearly separating their interdependencies (14, 15), and difficulties in rigorously falsifying their assumptions and predictions (16).More powerful tests of biodiversity theories need to move beyond species richness and instead explicitly focus on the mechanisms generating the gradient, by recasting the theories in terms of other measures of diversity, such as functional diversity (17–19). For example, explanations that assume species richness is limited by resource availability have often focused on the strength of species interactions, life history differences, and environmental constraints on how species pack into niche space (20). Evolutionary hypotheses have focused on differences in diversification rates, as well as the influence of species interactions on diversification rates (9). These interaction-based explanations implicitly refer to the degree of ecological differentiation among species, and therefore to trait dispersion within clades and assemblages, suggesting that patterns of functional diversity may provide a more powerful test of theory than taxonomic richness (21).A particularly important concept that unifies many ecological and evolutionary theories is the concept of the Hutchinsonian multidimensional niche (22). Hutchinsonian niches can be quantified by assessing the functional trait hypervolumes that characterize phenotypic space occupied by a set of species. Quantifying the volume, overlap, and packing of functional trait space at different spatial scales enables inferences about how differing ecological and evolutionary processes structure functional diversity and ecological strategies (23, 24).Here, we recast several contrasting hypotheses for the latitudinal gradient in terms of functional trait space. We focus on the proximate ecological mechanisms that ultimately can influence evolutionary processes. We quantify tree functional trait space across latitude at three spatial scales: (i) within assemblages (alpha), (ii) among assemblages (beta), and (iii) among biomes (gamma). For alpha and beta analyses, we use tree species assemblage data from 620 standardized 0.1-ha forest plots (Fig. 1A); for gamma analyses, we calculated the latitudinal range distributions for 520 New World tree species where we had sufficient data on geographic distribution and functional traits. In total, across all analyses, we used paired geographic occurrence data with trait data for 6,839 tree species.Open in a separate windowFig. 1.(A) Spatial distribution of the 620 0.1-ha forest plots used in this study. Plots are colored by richness. Plots cover most of the New World forested climate space (Fig. S1). (B) Relationship between absolute latitude and alpha hypervolume for tropical (red triangles) and temperate (blue pluses) plots. (C) Alpha hypervolume as a function of effective species richness (number of species with full trait coverage). We compare this hypervolume with a null expectation based on sampling the same number of species from the regional pool (median, dark gray line; 90% quantile range, light gray envelope).We primarily measured hypervolumes for three central traits hypothesized to characterize major axes of ecological strategy variation (25): specific leaf area (SLA), maximum height, and seed mass. SLA represents the tradeoff between leaf longevity and maximum photosynthetic rate (26); height is important for light competition and dispersal (27); and seed mass represents tradeoffs between fecundity, dispersal, and seedling survival (27). Although whole-plant resource strategies can be more fully assessed in higher dimensions (28, 29), we focus on these traits because of data availability (Materials and Methods). We use a hypervolume algorithm for calculating the volume and overlap of trait space (30) (Materials and Methods). All hypervolumes are reported in units of SDs of centered and scaled log-transformed trait values, raised to the power of the number of trait dimensions used.At all scales, our overall results and conclusions are similar (i) with and without gap-filling missing data, (ii) if we use convex hulls instead of hypervolumes to calculate trait spaces, and (iii) if we include additional trait axes. Additional details are given in Figs. S2–S7.     

Glycosylated hemoglobin and functional decline in community-dwelling nursing home-eligible elderly adults with diabetes mellitus

Objectives

To determine whether glycosylated hemoglobin (HbA1c) levels predict functional decline in older adults.

Design

Longitudinal cohort study.

Participants

Community‐dwelling, nursing home (NH)‐eligible individuals with diabetes mellitus enrolled at On Lok between October 2002 and December 2008 (367 participants, 1,579 HbA1c measurements).

Setting

On Lok Lifeways, the original model for Programs of All‐Inclusive Care for the Elderly.

Measurements

The outcomes were functional decline or death at 2 years. The primary predictor was HbA1c. Age, sex, race and ethnicity, baseline function, comorbid conditions, length of time enrolled at On Lok, insulin use, and clustering of HbA1c within participants were adjusted for with mixed‐effects Poisson regression.

Results

Mean age was 80, and 185 participants (50%) were taking insulin. Sixty‐three percent of participants experienced functional decline, and 75% experienced death or functional decline during the study period. At 2 years, higher HbA1c was associated with less functional decline or death (P for trend = .006). Accounting for clustering and confounding factors, HbA1c of 8.0% to 8.9% was associated with a lower likelihood (relative risk = 0.88, 95% confidence interval = 0.79–0.99) of functional decline or death than HbA1c of 7.0% to 7.9%.

Conclusion

In community‐dwelling, NH‐eligible individuals with diabetes mellitus, HbA1c of 8.0% to 8.9% is associated with better functional outcomes at 2 years than HbA1c of 7.0% to 7.9%, suggesting that the current American Geriatrics Society guideline recommending a HbA1c target of 8.0% or less for older adults with limited life expectancy may be lower than necessary to maintain function.     

The role of stem cells in the treatment of diabetic foot ulcers

Metformin is a cornerstone in the treatment of type 2 diabetes. Although its mechanism of action is not well understood, there is new evidence about its possible role in cancer. A Pubmed search from 1990 to 2011 was done using the terms metformin, cancer, mechanism of action, diabetes treatment and prevention. We found more than one thousand articles and reviewed studies that had assessed the efficacy of metformin in treatment and prevention of type 2 diabetes and its mechanisms of actions, as well as articles on its antitumoral effects. We found that the United Kingdom Prospective Diabetes Study and the Diabetes Prevention Program have demonstrated the efficacy of metformin in terms of treatment and prevention of type 2 diabetes; metformin is safe, cost effective and remains the first line of diabetes therapy with diet and exercise. The mechanisms of action include a decrease of hepatic insulin resistance, change in bile acids metabolism, incretins release and decreased amyloid deposits. The AMP-activated protein kinase seems to be an important target for these effects. Epidemiological retrospective studies point out a possible association between metformin and decreased cancer risk, data supported by in vitro and animal studies. These data should trigger randomized controlled trials to prove or disprove this additional benefit of metformin.