Mutations in LRP5 or FZD4 underlie the common familial exudative vitreoretinopathy locus on chromosome 11q

Familial exudative vitreoretinopathy (FEVR) is an inherited blinding disorder of the retinal vascular system. Autosomal dominant FEVR is genetically heterogeneous, but its principal locus, EVR1, is on chromosome 11q13-q23. The gene encoding the Wnt receptor frizzled-4 (FZD4) was recently reported to be the EVR1 gene, but our mutation screen revealed fewer patients harboring mutations than expected. Here, we describe mutations in a second gene at the EVR1 locus, low-density-lipoprotein receptor-related protein 5 (LRP5), a Wnt coreceptor. This finding further underlines the significance of Wnt signaling in the vascularization of the eye and highlights the potential dangers of using multiple families to refine genetic intervals in gene-identification studies.     

A PERSPECTIVE ON PHOTOSYNTHESIS IN THE OLIGOTROPHIC OCEANS: HYPOTHESES CONCERNING ALTERNATE ROUTES OF ELECTRON FLOW1

Many regions of the open, oligotrophic oceans are depleted of nutrients, especially nitrogen and iron. The biogenesis and the functioning of the photosynthetic apparatus may be specialized and tailored to the various marine habitats. In this minireview, we discuss some new findings with respect to photosynthetic processes in the oceans. We focus on findings that suggest that some cyanobacteria may route electrons derived from the splitting of H₂O to the reduction of O₂ and H⁺ in a water‐to‐water cycle, and that other cyanobacteria that fix nitrogen during the day are likely missing PSII and enzymes involved in the fixation of inorganic carbon. Both of these proposed “variant” forms of photosynthetic electron flow provide new insights into ways in which marine phytoplankton satisfy their energetic and nutritive requirements.     

Innate immunity in plants: a continuum of layered defenses

Plant responses to pathogenic invaders result from recognition of nonself elicitors. Host surveillance proteins activate distinct signaling pathways that induce partially overlapping defensive responses. Pathogen virulence is promoted by inhibition of these pathways. This evolutionary struggle has produced plant immune systems that rely on a continuum of layered defenses.     

Large scale international replication and meta-analysis study confirms association of the 15q14 locus with myopia. The CREAM consortium

Myopia is a complex genetic disorder and a common cause of visual impairment among working age adults. Genome-wide association studies have identified susceptibility loci on chromosomes 15q14 and 15q25 in Caucasian populations of European ancestry. Here, we present a confirmation and meta-analysis study in which we assessed whether these two loci are also associated with myopia in other populations. The study population comprised 31 cohorts from the Consortium of Refractive Error and Myopia (CREAM) representing 4 different continents with 55,177 individuals; 42,845 Caucasians and 12,332 Asians. We performed a meta-analysis of 14 single nucleotide polymorphisms (SNPs) on 15q14 and 5 SNPs on 15q25 using linear regression analysis with spherical equivalent as a quantitative outcome, adjusted for age and sex. We calculated the odds ratio (OR) of myopia versus hyperopia for carriers of the top-SNP alleles using a fixed effects meta-analysis. At locus 15q14, all SNPs were significantly replicated, with the lowest P value 3.87?×?10(-12) for SNP rs634990 in Caucasians, and 9.65?×?10(-4) for rs8032019 in Asians. The overall meta-analysis provided P value 9.20?×?10(-23) for the top SNP rs634990. The risk of myopia versus hyperopia was OR 1.88 (95?% CI 1.64, 2.16, P?相似文献   

The p53 Codon 72 PRO/PRO Genotype May Be Associated with Initial Central Visual Field Defects in Caucasians with Primary Open Angle Glaucoma

Background

Loss of vision in glaucoma is due to apoptotic retinal ganglion cell loss. While p53 modulates apoptosis, gene association studies between p53 variants and glaucoma have been inconsistent. In this study we evaluate the association between a p53 variant functionally known to influence apoptosis (codon 72 Pro/Arg) and the subset of primary open angle glaucoma (POAG) patients with early loss of central visual field.

Methods

Genotypes for the p53 codon 72 polymorphism (Pro/Arg) were obtained for 264 POAG patients and 400 controls from the U.S. and in replication studies for 308 POAG patients and 178 controls from Australia (GIST). The glaucoma patients were divided into two groups according to location of initial visual field defect (either paracentral or peripheral). All cases and controls were Caucasian with European ancestry.

Results

The p53-PRO/PRO genotype was more frequent in the U.S. POAG patients with early visual field defects in the paracentral regions compared with those in the peripheral regions or control group (p = 2.7×10⁻⁵). We replicated this finding in the GIST cohort (p  = 7.3×10⁻³, and in the pooled sample (p = 6.6×10⁻⁷) and in a meta-analysis of both the US and GIST datasets (1.3×10⁻⁶, OR 2.17 (1.58–2.98 for the PRO allele).

Conclusions

These results suggest that the p53 codon 72 PRO/PRO genotype is potentially associated with early paracentral visual field defects in primary open-angle glaucoma patients.     

Patent and Exclusivity Status of Essential Medicines for Non-Communicable Disease

Objective

The threat of non-communicable diseases (“NCDs”) is increasingly becoming a global health crisis and are pervasive in high, middle, and low-income populations resulting in an estimated 36 million deaths per year. There is a need to assess intellectual property rights (“IPRs”) that may impede generic production and availability and affordability to essential NCD medicines.

Methods

Using the data sources listed below, the study design systematically eliminated NCD drugs that had no patent/exclusivity provisions on API, dosage, or administration route. The first step identified essential medicines that treat certain high disease burden NCDs. A second step examined the patent and exclusivity status of active ingredient, dosage and listed route of administration using exclusion criteria outlined in this study.

Materials

We examined the patent and exclusivity status of medicines listed in the World Health Organization’s (“WHO”) Model List of Essential Drugs (Medicines) (“MLEM”) and other WHO sources for drugs treating certain NCDs. i.e., cardiovascular and respiratory disease, cancers, and diabetes. We utilized the USA Food and Drug Administration Orange Book and the USA Patent and Trademark Office databases as references given the predominant number of medicines registered in the USA.

Results

Of the 359 MLEM medicines identified, 22% (79/359) address targeted NCDs. Of these 79, only eight required in-depth patent or exclusivity assessment. Upon further review, no NCD MLEM medicines had study patent or exclusivity protection for reviewed criteria.

Conclusions

We find that ensuring availability and affordability of potential generic formulations of NCD MLEM medicines appears to be more complex than the presence of IPRs with API, dosage, or administration patent or exclusivity protection. Hence, more sophisticated analysis of NCD barriers to generic availability and affordability should be conducted in order to ensure equitable access to global populations for these essential medicines.     

Predicting cross-reactive immunological material (CRIM) status in Pompe disease using GAA mutations: lessons learned from 10 years of clinical laboratory testing experience

Enzyme replacement therapy (ERT) for Pompe disease using recombinant acid alpha-glucosidase (rhGAA) has resulted in increased survival although the clinical response is variable. Cross-reactive immunological material (CRIM)-negative status has been recognized as a poor prognostic factor. CRIM-negative patients make no GAA protein and develop sustained high antibody titers to ERT that render the treatment ineffective. Antibody titers are generally low for the majority of CRIM-positive patients and there is typically a better clinical outcome. Because immunomodulation has been found to be most effective in CRIM-negative patients prior to, or shortly after, initiation of ERT, knowledge of CRIM status is important before ERT is begun. We have analyzed 243 patients with infantile Pompe disease using a Western blot method for determining CRIM status and using cultured skin fibroblasts. Sixty-one out of 243 (25.1%) patients tested from various ethnic backgrounds were found to be CRIM-negative. We then correlated the CRIM results with GAA gene mutations where available (52 CRIM-negative and 88 CRIM-positive patients). We found that, in most cases, CRIM status can be predicted from GAA mutations, potentially circumventing the need for invasive skin biopsy and time wasted in culturing cells in the future. Continued studies in this area will help to increase the power of GAA gene mutations in predicting CRIM status as well as possibly identifying CRIM-positive patients who are at risk for developing high antibody titers.     

Protein-containing nutrient supplementation following strength training enhances the effect on muscle mass, strength, and bone formation in postmenopausal women.

We evaluated the response of various muscle and bone adaptation parameters with 24 wk of strength training in healthy, early postmenopausal women when a nutrient supplement (protein, carbohydrate, calcium, and vitamin D) or a placebo supplement (a minimum of energy) was ingested immediately following each training session. At inclusion, each woman was randomly and double-blindedly assigned to a nutrient group or a placebo (control) group. Muscle hypertrophy was evaluated from biopsies, MRI, and dual-energy X-ray absorptiometry (DEXA) scans, and muscle strength was determined in a dynamometer. Bone mineral density (BMD) was measured using DEXA scans, and bone turnover was determined from serum osteocalcin and collagen type I cross-linked carboxyl terminal peptide. The nutrient group improved concentric and isokinetic (60 degrees /s) muscle strength from 6 to 24 wk by 9 +/- 3% (P < 0.01), whereas controls showed no change (1 +/- 2%, P > 0.05). Only the nutrient group improved lean body mass (P < 0.05) over the 24 wk. BMD responded similarly at the lumbar spine but changed differently in the two groups at the femoral neck (P < 0.05) [control: 0.943 +/- 0.028 to 0.930 +/- 0.024 g/mm(3) (-1.0 +/- 1.4%); nutrient group: 0.953 +/- 0.051 to 0.978 +/- 0.043 g/mm(3) (3.8 +/- 3.4%)] when adjusted for age, body mass index, and BMD at inclusion. Bone formation displayed an interaction (P < 0.05), mainly caused by increased osteocalcin at 24 wk in the nutrient group. In conclusion, we report that nutrient supplementation results in superior improvements in muscle mass, muscle strength, femoral neck BMD, and bone formation during 24 wk of strength training. The observed differences following such a short intervention emphasize the significance of postexercise nutrient supply on musculoskeletal maintenance.     

High-selenium yeast supplementation in free-living North American men: no effect on thyroid hormone metabolism or body composition.

In a prior study, we observed decreased serum 3,3',5-triiodothyronine (T(3)), increased serum thyrotropin and increased body weight in five men fed 297 microg/d of selenium (Se) in foods naturally high in Se while confined in a metabolic research unit. In an attempt to replicate and confirm those observations, we conducted a randomized study of high-Se yeast supplements (300 microg/d) or placebo yeast administered to 42 healthy free-living men for 48 weeks. Serum thyroxine, T(3) and thyrotropin did not change in supplemented or control subjects. Body weight increased in both groups during the 48-week treatment period and remained elevated for the 48-week follow-up period. Body fat increased by 1.2 kg in both groups. Energy intake and voluntary activity levels were not different between the groups and remained unchanged during the treatment period. Dietary intakes of Se, macronutrients and micronutrients were not different between groups and remained unchanged during the treatment period. These results suggest that our previous observation of a hypothyroidal response to high-Se foods was confounded by some aspect of the particular foods used, or were merely chance observations. Because of the high dose and long administration period, the present study suggests that the effects of Se supplements on thyroid hormone metabolism and energy metabolism in healthy North American men with adequate Se status do not represent a significant risk for unhealthy weight gain.