Pharmacogenetics – Getting Closer

This review is written for the generalist to provide an understanding of the application of genetics to the care of patients with glaucoma and the broader concepts of personalized medicine. More specifically, the review will link advances in the genetics of glaucoma with the concepts of pharmacogenetics and its potential to improve patient care

Current Concepts in the Treatment of Retinitis Pigmentosa

Inherited retinal degenerations, including retinitis pigmentosa (RP) and Leber congenital amaurosis (LCA), affect 1 in 4000 individuals in the general population. A majority of the genes which are mutated in these conditions are expressed in either photoreceptors or the retinal pigment epithelium (RPE). There is considerable variation in the clinical severity of these conditions; the most severe being autosomal recessive LCA, a heterogeneous retinal degenerative disease and the commonest cause of congenital blindness in children. Here, we discuss all the potential treatments that are now available for retinal degeneration. A number of therapeutic avenues are being explored based on our knowledge of the pathophysiology of retinal degeneration derived from research on animal models, including: gene therapy, antiapoptosis agents, neurotrophic factors, and dietary supplementation. Technological advances in retinal implant devices continue to provide the promise of vision for patients with end-stage disease

A W:B4C multilayer phase retarder for broadband polarization analysis of soft x-ray radiation \ud

A W:B4C multilayer phase retarder has been designed and characterized which shows a nearly constant phase retardance between 640 and 850 eV photon energies when operated near the Bragg condition. This freestanding transmission multilayer was used successfully to determine, for the first time, the full polarization vector at soft x-ray energies above 600 eV, which was not possible before due to the lack of suitable optical elements. Thus, quantitative polarimetry is now possible at the 2p edges of the magnetic substances Fe, Co, and Ni for the benefit of magnetic circular dichroism spectroscopy employing circularly polarized synchrotron radiatio

Ocular Gene Therapy with Adeno-associated Virus Vectors: Current Outlook for Patients and Researchers

In this “Perspective”, we discuss ocular gene therapy – the patient’s perspective, the various strategies of gene replacement and gene editing, the place of adenoassociated virus vectors, routes of delivery to the eye and the remaining question - “why does immunity continue to limit efficacy?” Through the coordinated efforts of patients, researchers, granting agencies and industry, and after many years of pre-clinical studies, biochemical, cellular, and animal models, we are seeing clinical trials emerge for many previously untreatable heritable ocular disorders. The pathway to therapies has been led by the successful treatment of the RPE65 form of Leber congenital amaurosis with LUXTURNATM. In some cases, immune reactions to the vectors continue to occur, limiting efficacy. The underlying mechanisms of inflammation require further study, and new vectors need to be designed that limit the triggers of immunity. Researchers studying ocular gene therapies and clinicians enrolling patients in clinical trials must recognize the current limitations of these therapies to properly manage expectations and avoid disappointment, but we believe that gene therapies are well on their way to successful, widespread utilization to treat heritable ocular disorders

Dose–response effect of a whey protein preload on within-day energy intake in lean subjects

The effect of consuming different amounts of whey protein on appetite and energy intake was investigated in two separate studies using randomised, crossover designs. Healthy-weight men and women (range: BMI 19·0–25·0 kg/m2, age 19·4–40·4 years) consumed one of four 400 ml liquid preloads, followed by an ad libitum test meal 90 min later. In study 1, preloads were 1675 kJ with 12·5, 25 or 50 % of energy from protein, and in study 2, preloads were 1047 kJ with 10, 20 or 40 % energy from protein. Flavoured water was used as the control in both the studies. Appetite ratings were collected immediately before 30, 60 and 90 min after consuming the preloads; and immediately, 30 and 60 min after consuming the test meal. In study 1, energy intake following the control preload (4136 (sem 337) kJ) was significantly higher than each of the 12·5 % (3520 (sem 296) kJ), 25 % (3384 (sem 265) kJ) and 50 % (2853 (sem 244) kJ) protein preloads (P < 0·05). Intake after the 12·5 % preload was significantly higher than following 25 and 50 % preloads (P < 0·05). In study 2, energy intake following the control preload (4801 (sem 325) kJ) was higher than following the 10 % (4205 (sem 310) kJ), 20 % (3988 (sem 250) kJ) and 40 % (3801 (sem 245) kJ) protein preloads (P < 0·05). There were no differences in subjective appetite ratings between preloads in either study. These findings indicate a dose–response effect of protein content of the preload on energy intake at a subsequent meal

Responses to supplementation by dairy cows given low pasture allowances in different seasons 2. Milk production

Two factorial experiments were designed to determine the effects of stage of lactation, and season of the year, on cow responses to supplementary feeding. These experiments were conducted over consecutive years with 128 high genetic merit multiparous Holstein-Friesian cows in early, mid and late lactation in spring, summer, autumn and winter. At each stage of lactation, and in each season of the year, cows were offered a restricted pasture allowance (25 to 35 kg dry matter (DM) per cow per day), either unsupplemented (control) or with supplement at 50 MJ metabolizable energy (ME) per cow per day in experiment 1 and 80 MJ ME per cow per day in experiment 2. The two supplements given in both years were rolled maize grain (MG) and a mixture of foods formulated to nutritionally balance the diet (BR). In experiment 2, another treatment, of a generous pasture allowance (60 to 75 kg DM per cow per day) (AP), was imposed on an additional group of early lactation cows during each season. Direct milk solids (MS) (milk fat plus milk protein) responses in experiment 1 to MG were 169, 279, 195 and 251 g MS per cow per day in spring, summer, autumn and winter, respectively, while those to BR were 107, 250, 192, 289 g MS per cow per day. In experiment 2, however, milk solids responses to both supplements during spring were slightly below the control treatment, with values similar to those in experiment 1 in summer and autumn for cows on the BR but not the MG supplement. Milk solids responses to supplementary foods were largest during seasons of the year when the quantity and quality of pasture on offer resulted in the lowest milk solids yield from unsupplemented cows. When carry-over effects of feeding MG and BR on milk solids production were detected, they were only about half the magnitude of the direct effects. Serum urea concentrations were higher in control cows than those offered MG with a similar effect for BR in all but summer in experiment 1, while serum glucose concentrations were highest in winter and lowest in summer. The most important factor influencing milk solids responses was the relative food deficit (RFD) represented by the decline in milk solids yield of the respective control groups after,changing from a generous pasture allowance to restricted allowance when the feeding treatments were imposed. Total milk solids responses (direct and carry-over) to supplements were greatest when severe food restrictions, relative to the cows' current food demand, resulted in large reductions in milk solids yield of the control groups. The RFD was the best predictor of milk solids response to supplementary foods. Therefore, it is likely that cows are most responsive to supplementary foods during or immediately after the imposition of a severe food restriction

Responses to supplementation by dairy cows given low pasture allowances in different seasons 1. Pasture intake and substitution

Two factorial experiments were designed to determine the effects of stage of lactation, and season of the year, on cow responses to supplementary feeding. These experiments were conducted over consecutive years with 128 high genetic merit multiparous Holstein-Friesian cows in early, mid and late lactation in spring, summer, autumn and winter. At each stage of lactation, and in each season of the year, cows were offered a restricted pasture allowance (25 to 35 kg dry matter (DM) per cow per day), either unsupplemented (control) or supplemented with 50 MJ metabolizable energy (ME) per cow per day in experiment 1 and 80 MJ ME per cow per day in experiment 2. Two different supplements were offered, namely, rolled maize grain (MG) and a mixture of foods (BR) formulated to nutritionally balance the diet. In experiment 2, a fourth treatment consisting solely of a generous pasture allowance (60 to 75 kg DM per cow per day, AP) was introduced. Offering MG and BR increased DM intake (DMI). At the restricted pasture allowance, increasing total ME allowance (MEA) by offering supplementary foods increased ME intake (MEI) by 0.68 (s.e. 0.047) MJ per extra MJ ME offered. This highly significant (P < 0.001) linear relationship was consistent across seasons, and did not diminish at higher MEA. In experiment 2, cows in early lactation had lower substitution rates than mid and late lactation cows irrespective of season. Substitution rate was higher when higher pasture allowance or quality of pasture on offer enabled the unsupplemented cows to achieve higher DMI from pasture than at other times of the year. These results suggest that one of the key factors determining the intake response to supplementary foods is pasture allowance. Within spring calving dairying systems, the largest increases in total DMI per kg of supplement offered is likely when offering supplements to early lactation cows grazing restricted allowances of high quality pasture

AA and DHA are Decreased in Paediatric AD/HD and Inattention is Ameliorated by Increased Plasma DHA

The purpose of this study was to assess long chain polyunsaturated fatty acid (LCPUFA) status in relation to socio-behavioral outcomes in children with Attention Deficit/Hyperactivity Disorder (AD/HD). In a case-control design, plasma phospholipid fatty acid content was assessed in children aged 5–12 years with AD/HD and in typically functioning children. Dietary intakes of LCPUFAs arachidonic acid (AA; 20:4n6) and docosahexaenoic acid (DHA; 22:6n3) were quantified using a four-day food record, polymorphisms were determined in FADS1 and FADS2, and socio-behavioral outcomes were assessed using the Conners 3 Parent Rating Scales in a cross section of children with AD/HD. Compared to typically functioning children, plasma AA and DHA were 40% lower in children with AD/HD. Median intake of AA, but not DHA, was higher in children with AD/HD compared to typically functioning children. Polymorphisms in FADS1 (rs174546) and FADS2 (174575) were associated with higher plasma linoleic acid (LA; 18:2n6) level. Plasma DHA level was inversely associated with inattention score. Despite having an elevated intake of AA, children diagnosed with AD/HD have a reduction in plasma AA level which may be due in part to polymorphisms in the fatty acid desaturase (FADS) gene cluster or increased conversion to AA-derived metabolites. Increasing intake of DHA may ameliorate symptoms of inattention in AD/HD

Vitamin intake is associated with improved visuospatial and verbal semantic memory in middle-aged individuals

Objectives: Factors maintaining cognitive health are still largely unknown. In particular, the cognitive benefits associated with vitamin intake and vitamin supplementation are disputed. We investigated self-reported vitamin intake and serum vitamin levels with performance in cognitive factors sensitive to dementia progression in two large middle-aged general population cohorts. Methods: Survey data was used to assess regular vitamin intake in 4400 NCDS 1958 and 1177 TwinsUK cohort members, and serum homocysteine and B vitamin levels were measured in 675 individuals from the TwinsUK study. Principal component analysis was applied to cognitive test performance from both cohorts resulting in two dementia-sensitive cognitive factors reflecting visuospatial associative memory and verbal semantic memory. Results: In both cohorts, individuals who reported regular intake of vitamins, particularly B vitamins, showed significantly better performance in visuospatial associative memory and verbal semantic memory (p < 0.001). A significant association was also found between homocysteine levels, vitamin serum concentration and visuospatial associative memory performance which indicated that individuals with high B vitamin and homocysteine levels showed better visuospatial associative memory performance than individuals with low vitamin B levels (p < 0.05). Discussion: The findings demonstrate that early dementia-sensitive cognitive changes can be identified in middle-aged asymptomatic individuals and that regular vitamin intake is associated with improved cognitive performance. These findings reinforce the potential cognitive benefits of regular vitamin intake, which should be considered as an economically viable therapeutic strategy for maintaining cognitive health