Where the brain grows old: decline in anterior cingulate and medial prefrontal function with normal aging

Even healthy adults worry about declines in mental efficiency with aging. Subjective changes in mental flexibility, self-regulation, processing speed, and memory are often cited. We show here that focal decreases in brain activity occur with normal aging as measured with fluorodeoxyglucose and positron emission tomography. The largest declines localize to a medial network including the anterior cingulate/medial prefrontal cortex, dorsomedial thalamus, and sugenual cingulate/basal forebrain. Declining metabolism in this network correlates with declining cognitive function. The medial prefrontal metabolic changes with aging are similar in magnitude to the hypometabolism found in Mild Cognitive Impairment or Alzheimer's disease. These results converge with data from healthy elderly indicating dysfunction in the anterior attention system. The interaction of attention in the anterior cingulate cortex with memory in the medial temporal lobe may explain the global impairment that defines dementia. Despite the implications for an aging population, the neurophysiologic mechanisms of these metabolic decreases remain unknown.     

Centrosomal-ciliary gene CEP290/NPHP6 mutations result in blindness with unexpected sparing of photoreceptors and visual brain: implications for therapy of Leber congenital amaurosis

Mutations in the centrosomal-ciliary gene CEP290/NPHP6 are associated with Joubert syndrome and are the most common cause of the childhood recessive blindness known as Leber congenital amaurosis (LCA). An in-frame deletion in Cep290 shows rapid degeneration in the rod-rich mouse retina. To explore the mechanisms of the human retinal disease, we studied CEP290-LCA in patients of different ages (7-48 years) and compared results to Cep290-mutant mice. Unexpectedly, blind CEP290-mutant human retinas retained photoreceptor and inner laminar architecture in the cone-rich central retina, independent of severity of visual loss. Surrounding the cone-rich island was photoreceptor loss and distorted retina, suggesting neural-glial remodeling. The mutant mouse retina at 4-6 weeks of age showed similar features of retinal remodeling, with altered neural and synaptic laminae and Muller glial activation. The visual brain pathways in CEP290-LCA were anatomically intact. Our findings of preserved foveal cones and visual brain anatomy in LCA with CEP290 mutations, despite severe blindness and rapid rod cell death, suggest an opportunity for visual restoration of central vision in this common form of inherited blindness.     

Eubacterial diversity of activated biomass from a common effluent treatment plant

A common effluent treatment plant (CETP) is a biological wastewater treatment facility that receives wastewater from different industries. The activated biomass in the CETP survives on a wide range of chemicals with no fixed wastewater characteristics. We carried out a diversity analysis of this activated biomass using culture as well as culture-independent techniques. Using culture-based techniques, strains belonging to 26 different genera from the phyla Proteobacteria, Actinobacteria and Firmicutes were isolated. The gamma-proteobacteria was the best represented class, with 36.5% of the isolates. Bacterial diversity was also analyzed culture-independently by means of sequence determination of cloned 16S rRNA genes. Twenty-one different genera from the phyla Proteobacteria, Firmicutes, Planctomycetes and Bacteroidetes were identified. The total diversity of the activated biomass was composed of members of five known phyla, represented by 37 genera, with the Proteobacteria constituting the most abundant phylum detected. However, a very large fraction of the diversity represented a hitherto unidentified bacterial population. More than half (50.2%) of the 16S rDNA clones represented unidentified non-culturable bacteria, underlining the vast untapped diversity of CETP communities. Our results also indicate that both culture-based and culture-independent techniques should be combined to cover the microbial diversity of complex ecosystems.     

Hypertension in type 2 diabetes mellitus: effect of the disease and treatment on development of peripheral artery disease

Coexistence of diabetes and hypertension is well known so as their role as a risk factor for vasculopathy of lower limbs. Ankle brachial index (ABI) offers a simple, fairly reliable mean to quantify this problem. Very few studies in India have assessed the role of angiotensin-converting enzyme inhibitors (ACEI) in preventing vasculopathy in type 2 diabetics. A heterogeneous representative sample of 149 type 2 diabetics (103 ACEI user and 46 non-ACEI user) taking regular pharmacotherapy was tested by ABI using vascular Doppler to assess peripheral artery disease (PAD) following standard protocol. Distribution of risk factors for PAD and ABI values were compared between ACEI user and non-ACEI user diabetics. ABI ≤0.9 was defined as PAD and P value <0.05 considered as statistical significance. ACEI user and non-ACEI user group showed slight difference in prevalence of risk factors for PAD. ACEI user diabetics taking ACEI showed better ABI profile (ABI >0.9) than non-ACEI user diabetics. The non-ACEI user diabetics did not show statistically significant lower ABI difference. But by defining ABI ≤0.9 as PAD, type 2 diabetics not using ACEI proved to be at 2.12 times risk (OR to develop PAD) than those receiving it. Type 2 diabetic hypertensives taking ACEI with strict blood pressure control have an added benefit against PAD along with other established benefits, and the same pharmacotherapy may be used in non-ACEI user diabetics to turn secondary prevention into primary one.     

Osteonecrosis

Formerly referred to as avascular necrosis, the term osteonecrosis is now preferred. Simply defined, osteonecrosis means ‘dead bone’. The ‘avascular’ state of the necrotic bone is the result of a loss of circulation from numerous potential causes together with multiple risk factors. The resultant state is a sequelae of repair processes leading finally to gross deformation of the bony structural architecture and joint incongruity. Among the commonest sites are the femoral head, talus, lunate, knee and humeral head. In addition to normal radiography, bone scan and MRI have provided early diagnosis of subtle changes in the osteo-histology. Intervention depends upon the phase of disease progression; in the form of a series of preservation and/or salvage procedures.     

Tocotrienols Reverse Cardiovascular,Metabolic and Liver Changes in High Carbohydrate,High Fat Diet-Fed Rats

Tocotrienols have been reported to improve lipid profiles, reduce atherosclerotic lesions, decrease blood glucose and glycated haemoglobin concentrations, normalise blood pressure in vivo and inhibit adipogenesis in vitro, yet their role in the metabolic syndrome has not been investigated. In this study, we investigated the effects of palm tocotrienol-rich fraction (TRF) on high carbohydrate, high fat diet-induced metabolic, cardiovascular and liver dysfunction in rats. Rats fed a high carbohydrate, high fat diet for 16 weeks developed abdominal obesity, hypertension, impaired glucose and insulin tolerance with increased ventricular stiffness, lower systolic function and reduced liver function. TRF treatment improved ventricular function, attenuated cardiac stiffness and hypertension, and improved glucose and insulin tolerance, with reduced left ventricular collagen deposition and inflammatory cell infiltration. TRF improved liver structure and function with reduced plasma liver enzymes, inflammatory cell infiltration, fat vacuoles and balloon hepatocytes. TRF reduced plasma free fatty acid and triglyceride concentrations but only omental fat deposition was decreased in the abdomen. These results suggest that tocotrienols protect the heart and liver, and improve plasma glucose and lipid profiles with minimal changes in abdominal obesity in this model of human metabolic syndrome.     

Quercetin ameliorates cardiovascular, hepatic, and metabolic changes in diet-induced metabolic syndrome in rats

Metabolic syndrome is a risk factor for cardiovascular disease and nonalcoholic fatty liver disease (NAFLD). We investigated the responses to the flavonol, quercetin, in male Wistar rats (8-9 wk old) divided into 4 groups. Two groups were given either a corn starch-rich (C) or high-carbohydrate, high-fat (H) diet for 16 wk; the remaining 2 groups were given either a C or H diet for 8 wk followed by supplementation with 0.8 g/kg quercetin in the food for the following 8 wk (CQ and HQ, respectively). The H diet contained ~68% carbohydrates, mainly as fructose and sucrose, and ~24% fat from beef tallow; the C diet contained ~68% carbohydrates as polysaccharides and ~0.7% fat. Compared with the C rats, the H rats had greater body weight and abdominal obesity, dyslipidemia, higher systolic blood pressure, impaired glucose tolerance, cardiovascular remodeling, and NAFLD. The H rats had lower protein expressions of nuclear factor (erythroid-derived 2)-related factor-2 (Nrf2), heme oxygenase-1 (HO-1), and carnitine palmitoyltransferase 1 (CPT1) with greater expression of NF-κB in both the heart and the liver and less expression of caspase-3 in the liver than in C rats. HQ rats had higher expression of Nrf2, HO-1, and CPT1 and lower expression of NF-κB than H rats in both the heart and the liver. HQ rats had less abdominal fat and lower systolic blood pressure along with attenuation of changes in structure and function of the heart and the liver compared with H rats, although body weight and dyslipidemia did not differ between the H and HQ rats. Thus, quercetin treatment attenuated most of the symptoms of metabolic syndrome, including abdominal obesity, cardiovascular remodeling, and NAFLD, with the most likely mechanisms being decreases in oxidative stress and inflammation.     

Haplotype-Based Methods for Detecting Uncommon Causal Variants With Common SNPs

Detecting uncommon causal variants (minor allele frequency [MAF] < 5%) is difficult with commercial single-nucleotide polymorphism (SNP) arrays that are designed to capture common variants (MAF > 5%). Haplotypes can provide insights into underlying linkage disequilibrium (LD) structure and can tag uncommon variants that are not well tagged by common variants. In this work, we propose a wei-SIMc-matching test that inversely weights haplotype similarities with the estimated standard deviation of haplotype counts to boost the power of similarity-based approaches for detecting uncommon causal variants. We then compare the power of the wei-SIMc-matching test with that of several popular haplotype-based tests, including four other similarity-based tests, a global score test for haplotypes (global), a test based on the maximum score statistic over all haplotypes (max), and two newly proposed haplotype-based tests for rare variant detection. With systematic simulations under a wide range of LD patterns, the results show that wei-SIMc-matching and global are the two most powerful tests. Among these two tests, wei-SIMc-matching has reliable asymptotic P-values, whereas global needs permutations to obtain reliable P-values when the frequencies of some haplotype categories are low or when the trait is skewed. Therefore, we recommend wei-SIMc-matching for detecting uncommon causal variants with surrounding common SNPs, in light of its power and computational feasibility.