Quantitative analysis of senile plaques in Alzheimer disease: observation of log-normal size distribution and molecular epidemiology of differences associated with apolipoprotein E genotype and trisomy 21 (Down syndrome).

The discovery that the epsilon 4 allele of the apolipoprotein E (apoE) gene is a putative risk factor for Alzheimer disease (AD) in the general population has highlighted the role of genetic influences in this extremely common and disabling illness. It has long been recognized that another genetic abnormality, trisomy 21 (Down syndrome), is associated with early and severe development of AD neuropathological lesions. It remains a challenge, however, to understand how these facts relate to the pathological changes in the brains of AD patients. We used computerized image analysis to examine the size distribution of one of the characteristic neuropathological lesions in AD, deposits of A beta peptide in senile plaques (SPs). Surprisingly, we find that a log-normal distribution fits the SP size distribution quite well, motivating a porous model of SP morphogenesis. We then analyzed SP size distribution curves in genotypically defined subgroups of AD patients. The data demonstrate that both apoE epsilon 4/AD and trisomy 21/AD lead to increased amyloid deposition, but by apparently different mechanisms. The size distribution curve is shifted toward larger plaques in trisomy 21/AD, probably reflecting increased A beta production. In apoE epsilon 4/AD, the size distribution is unchanged but the number of SP is increased compared to apoE epsilon 3, suggesting increased probability of SP initiation. These results demonstrate that subgroups of AD patients defined on the basis of molecular characteristics have quantitatively different neuropathological phenotypes.

Neurobiological alterations in the human alcoholic brain: effect of genotype

Long-term alcohol abuse by human subjects leads to selective brain damage that is restricted in extent and variable in severity. Within the cerebral cortex, neuronal loss is most marked in the superior frontal cortex and relatively mild in motor cortex. Cirrhotic alcoholics and subjects with alcohol-related Wernicke-Korsakoff syndrome show more severe and more extensive damage than do uncomplicated cases. Accumulating evidence suggests that the likelihood of developing alcohol dependency is associated with one or more genetic markers. In previous work we showed that GABAA receptor functionality, and the subunit isoform expression that underlies this, differed in region- and disease-specific ways between alcoholics and controls. By contrast, glutamate receptor (NMDA, KA, AMPA) differences were muted or absent. Here we asked if genotype differentiated the form, pharmacology, or expression of glutamate and GABA receptors in pathologically vulnerable and spared cortical regions, with a view to determining whether such subject factors might influence the severity of alcohol-induced brain damage. Cerebrocortical tissue was obtained at autopsy under informed, written consent from uncomplicated and alcoholic-cirrhotic Caucasian (predominantly Anglo-Celtic) cases, together with matched controls and cases with cirrhosis of non-alcoholic origin. All subjects had pathological confirmation of liver and brain diagnosis; none had been polydrug abusers. Samples were processed for synaptic membrane receptor binding, mRNA analysis by quantitative RT-PCR, and protein analysis by Western blot. Genotyping was performed by PCR methods, in the main using published primers. Several genetic markers differentiated between our alcoholic and control subjects, including the GABAA receptor 2 subunit (GABB2) gene ( 2 (3) 10.329, P 0.01), the dopamine D2 receptor B1 (DRD2B) allele ( 2 (3) 10.109, P 0.01) and a subset of the alcohol dehydrogenase-3 (ADH3) alleles ( 2 (2) 4.730, P 0.05). Although neither the type-2 glutamate transporter (EAAT2) nor the serotonin transporter (5HTT) genes were significantly associated with alcoholism, only EAAT2 heterozygotes showed a significant association between ADH3 genotype and alcoholism ( 2 (3) 7.475, P 0.05). Other interactions between genotypes were also observed. DRD2A, DRD2B, GABB2, EAAT2 and 5HTT genotypes did not divide alcoholic cases and controls on NMDA receptor parameters, although in combined subjects there was a significant DRD2B X Area Interaction with glutamateNMDA receptor efficacy (F(1,57) 4.67; P 0.05), measured as the extent of glutamate-enhanced MK801 binding. In contrast, there was a significant Case-group X ADH3 X Area Interaction with glutamateNMDA receptor efficacy (F(3,57) 2.97; P 0.05). When GABAA receptor subunit isoform expression was examined, significant Case-group X Genotype X Area X Isoform interactions were found for EAAT2 with subunit mRNA (F(1,37) 4.22; P0.05), for GABB2 with isoform protein (F(1,37) 5.69; P 0.05), and for DRD2B with isoform protein (F(2,34)5.69; P0.05). The results suggest that subjects’ genetic makeup may modulate the effectiveness of amino acid-mediated transmission in different cortical regions, and thereby influence neuronal vulnerability to excitotoxicity.

The spatial pattern of beta-amyloid (Abeta) deposits in Alzheimer’s disease patients is related to apolipoprotein genotype

The spatial patterns of the diffuse, primitive, and classic beta-amyloid (Abeta) deposits was studied in the frontal and temporal cortex in cases of Alzheimer’s disease (AD) expressing different apolipoprotein (Apo E) genotypes. No significant differences in the density of the three Abeta deposit subtypes were observed in individuals expressing genotypes e2/3 and e3/3 compared with those expressing e3/4 and e4/4. In all patients, Abeta deposit subtypes occurred in the tissue in clusters. Chi-square contingency analyses of the data suggested that the cluster size of the diffuse and classic Abeta deposits was unrelated to Apo E genotype. However, the primitive (‘neuritic’) type Abeta deposits occurred more frequently in smaller, denser clusters in individuals expressing genotypes e3/4 and e4/4 compared with those expressing e2/3 and e3/3. Hence, the presence of the e4 allele may be associated with a more specific pattern of neuronal degeneration in the frontal and temporal cortex in AD.

Correlation between pre-treatment quasispecies complexity and treatment outcome in chronic HCV genotype 3a

Pre-treatment HCV quasispecies complexity and diversity may predict response to interferon based anti-viral therapy. The objective of this study was to retrospectively (1) examine temporal changes in quasispecies prior to the start of therapy and (2) investigate extensively quasispecies evolution in a group of 10 chronically infected patients with genotype 3a, treated with pegylated alpha 2a-Interferon and ribavirin. The degree of sequence heterogeneity within the hypervariable region 1 was assessed by analyzing 20-30 individual clones in serial serum samples. Genetic parameters, including amino acid Shannon entropy, Hamming distance and genetic distance were calculated for each sample. Treatment outcome was divided into (1) sustained virological responders (SVR) and (2) treatment failure (TF).Our results indicate, (1) quasispecies complexity and diversity are lower in the SVR group, (2) quasispecies vary temporally and (3) genetic heterogeneity at baseline can be used to predict treatment outcome. We discuss the results from the perspective of replicative homeostasis. We discuss the results from the perspective of replicative homeostasis.

Safety and efficacy of ledipasvir-sofosbuvir in black patients with hepatitis C virus infection: A retrospective analysis of phase 3 data.

UNLABELLED: Black patients chronically infected with genotype 1 hepatitis C virus (HCV) have historically had lower rates of response to interferon-based treatment than patients of other races. In the phase 3 ION program, the single-tablet regimen of the NS5A inhibitor ledipasvir and NS5B nucleotide polymerase inhibitor sofosbuvir was shown to be safe and highly effective in the general population. The aim of this study was to evaluate the safety and efficacy of ledipasvir/sofosbuvir in black patients using data from the three open-label ION clinical trials, which evaluated the safety and efficacy of 8, 12, and 24 weeks of ledipasvir/sofosbuvir with or without ribavirin for the treatment of treatment-naïve and treatment-experienced patients with genotype 1 HCV, including those with compensated cirrhosis. The primary endpoint was sustained virologic response at 12 weeks after the end of therapy (SVR12). For our analysis, rates of SVR12, treatment-emergent adverse events, and graded laboratory abnormalities were analyzed in black versus non-black patients. Of the 1949 patients evaluated, 308 (16%) were black. On average, black patients were older, had higher body mass index, were more likely to be IL28B non-CC, and had a lower serum alanine aminotransferase at baseline than non-black patients. Overall, 95% of black and 97% of non-black patients achieved SVR12. The rate of relapse was 3% in black patients as compared with 2% in non-black patients. The most common adverse events included fatigue, headache, nausea, and insomnia. The majority of adverse events occurred more frequently in the ribavirin-containing arms of the studies. No differences were observed in overall safety by race. CONCLUSION: A once-daily dosage of ledipasvir/sofosbuvir was similarly effective in black and non-black patients with genotype 1 HCV infection. The addition of ribavirin did not appear to increase SVR12 but was associated with higher rates of adverse events.

Enteric methane emissions and nitrogen utilisation efficiency for two genotype of hill hoggets offered fresh, ensiled and pelleted ryegrass

Thirty-six 12-month-old hill hoggets were used in a 2 genotype (18 Scottish Blackface vs. 18 Swaledale×Scottish Blackface)×3 diet (fresh vs. ensiled vs. pelleted ryegrass) factorial design experiment to evaluate the effects of hogget genotype and forage type on enteric methane (CH4) emissions and nitrogen (N) utilisation. The hoggets were offered 3 diets ad libitum with no concentrate supplementation in a single period study with 6 hoggets for each of the 6 genotype×diet combinations (n=6). Fresh ryegrass was harvested daily in the morning. Pelleted ryegrass was sourced from a commercial supplier (Aylescott Driers & Feeds, Burrington, UK) and the ryegrass silage was ensiled with Ecosyl (Lactobacillus plantarum, Volac International Limited, Hertfordshire, UK) as an additive. The hoggets were housed in individual pens for at least 14 d before being transferred to individual respiration chambers for a further 4 d with feed intake, faeces and urine outputs and CH4 emissions measured. There was no significant interaction between genotype and forage type on any parameter evaluated. Sheep offered pelleted grass had greater feed intake (e.g. DM, energy and N) but less energy and nutrient apparent digestibility (e.g. DM, N and neutral detergent fibre (NDF)) than those given fresh grass or grass silage (P<0.001). Feeding pelleted grass, rather than fresh grass or grass silage, reduced enteric CH4 emissions as a proportion of DM intake and gross energy (GE) intake (P<0.01). Sheep offered fresh grass had a significantly lower acid detergent fibre (ADF) apparent digestibility, and CH4 energy output (CH4-E) as a proportion of GE intake than those offered grass silage (P<0.001). There was no significant difference, in CH4 emission rate or N utilisation efficiency when compared between Scottish Blackface and Swaledale × Scottish Blackface. Linear and multiple regression techniques were used to develop relationships between CH4 emissions or N excretion and dietary and animal variables using data from sheep offered fresh ryegrass and grass silage. The equation relating CH4-E (MJ/d) to GE intake (GEI, MJ/d), energy apparent digestibility (DE/GE) and metabolisability (ME/GE) resulted in a high r2 (CH4-E=0.074 GEI+9.2 DE/GE−10.2 ME/GE−0.37, r2=0.93). N intake (NI) was the best predictor for manure N excretion (Manure N=0.66 NI+0.96, r2=0.85). The use of these relationships can potentially improve the precision and decrease the uncertainty in predicting CH4 emissions and N excretion for sheep production systems managed under the current feeding conditions.

STARTVerso1: A Randomized Trial of Faldaprevir Plus Pegylated Interferon/Ribavirin for Chronic HCV Genotype-1 Infection

BACKGROUND & AIMS: The efficacy and tolerability of faldaprevir, a potent hepatitis C virus (HCV) NS3/4A protease inhibitor, plus peginterferon (PegIFN) and ribavirin (RBV) was assessed in a double-blind, placebo-controlled phase 3 study of treatment-naïve patients with HCV genotype-1 infection. METHODS: Patients were randomly assigned (1:2:2) to PegIFN/RBV plus: placebo (arm 1, n = 132) for 24 weeks; faldaprevir (120 mg, once daily) for 12 or 24 weeks (arm 2, n = 259); or faldaprevir (240 mg, once daily) for 12 weeks (arm 3, n = 261). In arms 2 and 3, patients with early treatment success (HCV-RNA <25 IU/ml at week 4 and undetectable at week 8) stopped all treatment at week 24. Other patients received PegIFN/RBV until week 48 unless they met futility criteria. The primary endpoint was sustained virologic response 12 weeks post-treatment (SVR12). RESULTS: SVR12 was achieved by 52%, 79%, and 80% of patients in arms 1, 2, and 3, respectively (estimated difference for arms 2 and 3 vs. arm 1: 27%, 95% confidence interval 17%-36%; and 29%, 95% confidence interval, 19%-38%, respectively; p < 0.0001 for both). Early treatment success was achieved by 87% (arm 2) and 89% (arm 3) of patients, of whom 86% and 89% achieved SVR12. Adverse event rates were similar among groups; few adverse events led to discontinuation of all regimen components. CONCLUSIONS: Faldaprevir plus PegIFN/RBV significantly increased SVR12, compared with PegIFN/RBV, in treatment-naïve patients with HCV genotype-1 infection. No differences were seen in responses of patients given faldaprevir once daily at 120 or 240 mg.

Association between the il28b rs12979860 polymorphism and therapy response in patients infected with genotype 1 of hepatitis c virus in Central Brazil

v. 45, n.2, p.152-160, abr/.jun. 2016.

A 1.77 Mb deletion in 3p26.3 encompassing CNTN6 and CNTN4 genes: case report

Chromosome microarray analysis is a powerful diagnostic tool and is being used as a first-line approach to detect chromosome imbalances associated with intellectual disability, dysmorphic features and congenital abnormalities. This test enables the identification of new copy number variants (CNVs) and their association with new microdeletion/microduplication syndromes in patients previously without diagnosis. We report the case of a 7 year-old female with moderate intellectual disability, severe speech delay and auto and hetero aggressivity with a previous 45,XX,der(13;14)mat karyotype performed at a younger age. Affymetrix CytoScan 750K chromosome microarray analysis was performed detecting a 1.77 Mb deletion at 3p26.3, encompassing 2 OMIM genes, CNTN6 and CNTN4. These genes play an important role in the formation, maintenance, and plasticity of functional neuronal networks. Deletions or mutations in CNTN4 gene have been implicated in intellectual disability and learning disabilities. Disruptions or deletions in the CNTN6 gene have been associated with development delay and other neurodevelopmental disorders. The haploinsufficiency of these genes has been suggested to participate to the typical clinical features of 3p deletion syndrome. Nevertheless inheritance from a healthy parent has been reported, suggesting incomplete penetrance and variable phenotype for this CNV. We compare our patient with other similar reported cases, adding additional value to the phenotype-genotype correlation of deletions in this region.

The influence of ApoE genotype on the lipid profile and lipoproteins during normal pregnancy in a Southern African population.

Background: Pregnancy is associated with increases in fasting triglycerides and total cholesterol.1 ApoE isoforms are known to influence the concentration of cholesterol, with apoE2 homozygosity lowering and apoE4 homozygosity raising the cholesterol concentration compared with E3 homozygosity.2 The lipid profiles ApoE status and prevalence of small dense LDL species were evaluated for subjects attending an antenatal clinic. Results: Samples from 690 women aged between 16 and 42 years of age were analyzed during and after pregnancy. The fasting plasma triglyceride concentration (in mmol/L) was significantly higher in pregnancy (median = 1.5, IQR 1.0-2.0 vs median = 0.6, IQR 0.5-0.8 respectively, p < 0.0001). Similarly, the total cholesterol (in mmol/L) was increased during pregnancy (median=4.1, IQR 3.6-4.7 vs median 3.5, IQR 3.1-3.5, respectively p=0.0167). The median LDL cholesterol and HDL cholesterol did not change. Higher proportions of small density LDL species were seen during pregnancy compared to after pregnancy. The distribution of the LDL species during pregnancy and 6 weeks post-partum were significantly different p<0.0001 with the smaller species being much higher during pregnancy. Conclusion: ApoE4 genotype was associated with increased total cholesterol and LDL cholesterol concentrations during pregnancy. Pregnancy results in a reversible remodeling of LDL to smaller species, the significance of which is unknown but may indicate a predisposition to atherosclerosis

Porphyromonas gingivalis Fim-A genotype distribution among Colombians

Introduction: Porphyromonas gingivalis is associated with periodontitis and exhibit a wide array of virulence factors, including fimbriae which is encoded by the FimA gene representing six known genotypes. Objetive: To identify FimA genotypes of P. gingivalis in subjects from Cali-Colombia, including the co-infection with Aggregatibacter actinomycetemcomitans , Treponema denticola , and Tannerella forsythia . Methods: Subgingival samples were collected from 151 people exhibiting diverse periodontal condition. The occurrence of P. gingivalis, FimA genotypes and other bacteria was determined by PCR. Results: Porphyromonas gingivalis was positive in 85 patients. Genotype FimA II was more prevalent without reach significant differences among study groups (54.3%), FimA IV was also prevalent in gingivitis (13.0%). A high correlation (p= 0.000) was found among P. gingivalis, T. denticola, and T. forsythia co-infection. The FimA II genotype correlated with concomitant detection of T. denticola and T. forsythia. Conclusions: Porphyromonas gingivalis was high even in the healthy group at the study population. A trend toward a greater frequency of FimA II genotype in patients with moderate and severe periodontitis was determined. The FimA II genotype was also associated with increased pocket depth, greater loss of attachment level, and patients co-infected with T. denticola and T. forsythia.

Déterminants génétiques de la variabilité des triglycérides plasmatiques en réponse à une supplémentation en acides gras oméga-3 d’origine marine

Il est reconnu que la consommation d’acides gras (AG) oméga-3 (n-3) d’origine marine est bénéfique pour la prévention des maladies cardiovasculaires (MCV), notamment en raison de leurs effets hypotriglycéridémiants. Toutefois, il existe une importante hétérogénéité dans la réponse des triglycérides (TG) plasmatiques à une supplémentation en AG n-3 et ce phénomène est en partie attribuable à des facteurs génétiques. Notre groupe de recherche a récemment réalisé une étude d’association à l’échelle du génome (GWAS) sur les participants de l’étude Fatty Acid Sensor (FAS), qui a permis d’identifier plusieurs loci associés à la réponse des TG suite à une supplémentation de 3g d’AG n-3 par jour. La plupart de ces loci sont localisés dans les gènes IQCJ, NXPH1, PHF17 et MYB. Des effets du génotype ainsi que des interactions gène-diète ont été observés avec plusieurs polymorphismes nucléotidiques simples (SNPs) des quatre gènes candidats. Ces résultats suggèrent que des variations génétiques à l’intérieur de gènes identifiés par GWAS peuvent expliquer en partie la variabilité de la réponse des TG plasmatiques à une supplémentation en AG n-3 d’origine marine.

Effect Of Platform Connection And Abutment Material On Stress Distribution In Single Anterior Implant-supported Restorations: A Nonlinear 3-dimensional Finite Element Analysis.

Although various abutment connections and materials have recently been introduced, insufficient data exist regarding the effect of stress distribution on their mechanical performance. The purpose of this study was to investigate the effect of different abutment materials and platform connections on stress distribution in single anterior implant-supported restorations with the finite element method. Nine experimental groups were modeled from the combination of 3 platform connections (external hexagon, internal hexagon, and Morse tapered) and 3 abutment materials (titanium, zirconia, and hybrid) as follows: external hexagon-titanium, external hexagon-zirconia, external hexagon-hybrid, internal hexagon-titanium, internal hexagon-zirconia, internal hexagon-hybrid, Morse tapered-titanium, Morse tapered-zirconia, and Morse tapered-hybrid. Finite element models consisted of a 4×13-mm implant, anatomic abutment, and lithium disilicate central incisor crown cemented over the abutment. The 49 N occlusal loading was applied in 6 steps to simulate the incisal guidance. Equivalent von Mises stress (σvM) was used for both the qualitative and quantitative evaluation of the implant and abutment in all the groups and the maximum (σmax) and minimum (σmin) principal stresses for the numerical comparison of the zirconia parts. The highest abutment σvM occurred in the Morse-tapered groups and the lowest in the external hexagon-hybrid, internal hexagon-titanium, and internal hexagon-hybrid groups. The σmax and σmin values were lower in the hybrid groups than in the zirconia groups. The stress distribution concentrated in the abutment-implant interface in all the groups, regardless of the platform connection or abutment material. The platform connection influenced the stress on abutments more than the abutment material. The stress values for implants were similar among different platform connections, but greater stress concentrations were observed in internal connections.

Genetic Aspects Of Athletic Performance: The African Runners Phenomenon.

The current dominance of African runners in long-distance running is an intriguing phenomenon that highlights the close relationship between genetics and physical performance. Many factors in the interesting interaction between genotype and phenotype (eg, high cardiorespiratory fitness, higher hemoglobin concentration, good metabolic efficiency, muscle fiber composition, enzyme profile, diet, altitude training, and psychological aspects) have been proposed in the attempt to explain the extraordinary success of these runners. Increasing evidence shows that genetics may be a determining factor in physical and athletic performance. But, could this also be true for African long-distance runners? Based on this question, this brief review proposed the role of genetic factors (mitochondrial deoxyribonucleic acid, the Y chromosome, and the angiotensin-converting enzyme and the alpha-actinin-3 genes) in the amazing athletic performance observed in African runners, especially the Kenyans and Ethiopians, despite their environmental constraints.