Several components in the Wnt pathway, including β-catenin and glycogen synthase kinase 3 beta, have been implied in AD pathogenesis. Here, mRNA brain levels from five-month-old tg-ArcSwe and ...nontransgenic mice were compared using Affymetrix microarray analysis. With surprisingly small overall changes, Wnt signaling was the most affected pathway with altered expression of nine genes in tg-ArcSwe mice. When analyzing mRNA levels of these genes in human brain, transcription factor 7-like 2 (TCF7L2) and v-myc myelocytomatosis viral oncogene homolog (MYC), were increased in Alzheimer's disease (AD) (P<.05). Furthermore, no clear differences in TCF7L2 and MYC mRNA were found in brains with frontotemporal lobar degeneration, suggesting that altered regulation of these Wnt-related genes could be specific to AD. Finally, mRNA levels of three neurogenesis markers were analyzed. Increased mRNA levels of dihydropyrimidinase-like 3 were observed in AD brain, suggesting that altered Wnt pathway regulation may signify synaptic rearrangement or neurogenesis.
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FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
Impaired angiogenesis in ischemic tissue is a hallmark of diabetes. Thioredoxin-interacting protein (TXNIP) is an exquisitely glucose-sensitive gene that is overexpressed in diabetes. As TXNIP ...modulates the activity of the key angiogenic cytokine vascular endothelial growth factor (VEGF), we hypothesized that hyperglycemia-induced dysregulation of TXNIP may play a role in the pathogenesis of impaired angiogenesis in diabetes. In the current study, we report that high glucose-mediated overexpression of TXNIP induces a widespread impairment in endothelial cell (EC) function and survival by reducing VEGF production and sensitivity to VEGF action, findings that are rescued by silencing TXNIP with small interfering RNA. High glucose-induced EC dysfunction was recapitulated in normal glucose conditions by overexpressing either TXNIP or a TXNIP C247S mutant unable to bind thioredoxin, suggesting that TXNIP effects are largely independent of thioredoxin activity. In streptozotocin-induced diabetic mice, TXNIP knockdown to nondiabetic levels rescued diabetes-related impairment of angiogenesis, arteriogenesis, blood flow, and functional recovery in an ischemic hindlimb. These findings were associated with in vivo restoration of VEGF production to nondiabetic levels. These data implicate a critical role for TXNIP in diabetes-related impairment of ischemia-mediated angiogenesis and identify TXNIP as a potential therapeutic target for the vascular complications of diabetes.
Mammalian mitochondrial transcription is executed by a single subunit mitochondrial RNA polymerase (Polrmt) and its two accessory factors, mitochondrial transcription factors A and B2 (Tfam and ...Tfb2m). Polrmt is structurally related to single-subunit phage RNA polymerases, but it also contains a unique N-terminal extension (NTE) of unknown function. We here demonstrate that the NTE functions together with Tfam to ensure promoter-specific transcription. When the NTE is deleted, Polrmt can initiate transcription in the absence of Tfam, both from promoters and non-specific DNA sequences. Additionally, when in presence of Tfam and a mitochondrial promoter, the NTE-deleted mutant has an even higher transcription activity than wild-type polymerase, indicating that the NTE functions as an inhibitory domain. Our studies lead to a model according to which Tfam specifically recruits wild-type Polrmt to promoter sequences, relieving the inhibitory effect of the NTE, as a first step in transcription initiation. In the second step, Tfb2m is recruited into the complex and transcription is initiated.
The in vitro activities of mupirocin, quinupristin/dalfopristin, linezolid, eperezolid, sitafloxacin, clinafloxacin, moxifloxacin, amoxycillin, metronidazole and clarithromycin were tested at pH 7.4 ...against 57 strains of Helicobacter pylori. The most active agents (mupirocin, sitafloxacin and clinafloxacin) were also tested for activity at pH 5.4 against the same strains. Mupirocin was very active at pH 7.4 and 5.4 (MIC90 0.25 and 0.12 mg/L, respectively). Quinupristin/dalfopristin, linezolid and eperezolid had low activity (MIC90 4, 8 and 4 mg/L, respectively). Sitafloxacin (MIC90 ≤ 0.008 mg/L) was the most active fluoroquinolone, while clinafloxacin (MIC90 0.12 mg/L) and moxifloxacin (MIC90 2 mg/L) were least active.
Epidemiological and genetic data support the notion that schizophrenia and bipolar disorder share genetic risk factors. In our previous genome-wide association study, meta-analysis and follow-up ...(totaling as many as 18 206 cases and 42 536 controls), we identified four loci showing genome-wide significant association with schizophrenia. Here we consider a mixed schizophrenia and bipolar disorder (psychosis) phenotype (addition of 7469 bipolar disorder cases, 1535 schizophrenia cases, 333 other psychosis cases, 808 unaffected family members and 46 160 controls). Combined analysis reveals a novel variant at 16p11.2 showing genome-wide significant association (rs4583255T; odds ratio=1.08; P=6.6 × 10(-11)). The new variant is located within a 593-kb region that substantially increases risk of psychosis when duplicated. In line with the association of the duplication with reduced body mass index (BMI), rs4583255T is also associated with lower BMI (P=0.0039 in the public GIANT consortium data set; P=0.00047 in 22 651 additional Icelanders).
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Left ventricular (LV) global longitudinal strain (GLS) is a measure of the active shortening of the LV in the longitudinal direction, which can be assessed with speckle-tracking echocardiography. The ...aims of this evaluation were to validate the prognostic value of GLS as a new index of LV systolic function in a large cohort of patients with chronic ischemic cardiomyopathy and to determine the incremental value of GLS to predict long-term outcome over other strong and well-established prognostic factors.
A total of 1060 patients underwent baseline clinical evaluation and transthoracic echocardiography. Median age was 66.9 years (interquartile range, 58.4, 74.2 years); 739 (70%) were men. The median follow-up duration for the entire patient population was 31 months. During the follow-up, 270 patients died and 309 patients reached the combined end point (all-cause mortality and heart failure hospitalization). Compared with survivors, patients who died (270, 25%) had larger LV volumes (P<0.05), lower LV ejection fraction (P=0.004), higher wall motion score index (P=0.001), and greater impairment of LV GLS (P<0.001). After dichotomizing the population on the basis of the median value of LV GLS (-11.5%), patients with an LV GLS ≤-11.5% had superior outcome compared with patients with an LV GLS >-11.5% (log-rank χ(2), 13.86 and 14.16 for all-cause mortality and combined end point, respectively, P<0.001 for both). On multivariate analysis, GLS was independently related to all-cause mortality (hazard ratio per 5% increase, 1.69; 95% confidence interval, 1.33-2.15; P<0.001) and combined end point (1.64; 95% confidence interval, 1.32-2.04; P<0.001).
The assessment of LV GLS with speckle-tracking echocardiography is significantly related to long-term outcome in patients with chronic ischemic cardiomyopathy.
Objectives: Breast-fed C-allele carriers of the rs single nucleotide polymorphism in the fatty acyl desaturase 2 ("FADS2") gene have been reported to show a 6.4 to 7 IQ point advantage over ...formula-fed C-allele carriers, with no effect of breast-feeding in GG carriers. An Australian sample was examined to determine if an interaction between breast-feeding and the rs174575 single nucleotide polymorphism had any effect on IQ. Method: This hypothesis was tested in more than 700 families of adolescent twins assessed for IQ and breast-feeding, birth weight, and "FADS2" polymorphisms, and parental socioeconomic status and education, and maternal "FADS2" status. Results: No significant evidence for a moderating effect on IQ of rs174575 C-carrier status and breast-feeding was found, and there no effects of maternal "FADS2" status on offspring IQ. In addition, no main effects of any "FADS2" polymorphisms on IQ were found when the genotype was kept as two-homozygote and one-heterozygote categories and indeed no evidence for effects of breast-feeding on IQ scores after controlling for parental socioeconomic status and education. The investigation was extended to two additional "FADS2" polymorphisms (rs1535 and rs174583), but again, although these polymorphisms code alleles affecting fatty acid metabolism, no main or interaction effects were found on IQ. Conclusion: These results support the view that apparent effects of breast-feeding on IQ reflect differential likelihood of breast-feeding as a function of parental education and did not support the predicted interaction effect of "FADS2" and breast-feeding on IQ. (Contains 6 tables and 1 figure.)
Inbreeding depression refers to lower fitness among offspring of genetic relatives. This reduced fitness is caused by the inheritance of two identical chromosomal segments (autozygosity) across the ...genome, which may expose the effects of (partially) recessive deleterious mutations. Even among outbred populations, autozygosity can occur to varying degrees due to cryptic relatedness between parents. Using dense genome-wide single-nucleotide polymorphism (SNP) data, we examined the degree to which autozygosity associated with measured cognitive ability in an unselected sample of 4854 participants of European ancestry. We used runs of homozygosity-multiple homozygous SNPs in a row-to estimate autozygous tracts across the genome. We found that increased levels of autozygosity predicted lower general cognitive ability, and estimate a drop of 0.6 s.d. among the offspring of first cousins (P=0.003-0.02 depending on the model). This effect came predominantly from long and rare autozygous tracts, which theory predicts as more likely to be deleterious than short and common tracts. Association mapping of autozygous tracts did not reveal any specific regions that were predictive beyond chance after correcting for multiple testing genome wide. The observed effect size is consistent with studies of cognitive decline among offspring of known consanguineous relationships. These findings suggest a role for multiple recessive or partially recessive alleles in general cognitive ability, and that alleles decreasing general cognitive ability have been selected against over evolutionary time.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
BACKGROUND—Periprocedural myocardial infarction (MI) occurs in a significant proportion of patients undergoing percutaneous coronary intervention (PCI) and portends poor outcomes. Currently, no ...clinically applicable method predicts periprocedural MI in the cardiac catheterization laboratory before it occurs. We hypothesized that impaired baseline coronary microcirculatory reserve, which reduces the ability to tolerate ischemic insults, is a risk for periprocedural MI and that the index of microcirculatory resistance (IMR) measured during PCI can predict occurrence of periprocedural MI.
METHODS AND RESULTS—Consecutive patients undergoing elective PCI of a single lesion in the left anterior descending coronary artery were recruited. A pressure-temperature sensor wire was used to measure IMR before PCI. Of the 50 patients studied, 10 had periprocedural MI. From binary logistic regression analyses of all clinical, procedural, and physiological parameters, univariable predictors of periprocedural MI were pre-PCI IMR (P=0.003) and the number of stents used (P=0.039). Pre-PCI IMR was the only independent predictor in bivariable regression analyses performed by adjusting for each available covariate one at a time (all P≤0.02). Pre-PCI IMR ≥27 U had 80.0% sensitivity and 85.0% specificity for predicting periprocedural MI (C statistic, 0.80; P=0.003). Pre-PCI IMR ≥27 U was independently associated with a 23-fold risk of developing periprocedural MI (odds ratio, 22.7; 95% CI, 3.8–133.9).
CONCLUSIONS—These data suggest that the status of the coronary microcirculation plays a role in determining susceptibility toward periprocedural MI at the time of elective PCI. The IMR can predict subsequent risk of developing myocardial necrosis and may guide adjunctive prevention strategies.
Serum carbohydrate-deficient transferrin (CDT) is a specific and comparatively sensitive marker of excessive alcohol use; however, reports of its sensitivity vary according to the population or ...patient groups studied and their average alcohol intake. We have characterized the dose-response curve between alcohol intake and CDT concentrations in a study of 1400 men and women from a community-based twin registry. Our results show that mean CDT increases with increasing reported alcohol consumption even within the range of alcohol use considered to be nonhazardous. We found significant effects of sex, age, smoking, previous alcohol dependence, body mass index, and diastolic hypertension on the alcohol-CDT dose-response curve. These variables either affect test sensitivity or require adjustment of reference intervals. The results also provide insight into the physiological and biochemical factors that affect CDT concentration.
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