Association of total tau and phosphorylated tau 181 protein levels in cerebrospinal fluid with cerebral atrophy in mild cognitive impairment and Alzheimer disease

Background

We sought to examine the association of levels of total tau (t-tau) and phosphorylated tau 181 (p-tau181) protein with brain morphology in mild cognitive impairment, as defined by the concept of aging-associated cognitive decline (AACD) and Alzheimer disease.

Methods

Twenty-three participants with AACD, 16 with Alzheimer disease and 15 healthy controls underwent magnetic resonance imaging and lumbar puncture. We performed voxel-based morphometry to investigate the association between tau levels in cerebrospinal fluid (CSF) and cerebral grey matter density throughout the entire brain.

Results

Voxel-based morphometry revealed that both elevated t-tau and p-tau181 concentrations were associated with reduced grey matter density in temporal, parietal and frontal regions. Among participants with AACD, elevated levels of p-tau181 (but not t-tau) in CSF were correlated with a pronounced atrophy in the right hippocampus.

Limitations

Our study was limited by the small sample, especially with respect to the analysis comprising the AACD subgroups. Moreover, we did not correct our voxel-based morphometry analyses for multiple dependent comparisons, therefore they harbour a risk of false-positive results.

Conclusion

Elevated levels of t-tau and p-tau181 in CSF reflect degenerative processes in the cortical regions typically affected in Alzheimer disease. Our findings in participants with AACD support the hypothesis that p-tau181 might be more specifically related to neurodegenerative changes in early Alzheimer disease.     

Effect modification of air pollution on Urinary 8-Hydroxy-2'-Deoxyguanosine by genotypes: an application of the multiple testing procedure to identify significant SNP interactions

Background  

Air pollution is associated with adverse human health, but mechanisms through which pollution exerts effects remain to be clarified. One suggested pathway is that pollution causes oxidative stress. If so, oxidative stress-related genotypes may modify the oxidative response defenses to pollution exposure.     

Hemoglobin Affinity for Oxygen in the Anginal Syndrome with Normal Coronary Arteriograms

Oxyhemoglobin dissociation (OHD) curves were performed on whole blood (WB) from 20 patients with anginal pain, normal hemodynamics, and normal coronary arteries, as demonstrated by selective coronary cinearteriography. OHD curves in 19 of 20 patients, from zero to full saturation, were nearly identical to those in normal control subjects with values for P(50) (Po(2) at 50% saturation and pH 7.4) of 26.7+/-1.5 (mean+/-SD of the mean) torr (mm Hg) and red blood cell (RBC) levels of 2,3-diphosphoglyceric acid (2, 3-DPG) of 0.72+/-0.10 (mean+/-SD of the mean) M/M hemoglobin (Hb). Normal values for nonsmoking adults were: P(50), 26.6+/-1.4 (mean+/-SD of the mean) torr: and RBC 2,3-DPG, 0.81+/-0.09 (mean+/-SD of the mean) M/M Hb. Mean levels of carbon monoxide were normal at 0.14+/-0.01 (mean+/-SEM) ml/100 ml WB in 10 patients who were nonsmokers and 0.45+/-0.15 (mean+/-SEM) ml/100 ml WB in 10 smokers. In one patient, a heavy smoker with markedly elevated blood carbon monoxide levels, an abnormal leftward shift of the OHD curve was observed. This was corrected after discontinuation of smoking. In utilizing these methods, we could not detect consistent abnormalities of Hb affinity for oxygen at rest in the patients studied, which suggests that a defect in oxygen transport at rest is an unlikely explanation for the symptoms of chest pain in patients with the anginal syndrome and normal coronary arteriograms.     

Metastasiertes kastrationsresistentes Prostatakarzinom

Background

At the 2016 ASCO annual meeting, new data from two randomized phase III studies concerning taxane-based chemotherapy as a treatment option for patients with metastatic castration-resistant prostate cancer (mCRPC) were presented.

Objectives

The focus is on the clinical impact of these data.

Materials and methods

A group of German experts in the field of urogenital–oncologic expertise discussed the clinical impact with respect to the current data.

Results

The study results support the current clinical data. They confirm the efficacy and safety of cabazitaxel beyond first-line therapy with docetaxel for patients with mCRPC.

Conclusions

Cabazitaxel is an important treatment option after docetaxel progression. With respect to the performance status of a patient, it is adequate to reduce the dosage to 20?mg/m² cabazitaxel.

     

Repetitive element hypomethylation in blood leukocyte DNA and cancer incidence, prevalence, and mortality in elderly individuals: the Normative Aging Study

Background

Global genomic hypomethylation is a common epigenetic event in cancer that mostly results from hypomethylation of repetitive DNA elements. Case?Ccontrol studies have associated blood leukocyte DNA hypomethylation with several cancers. Because samples in case?Ccontrol studies are collected after disease development, whether DNA hypomethylation is causal or just associated with cancer development is still unclear.

Methods

In 722 elderly subjects from the Normative Aging Study cohort, we examined whether DNA methylation in repetitive elements (Alu, LINE-1) was associated with cancer incidence (30 new cases, median follow-up: 89 months), prevalence (205 baseline cases), and mortality (28 deaths, median follow-up: 85 months). DNA methylation was measured by bisulfite pyrosequencing.

Results

Individuals with low LINE-1 methylation (Conclusion These findings suggest that individuals with lower repetitive element methylation are at high risk of developing and dying from cancer.     

Apoptosis-related deregulation of proteolytic activities and high serum levels of circulating nucleosomes and DNA in blood correlate with breast cancer progression

Background  

As cell-free circulating DNA exists predominantly as mono- and oligonucleosomes, the focus of the current study was to examine the interplay of circulating nucleosomes, DNA, proteases and caspases in blood of patients with benign and malignant breast diseases.     

Iron Metabolism Genes,Low-Level Lead Exposure,and QT Interval

Background

Cumulative exposure to lead has been shown to be associated with depression of electrocardiographic conduction, such as QT interval (time from start of the Q wave to end of the T wave). Because iron can enhance the oxidative effects of lead, we examined whether polymorphisms in iron metabolism genes [hemochromatosis (HFE), transferrin (TF) C2, and heme oxygenase-1 (HMOX-1)] increase susceptibility to the effects of lead on QT interval in 613 community-dwelling older men.

Methods

We used standard 12-lead electrocardiograms, K-shell X-ray fluorescence, and graphite furnace atomic absorption spectrometry to measure QT interval, bone lead, and blood lead levels, respectively.

Results

A one-interquartile-range increase in tibia lead level (13 μg/g) was associated with a 11.35-msec [95% confidence interval (CI), 4.05–18.65 msec] and a 6.81-msec (95% CI, 1.67–11.95 msec) increase in the heart-rate–corrected QT interval among persons carrying long HMOX-1 alleles and at least one copy of an HFE variant, respectively, but had no effect in persons with short and middle HMOX-1 alleles and the wild-type HFE genotype. The lengthening of the heart-rate–corrected QT interval with higher tibia lead and blood lead became more pronounced as the total number (0 vs. 1 vs. ≥2) of gene variants increased (tibia, p-trend = 0.01; blood, p-trend = 0.04). This synergy seems to be driven by a joint effect between HFE variant and HMOX-1 L alleles.

Conclusion

We found evidence that gene variants related to iron metabolism increase the impacts of low-level lead exposure on the prolonged QT interval. This is the first such report, so these results should be interpreted cautiously and need to be independently verified.     

Detection of tumor-specific DNA in blood and bone marrow plasma from patients with prostate cancer

Tumor tissues, blood plasma and bone marrow (BM) aspirates of 57 prostate cancer patients (PCa) without clinical signs of overt metastases were assessed for LOH (loss of heterozygosity) by a PCR-based fluorescence microsatellite analysis, using a panel of 15 markers. Additionally, micrometastatic tumor cells in BM were monitored by an immunocytological cytokeratin assay. In total, 25 (44%), 32 (56%) and 41 (72%) of the patients had at least 1 LOH in their blood, BM and tumor samples, respectively. Among the informative cases, the frequency of LOH was highest in blood plasma for the markers D8S360 (18%) and D10S1765 (15%), and in BM plasma for THRB (24%) and D8S137 (22%). Comparison of blood plasma and BM with tumors showed discrepant results in 35% and 45% of patients, respectively. Whereas all LOHs at THRB in BM plasma were also detected in the autologous tumor tissues, LOHs at D6S474 and D11S898 in BM were not retrieved in the tumors. The comparison with established risk factors showed a correlation of borderline significance for LOH at D9S1748 in the BM aspirates (p=0.055) and a significant correlation in the tumor samples (p=0.004) with increasing pathologic Gleason scores. Interestingly, 22% of the PCa patients harbored tumor cells in their BM and tended (p=0.065) to have more frequent LOH (16%) in BM plasma compared to patients without tumor cells (9%). These data demonstrate, for the first time, the presence of free tumor-specific DNA in blood and BM of PCa patients and suggest a possible relationship to BM micrometastasis.     

Source location of air pollution and cardiac autonomic function: trajectory cluster analysis for exposure assessment

Although many studies report that exposure to air pollution harms health, few have examined associations between pollution sources and health outcomes. We hypothesized that pollution originating in different locations has different associations with heart rate variability (HRV) among 497 men from the Normative Aging Study in Boston, Massachusetts. We identified the paths that air masses traveled ('back-trajectories') before arriving in Boston on the days the men were examined. Next, we classified these trajectories into six clusters. We examined whether the association of measured air pollutants with HRV (standard deviation of normal-to-normal intervals, high-frequency power (HF) and low-frequency power (LF), and LF/HF ratio) differed by cluster. We also examined whether the clusters alone (not considering air pollution measurements) showed different associations with HRV. The effects of black carbon (BC) on all HRV measures were strongest on days with southwest trajectories. Subjects who were examined on days where air parcels came from west had the strongest associations with ozone. All particle pollutants (particulate matter <2.5 microm in aerodynamic diameter (PM2.5), BC, and sulfates) were associated with increased LF/HF ratio on days with relatively short trajectories, which are related to local, slow-moving air masses. We also observed significant increases in LF/HF in days where air came from the northwest and west, compared to north trajectory days. Health effects associated with exposure to air pollution can be evaluated using pollutant concentrations as well as aspects of the pollution mixture captured by identifying locations where air masses originate. Independent effects of both these indicators of pollution exposure were seen on cardiac autonomic function.