Phosphorylation plays a key role in Alzheimer's disease (AD) pathogenesis, impacting distinct processes such as amyloid-beta (Aβ) peptide production and tau phosphorylation. Impaired phosphorylation ...events contribute to senile plaques and neurofibrillary tangles' formation, two major histopathological hallmarks of AD. Blood-derived extracellular particles (bdEP) can represent a disease-related source of phosphobiomarker candidates, and hence, in this pilot study, bdEP of Control and AD cases were analyzed by a targeted phosphoproteomics approach using a high-density microarray that featured at least 1145 pan-specific and 913 phosphosite-specific antibodies. This approach, innovatively applied to bdEP, allowed the identification of 150 proteins whose expression levels and/or phosphorylation patterns were significantly altered across AD cases. Gene Ontology enrichment and Reactome pathway analysis unraveled potentially relevant molecular targets and disease-associated pathways, and protein-protein interaction networks were constructed to highlight key targets. The discriminatory value of both the total proteome and the phosphoproteome was evaluated by univariate and multivariate approaches. This pilot experiment supports that bdEP are enriched in phosphotargets relevant in an AD context, holding value as peripheral biomarker candidates for disease diagnosis.
Photonic crystal fibers (PCFs) offer new possibilities of realizing highly birefringent fibers due to a higher intrinsic index contrast compared to conventional fibers. In this letter, we analyze ...theoretically the levels of birefringence that can be expected using relatively simple PCF designs. While extremely high degrees of birefringence may be obtained for the fibers, we demonstrate that careful design with respect to multimode behavior must be performed. We further discuss the cutoff properties of birefringent PCFs and present experimental results in agreement with theoretical predictions on both single- and multimode behavior and on levels of birefringence.
Many econometric testing problems involve nuisance parameters which are not identified under the null hypotheses. This paper studies the asymptotic distribution theory for such tests. The asymptotic ...distributions of standard test statistics are described as functionals of chi-square processes. In general, the distributions depend upon a large number of unknown parameters. We show that a transformation based upon a conditional probability measure yields an asymptotic distribution free of nuisance parameters, and we show that this transformation can be easily approximated via simulation. The theory is applied to threshold models, with special attention given to the so-called self-exciting threshold autoregressive model. Monte Carlo methods are used to assess the finite sample distributions. The tests are applied to U.S. GNP growth rates, and we find that Potter's (1995) threshold effect in this series can be possibly explained by sampling variation.
Objective. The purpose of the present study was to determine the prevalence and incidence of virological triple drug-class failure (TCF) and to summarize the clinical outcome for patients who started ...receiving highly active antiretroviral therapy (HAART). Methods. The present study is an observational longitudinal study of 3496 treatment-experienced (TE) and treatment-naive (TN) patients monitored from the time they started receiving HAART (baseline) until TCF occurred (as determined on the basis of viral loads), until AIDS was newly diagnosed, or until death. Results. Four hundred forty-five patients (12.7%) had TCF; 370 (16.6%) of 2230 patients were TE, and 75 (5.9%) of 1266 patients were TN. At 6 years after starting HAART, 21.4% of TE and 11.2% of TN patients had TCF (P < .0001). The prevalence of TCF at or after 2002 was 15.5% in TE patients and 4.8% in TN patients. TN patients had a 32% annual increase in the incidence of TCF (95% confidence interval CI, 14%–54%; P < .0001); at 5 years after starting HAART, the rate was comparable for TE and TN patients (3.3 and 3.4 cases/100 person-years of follow-up PYFU, respectively). The incidence of new cases of AIDS or death was 2.7 cases/100 PYFU in patients who did not experience TCF and 5.0 cases/100 PYFU in patients who did experience TCF, an estimated 36% increase with each category of TCF (95% CI, 19%–56%; P < .0001). Conclusion. The prevalence of TCF was low after patients started receiving HAART, particularly among TN patients. Despite the influx of patients who had started receiving HAART more recently, the prevalence of TCF increased over calendar time. Patients with TCF had a higher incidence of newly diagnosed AIDS or death. Treatment of patients with TCF deserves further investigation.
•LST used on both faces of contact to increase static friction coefficient.•Extremely high static friction coefficients obtained by laser surface texturing.•Friction coefficient found to be dependent ...on laser texture and normal pressure.•High friction enabled by significant deformation and interlocking of the surfaces.•Overloading normal pressure results in even higher friction coefficients.
A pulsed, nanosecond fibre laser with wavelength of 1064nm was used to texture grade 316 stainless steel and ‘low alloy’ carbon steel in order to generate contacts with high static friction coefficients. High friction contacts have applications in reducing the tightening force required in joints or to easily secure precision fittings, particularly for larger components where standard methods are difficult and expensive. Friction tests performed at normal pressures of 100MPa and 50MPa have shown that very high static friction coefficients greater than 1.25, an increase of 346% over untextured samples at 100MPa, can be easily achieved by single pass laser texturing of both contacting surfaces with the use of low pulse separations. The high static friction coefficients, obtained at 100MPa normal pressure with textures with up to 62.5μm pulse separation (processing speed ∼0.67cm2/s), were found to be associated with a significant amount of plastic deformation caused by the high normal pressures. As a result, higher normal pressures were found to result in higher friction coefficients.
Summary
Background
Before stopping nucleos(t)ide analogue (NA) treatment in chronic hepatitis B (CHB), 6–12 months of consolidation therapy is recommended.
Aim
To investigate the effect of ...consolidation therapy on off‐treatment outcomes in CHB patients.
Methods
We included 94 patients who stopped NA after at least 1 year of therapy. Patients could be HBeAg‐positive or HBeAg‐negative at start‐of‐treatment, but were HBeAg‐negative and had undetectable HBV DNA at time of discontinuation. Consolidation therapy was defined as treatment after the first undetectable HBV DNA (and HBeAg loss for HBeAg‐positive patients) until NA cessation.
Results
At 3 years, 74% of the start‐of‐treatment HBeAg‐positive and 75% of the start‐of‐treatment HBeAg‐negative patients developed HBV DNA >2000 IU/mL at a single time point, whereas a persistent virological relapse (≥2 tests of HBV DNA >2000 IU/mL 6 months apart within 1 year) developed in 49% of the start‐of‐treatment HBeAg‐positive and 53% of the start‐of‐treatment HBeAg‐negative patients. For both HBeAg‐positive and HBeAg‐negative patients, consolidation therapy of ≥3 years was associated with lower persistent virological relapse rates compared to <1 year (1‐year relapse rate: 25% vs. 54%; P = 0.063 and 24% vs. 57%; P = 0.036, respectively). At 3 years, 9% of the HBeAg‐positive and 14% of the HBeAg‐negative patients became HBsAg‐negative. Prolonged consolidation therapy increased the likelihood of HBsAg loss. Two cirrhotic patients developed hepatic decompensation but both recovered.
Conclusions
After nucleos(t)ide analogue discontinuation, relapse was common in patients with chronic hepatitis B. Prolongation of consolidation therapy beyond 3 years decreased the risk of persistent virological relapse and increased the likelihood of HBsAg loss.
Summary
Background
Thiopurines are widely used for the treatment of inflammatory bowel disease, but are associated with the development of side effects. It has been suggested that the enzyme inosine ...triphosphate pyrophosphatase (ITPA) plays a role in the digestion of thiopurines and that defective activity resulting from polymorphisms in the inosine triphosphate pyrophosphatase encoding genes may be associated with thiopurine‐induced side effects. Current studies are controversial regarding this hypothesis.
Aim
To perform a meta‐analysis and gain more insight into a possible correlation between thiopurine‐induced side effects and ITPA polymorphisms.
Methods
We explored Medline for articles on ITPA polymorphisms and thiopurine toxicity. Studies that compared ITPA polymorphism frequencies among thiopurine‐tolerant and ‐intolerant adult inflammatory bowel disease patients were included in this meta‐analysis.
Results
Nine published studies investigated associations between ITPA polymorphisms and thiopurine toxicity. Six studies (with 751 patients included) met our inclusion criteria and were processed in the meta‐analysis. This analysis demonstrates that the ITPA 94C→A polymorphism, is not significantly associated with any of the studied side effect parameters.
Conclusions
This meta‐analysis does not prove a correlation between the development of thiopurine toxicity and the ITPA 94C→A polymorphism. This implies that there is no clinical relevance to determine ITPA polymorphisms in thiopurine‐treated patients.
Leukocyte telomere length (LTL) might be causal in cardiovascular disease and major cancers. To elucidate the roles of genetics and geography in LTL variability across humans, we compared LTL ...measured in 1295 sub-Saharan Africans (SSAs) with 559 African-Americans (AAms) and 2464 European-Americans (EAms). LTL differed significantly across SSAs (P = 0.003), with the San from Botswana (with the oldest genomic ancestry) having the longest LTL and populations from Ethiopia having the shortest LTL. SSAs had significantly longer LTL than AAms P = 6.5(e-16) whose LTL was significantly longer than EAms P = 2.5(e-7). Genetic variation in SSAs explained 52% of LTL variance versus 27% in AAms and 34% in EAms. Adjustment for genetic variation removed the LTL differences among SSAs. LTL genetic variation among SSAs, with the longest LTL in the San, supports the hypothesis that longer LTL was ancestral in humans. Identifying factors driving LTL variation in Africa may have important ramifications for LTL-associated diseases.
Increases in prescriptions of opioid medications for chronic pain have been accompanied by increases in opioid overdoses, abuse, and other harms and uncertainty about long-term effectiveness.
To ...evaluate evidence on the effectiveness and harms of long-term (>3 months) opioid therapy for chronic pain in adults.
MEDLINE, the Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, PsycINFO, and CINAHL (January 2008 through August 2014); relevant studies from a prior review; reference lists; and ClinicalTrials.gov.
Randomized trials and observational studies that involved adults with chronic pain who were prescribed long-term opioid therapy and that evaluated opioid therapy versus placebo, no opioid, or nonopioid therapy; different opioid dosing strategies; or risk mitigation strategies.
Dual extraction and quality assessment.
No study of opioid therapy versus no opioid therapy evaluated long-term (>1 year) outcomes related to pain, function, quality of life, opioid abuse, or addiction. Good- and fair-quality observational studies suggest that opioid therapy for chronic pain is associated with increased risk for overdose, opioid abuse, fractures, myocardial infarction, and markers of sexual dysfunction, although there are few studies for each of these outcomes; for some harms, higher doses are associated with increased risk. Evidence on the effectiveness and harms of different opioid dosing and risk mitigation strategies is limited.
Non-English-language articles were excluded, meta-analysis could not be done, and publication bias could not be assessed. No placebo-controlled trials met inclusion criteria, evidence was lacking for many comparisons and outcomes, and observational studies were limited in their ability to address potential confounding.
Evidence is insufficient to determine the effectiveness of long-term opioid therapy for improving chronic pain and function. Evidence supports a dose-dependent risk for serious harms.
Agency for Healthcare Research and Quality.
Starter cultures for fermented foods are today developed mainly by design rather than by screening. The design principles are based on knowledge of bacterial metabolism and physiology as well as on ...the interaction with the food product. In the genomics era, we will obtain a wealth of data making design on a rational basis even simpler. The design tools available are food grade tools for genetic, metabolic and protein engineering and an increased use of laboratory automation and high throughput screening methods. The large body of new data will influence the future patterns of regulation. It is currently difficult to predict in what direction the future regulatory requirements will influence innovation in the food industry. It can either become a promoting force for the practical use of biotechnology to make better and safer products, or it can be limiting the use of starter cultures to a few strains with official approval. Successful cultures based on modern technology is expected to be launched in the areas of: probiotics, bioprotection, general improvement of yield and performance for the existing culture market and probably the introduction of cultures for fermenting other food products. A scientific basis for dramatic innovations that could transform the culture industry is currently being established.
PDF
