Revolutionizing Alzheimer\u27s disease and clinical trials through biomarkers

AbstractThe Alzheimer's Association's Research Roundtable met in May 2014 to explore recent progress in developing biomarkers to improve understanding of disease pathogenesis and expedite drug development. Although existing biomarkers have proved extremely useful for enrichment of subjects in clinical trials, there is a clear need to develop novel biomarkers that are minimally invasive and that more broadly characterize underlying pathogenic mechanisms, including neurodegeneration, neuroinflammation, and synaptic dysfunction. These may include blood-based assays and new neuropsychological testing protocols, as well as novel ligands for positron emission tomography imaging, and advanced magnetic resonance imaging methodologies. In addition, there is a need for biomarkers that can serve as theragnostic markers of response to treatment. Standardization remains a challenge, although international consortia have made substantial progress in this area and provide lessons for future standardization efforts

Susceptibility of Eggs and Adult Fecundity of the Lesser Grain Borer, Rhyzopertha dominca, Exposed to Methoprene

A series of tests were conducted to determine the susceptibility of eggs and neonates of the lesser grain borer Rhyzopertha dominica (F.) (Coleoptera: Bostrichidae = Bostrychidae), exposed to the insect growth regulator, methoprene, on filter paper and on rough rice. In the first test, the hatch rate of eggs exposed on filter paper treated with methoprene at the label rate of 0.003 mg [AI]/cm2 when used as a surface treatment in structures was 52.0 ± 7.3% compared to 93.0 ± 3.3% on untreated controls. In the second test, eggs were exposed to a dose-response series of 0.00003 to 0.03 mg[AI]/cm2. Egg hatch was directly proportional to concentration and ranged from 85.0 ± 2.0% on untreated controls to 26.7 ± 8.3% at the highest concentration tested. In the third test, 1 ppm of methoprene was sprayed on long grain rough rice (paddy) (Cocodrie variety), and then individual kernels were cracked and an egg of R. dominica was placed directly on the kernel. On untreated rice kernels, 67.5 ± 11.6% of the eggs hatched and were able to bore inside, and all of these larvae emerged as adults. In contrast, 40.0 ± 5.3% of the eggs placed on treated cracked kernels were able to develop to where the larvae were visible through X-ray detection, but none emerged as adults. In the final test, newly-emerged adults were exposed on rough rice treated with 1 ppm methoprene. The number of eggs from adults on untreated rice was 52.1 ± 4.3 eggs per female, and on treated rice the average egg production was 12.5 ± 1.1 eggs per female. Methoprene applied on a surface or on rough rice affected development of egg hatch also reduced fecundity of parent adults exposed on the treated rough rice

Comparative study of imaging at 3.0 T versus 1.5 T of the knee

The objectives of the study were to compare MR imaging at 1.5 and 3.0 T in the same patients concerning image quality and visualization of cartilage pathology and to assess diagnostic performance using arthroscopy as a standard of reference. Twenty-six patients were identified retrospectively as having comparative 1.5 and 3.0 T MR studies of the knee within an average of 102 days. Standard protocols included T1-weighted and fat-saturated intermediate-weighted fast spin-echo sequences in three planes; sequence parameters had been adjusted to account for differences in relaxation at 3.0 T. Arthroscopy was performed in 19 patients. Four radiologists reviewed each study independently, scored image quality, and analyzed pathological findings. Sensitivities, specificities, and accuracies in diagnosing cartilage lesions were calculated in the 19 patients with arthroscopy, and differences between 1.5 and 3.0 T exams were compared using paired Student’s t tests with a significance threshold of p < 0.05. Each radiologist scored the 3.0 T studies higher than those obtained at 1.5 T in visualizing anatomical structures and abnormalities (p < 0.05). Using arthroscopy as a standard of reference, diagnosis of cartilage abnormalities was improved at 3.0 T with higher sensitivity (75.7% versus 70.6%), accuracy (88.2% versus 86.4%), and correct grading of cartilage lesions (51.3% versus 42.9%). Diagnostic confidence scores were higher at 3.0 than 1.5 T (p < 0.05) and signal-to-noise ratio at 3.0 T was approximately twofold higher than at 1.5 T. MRI at 3.0 T improved visualization of anatomical structures and improved diagnostic confidence compared to 1.5 T. This resulted in significantly better sensitivity and grading of cartilage lesions at the knee

“cAMP Sponge”: A Buffer for Cyclic Adenosine 3′, 5′-Monophosphate

Background: While intracellular buffers are widely used to study calcium signaling, no such tool exists for the other major second messenger, cyclic AMP (cAMP). Methods/Principal Findings: Here we describe a genetically encoded buffer for cAMP based on the high-affinity cAMP-binding carboxy-terminus of the regulatory subunit $RI\beta$ of protein kinase A (PKA). Addition of targeting sequences permitted localization of this fragment to the extra-nuclear compartment, while tagging with mCherry allowed quantification of its expression at the single cell level. This construct (named “cAMP sponge”) was shown to selectively bind cAMP in vitro. Its expression significantly suppressed agonist-induced cAMP signals and the downstream activation of PKA within the cytosol as measured by FRET-based sensors in single living cells. Point mutations in the cAMP-binding domains of the construct rendered the chimera unable to bind cAMP in vitro or in situ. Cyclic AMP sponge was fruitfully applied to examine feedback regulation of gap junction-mediated transfer of cAMP in epithelial cell couplets. Conclusions: This newest member of the cAMP toolbox has the potential to reveal unique biological functions of cAMP, including insight into the functional significance of compartmentalized signaling events

Introducing the national COPD resources and outcomes project

<p>Abstract</p> <p>Background</p> <p>We report baseline data on the organisation of COPD care in UK NHS hospitals participating in the National COPD Resources and Outcomes Project (NCROP).</p> <p>Methods</p> <p>We undertook an initial survey of participating hospitals in 2007, looking at organisation and performance indicators in relation to general aspects of care, provision of non-invasive ventilation (NIV), pulmonary rehabilitation, early discharge schemes, and oxygen. We compare, where possible, against the national 2003 audit.</p> <p>Results</p> <p>100 hospitals participated. These were typically larger sized Units. Many aspects of COPD care had improved since 2003. Areas for further improvement include organisation of acute care, staff training, end-of-life care, organisation of oxygen services and continuation of pulmonary rehabilitation.</p> <p>Conclusion</p> <p>Key Points: positive change occurs over time and repeated audit seems to deliver some improvement in services. It is necessary to assess interventions such as the Peer Review used in the NCROP to achieve more comprehensive and rapid change.</p

Methods for specifying the target difference in a randomised controlled trial : the Difference ELicitation in TriAls (DELTA) systematic review

Peer reviewedPublisher PD

Health-promoting behaviors and social support of women of reproductive age, and strategies for advancing their health: Protocol for a mixed methods study

<p>Abstract</p> <p>Background</p> <p>Determining the health-promoting behaviors of women during the important period of reproduction provides valuable information for designing appropriate intervention programs for advancing women's health. There is no study on the health-promoting behaviors of women of reproductive age in Iran. Thus, the aim of this study is to explore these health-promoting behaviors for the purpose of developing comprehensive and culturally sensitive health advancement strategies for Iranian women.</p> <p>Methods/Design</p> <p>This study has a sequential explanatory mixed methods design. The follow-up explanation model is used to elaborate the quantitative results by collecting qualitative data from participants who could best assist in elucidating the results. The study is conducted in two sequential phases. The first phase is a population-based cross-sectional survey in which 1350 Iranian women of reproductive age are selected by proportional random multistage cluster sampling of the 22 main municipal sectors of Tehran, Iran. Questionnaires are completed through a face-to-face interview. The second phase is a qualitative study in which participants are selected using purposive sampling in the form of extreme case sampling on the basis of health-promoting behavior scores. The qualitative phase is based on data collected from focus group discussions or individual in-depth interviews. A conventional qualitative content analysis approach is used, and the data are managed with a computer-assisted program. Women's health-promoting strategies are developed using the qualitative and quantitative results, a review of the related literature, and the nominal group technique among experts.</p> <p>Discussion</p> <p>The findings of this mixed methods sequential explanatory study, obtained using a culturally sensitive approach, provide insights into the health behavioral factors that need to be considered if preventive strategies and intervention programs are to be designed to promote women's health in the community.</p

Is DRE essential for the follow up of prostate cancer patients? A prospective audit of 194 patients

BACKGROUND: Prostate cancer follow up forms a substantial part of the urology outpatient workload. Nurse led prostate cancer follow up clinics are becoming more common. Routine follow-up may involve performing DRE, which may require training. OBJECTIVES: The aim of this audit was to assess the factors that influenced the change in the management of prostate cancer patients during follow up. This would allow us to pave the way towards a protocol driven follow up clinic led by nurse specialists without formal training in DRE. RESULTS: 194 prostate cancer patients were seen over a period of two months and all the patients had DRE performed on at least one occasion. The management was changed in 47 patients. The most common factor influencing this change was PSA trend. A change in DRE findings influenced advancement of the clinic visit in 2 patients. CONCLUSIONS: PSA is the most common factor influencing change in the management of these patients. Nurse specialists can run prostate cancer follow-up clinics in parallel to existing consultant clinics and reserve DRE only for those patients who have a PSA change or have onset of new symptoms. However larger studies are required involving all the subgroups of patients to identify the subgroups of patients who will require DRE routinely

Impacts of large-scale climatic disturbances on the terrestrial carbon cycle

BACKGROUND: The amount of carbon dioxide in the atmosphere steadily increases as a consequence of anthropogenic emissions but with large interannual variability caused by the terrestrial biosphere. These variations in the CO(2 )growth rate are caused by large-scale climate anomalies but the relative contributions of vegetation growth and soil decomposition is uncertain. We use a biogeochemical model of the terrestrial biosphere to differentiate the effects of temperature and precipitation on net primary production (NPP) and heterotrophic respiration (Rh) during the two largest anomalies in atmospheric CO(2 )increase during the last 25 years. One of these, the smallest atmospheric year-to-year increase (largest land carbon uptake) in that period, was caused by global cooling in 1992/93 after the Pinatubo volcanic eruption. The other, the largest atmospheric increase on record (largest land carbon release), was caused by the strong El Niño event of 1997/98. RESULTS: We find that the LPJ model correctly simulates the magnitude of terrestrial modulation of atmospheric carbon anomalies for these two extreme disturbances. The response of soil respiration to changes in temperature and precipitation explains most of the modelled anomalous CO(2 )flux. CONCLUSION: Observed and modelled NEE anomalies are in good agreement, therefore we suggest that the temporal variability of heterotrophic respiration produced by our model is reasonably realistic. We therefore conclude that during the last 25 years the two largest disturbances of the global carbon cycle were strongly controlled by soil processes rather then the response of vegetation to these large-scale climatic events