Alzheimer's disease (AD) drug development is burdened with the current requirement to conduct large, lengthy, and costly trials to overcome uncertainty in patient progression and effect size on ...treatment outcome measures. There is an urgent need for the discovery, development, and implementation of novel, objectively measured biomarkers for AD that would aid selection of the appropriate subpopulation of patients in clinical trials, and presumably, improve the likelihood of successfully evaluating innovative treatment options. Amyloid deposition and tau in the brain, which are most commonly assessed either in cerebrospinal fluid (CSF) or by molecular imaging, are consistently and widely accepted. Nonetheless, a clear gap still exists in the accurate identification of subjects that truly have the hallmarks of AD. The Coalition Against Major Diseases (CAMD), one of 12 consortia of the Critical Path Institute (C-Path), aims to streamline drug development for AD and related dementias by advancing regulatory approved drug development tools for clinical trials through precompetitive data sharing and adoption of consensus clinical data standards. This report focuses on the regulatory process for biomarker qualification, briefly comments on how it contrasts with approval or clearance of companion diagnostics, details the qualifications currently available to the field of AD, and highlights the current challenges facing the landscape of CSF biomarkers qualified as hallmarks of AD. Finally, it recommends actions to accelerate regulatory qualification of CSF biomarkers that would, in turn, improve the efficiency of AD therapeutic development.
Prolactin is a polypeptide hormone secreted by the anterior pituitary gland that plays an essential role in lactation, tissue growth, and suppressing apoptosis to increase cell survival. Prolactin ...serves as a key player in many life-critical processes, including immune system and reproduction. Prolactin is also found in multiple fluids throughout the body, including plasma and cerebrospinal fluid (CSF).
In this study, we measured prolactin levels in both plasma and CSF, and performed a genome-wide association study. We then performed meta-analyses using METAL with a significance threshold of p < 5 × 10(-8) and removed SNPs where the direction of the effect was different between the two datasets.
We identified 12 SNPs associated with increased prolactin levels in both biological fluids.
Our efforts will help researchers understand how prolactin is regulated in both CSF and plasma, which could be beneficial in research for the immune system and reproduction.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Prostatic Acid Phosphatase (PAP) is an enzyme that is produced primarily in the prostate and functions as a cell growth regulator and potential tumor suppressor. Understanding the genetic regulation ...of this enzyme is important because PAP plays an important role in prostate cancer and is expressed in other tissues such as the brain.
We tested association between 5.8 M SNPs and PAP levels in cerebrospinal fluid across 543 individuals in two datasets using linear regression. We then performed meta-analyses using METAL =with a significance threshold of p < 5 × 10(-8) and removed SNPs where the direction of the effect was different between the two datasets, identifying 289 candidate SNPs that affect PAP cerebrospinal fluid levels. We analyzed each of these SNPs individually and prioritized SNPs that had biologically meaningful functional annotations in wANNOVAR (e.g. non-synonymous, stop gain, 3' UTR, etc.) or had a RegulomeDB score less than 3.
Thirteen SNPs met our criteria, suggesting they are candidate causal alleles that underlie ACPP regulation and expression.
Given PAP's expression in the brain and its role as a cell-growth regulator and tumor suppressor, our results have important implications in brain health such as cancer and other brain diseases including neurodegenerative diseases (e.g., Alzheimer's disease and Parkinson's disease) and mental health (e.g., anxiety, depression, and schizophrenia).
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
In this Journal in 1972, 100 leaders in obstetrics and gynecology published a compelling statement that recognized the legalization of abortion in several states and anticipated the 1973 Supreme ...Court decision in Roe v Wade. They projected the numbers of legal abortions that likely would be required by women in the United States and described the role of the teaching hospital in meeting that responsibility. They wrote to express their concern for women’s health in a new legal and medical era of reproductive control and to define the responsibilities of academic obstetrician-gynecologists. Forty years later, 100 professors examine the statement of their predecessors in light of medical advances and legal changes and suggest a further course of action for obstetrician gynecologists.
The English language: A linguistic history Fitzmaurice, Susan; Brinton; Arnovick, Laurel J ; Leslie K
English Language and Linguistics,
03/2009, Letnik:
13, Številka:
1
Book Review
Recenzirano
As textbooks for two different formats of American undergraduate courses on the history of the language, each succeeds in serving its constituency (and I conclude this having taught in both formats). ...But which one would work best for the problem-based, electronically enhanced module that I teach now? Although I will unhesitatingly draw upon the questions posed and texts offered by G, and the web resources and further readings produced by both, I haven't found in either textbook the book that would fit my course. The solution? No coursebook at all but a discerning dabble in everything out there.
A number of complex factors contribute to pregnant and parenting women's alcohol and substance use. To date, little research has focused on the implications, meaning and experiences of father ...involvement on mothers with substance use problems.
The current study explores the experiences of mothers with substance use problems with respect to the role, impact and meaning of father involvement.
This study conducted two focus groups utilizing a phenomenological approach. Mothers receiving clinical services at a comprehensive, community based program serving pregnant and parenting women with substance use problems were recruited to participate in this research.
The meaning of father involvement among this group of women centered on four dimensions: emotional support, financial contributions to the family, amount and quality of time spent with the children and the family, and was dependent upon the particular expectations of the mother involved. Barriers and influences of father involvement were identified. The nature of father involvement had negative and positive impacts on participants.
Maternal use of alcohol is a complex issue, one factor often ignored in father involvement. For mothers with substance use problems father involvement has a number of implications, both positive and negative.
Protein kinase C assay-guided study of the extracts of
Pseudopterogorgia sp. led to the isolation of three new 9,11-secosterols
1–3, in addition to a known secosterol
4. The latter was converted to ...semi-synthetic sterols
6 and
7, and the structures of these were determined by the analysis of NMR and MS data. Secosterols
1–3,
6 and
7 exhibited moderate inhibitory activity aganist protein kinase C, and
6 showed potent antiproliferative and antiinflammatory activity.
Three new 9,11-secosterols
1–3, inaddition to a known secosterol
4 have been isolated from
Pseudopterogorgia sp. The latter was converted to semi-synthetic sterols
6 and
7. Secosterols
1–3,
6 and
7 exhibited moderate PKC activity, and
6 showed potent antiproliferative and antiinflammatory activity.
The purpose of this investigation was to assess the method proposed by Skieller, Björk, and Linde-Hansen in 1984 to predict mandibular growth rotation. Our sample consisted of 40 randomly selected, ...untreated, adolescent subjects representative of the patient population generally encountered in orthodontic practice. The four independent variables identified in the Skieller study as having the highest predictive value (mandibular inclination, intermolar angle, shape of the lower border of the mandible, and inclination of the symphysis) were identified on initial lateral cephalograms. The proposed regression equations were applied and predicted mandibular rotations obtained. Final lateral cephalograms made 6 years after the initial profile radiographs were superimposed and actual mandibular rotation recorded. The observed and predicted rotations were compared and regression analyses performed to determine the amount of variability in observed values accounted for by the four variables individually and in combination. Only 5.6% of the variability in mandibular growth rotation could be accounted for using the four variables individually. Only 9% of the variability could be accounted for with a combination of the variables. In addition, we performed a Monte Carlo analysis, which mirrored the Skieller analysis but used random numbers instead of actual cephalometric data, to determine if the Skieller results may simply have capitalized on chance. Using the same forward stepwise selection procedure with a rejection level of
P > .1, we found after 5000 simulations that a mean of 84% and a median of 94% of mandibular growth rotation variability could be accounted for using meaningless data in the Skieller analysis. This result was comparable to the Skieller value of 86%. In conclusion, information derived from pretreatment lateral cephalograms using the Skieller, Björk, and Linde-Hansen method does not permit clinically useful predictions to be made in a general population relative to the direction of future mandibular growth rotation. (Am J Orthod Dentofacial Orthop 1998;114:659-67)
Comprehensive data available in the Canadian province of Manitoba since 1970 have aided study of the interaction between population health, health care utilization, and structural features of the ...health care system. Given a complex linked database and many ongoing projects, better organization of available epidemiological, institutional, and technical information was needed.
The Manitoba Centre for Health Policy and Evaluation wished to develop a knowledge repository to handle data, document research Methods, and facilitate both internal communication and collaboration with other sites.
This evolving knowledge repository consists of both public and internal (restricted access) pages on the World Wide Web (WWW). Information can be accessed using an indexed logical format or queried to allow entry at user-defined points. The main topics are: Concept Dictionary, Research Definitions, Meta-Index, and Glossary. The Concept Dictionary operationalizes concepts used in health research using administrative data, outlining the creation of complex variables. Research Definitions specify the codes for common surgical procedures, tests, and diagnoses. The Meta-Index organizes concepts and definitions according to the Medical Sub-Heading (MeSH) system developed by the National Library of Medicine. The Glossary facilitates navigation through the research terms and abbreviations in the knowledge repository. An Education Resources heading presents a web-based graduate course using substantial amounts of material in the Concept Dictionary, a lecture in the Epidemiology Supercourse, and material for Manitoba's Regional Health Authorities. Confidential information (including Data Dictionaries) is available on the Centre's internal website.
Use of the public pages has increased dramatically since January 1998, with almost 6,000 page hits from 250 different hosts in May 1999. More recently, the number of page hits has averaged around 4,000 per month, while the number of unique hosts has climbed to around 400.
This knowledge repository promotes standardization and increases efficiency by placing concepts and associated programming in the Centre's collective memory. Collaboration and project management are facilitated.
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