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At least 1,639 records · Page 91Linked to original sources
PubMed2002

Human 3'-phosphoadenosine 5'-phosphosulfate synthetase 2 (PAPSS2) pharmacogenetics: gene resequencing, genetic polymorphisms and functional characterization of variant allozymes.

3'-Phosphoadenosine 5'-phosphosulfate (PAPS) is the sulfate donor cosubstrate for all sulfotransferase (SULT) enzymes. SULTs catalyze the sulfate conjugation of many endogenous and exogenous compounds, including drugs and other xenobiotics. In humans, PAPS is synthesized from adenosine 5'-triphosphate (ATP) and inorganic sulfate (SO2-4) by two isoforms, PAPSS1 and PAPSS2. Rare mutations that inactivate PAPSS2 are associated with human spondyloepimetaphyseal dysplasia and murine brachymorphism. To determine whether more common genetic polymorphisms that do not completely inactivate the enzyme might be one factor responsible for individual differences in sulfate conjugation, we previously cloned the human PAPSS2 gene. In the present studies, we 'resequenced' all twelve PAPSS2 exons and splice junctions, as well as approximately 500 bp of the 5'-flanking region, using 90 Polymorphism Discovery Resource (PDR) DNA samples from the Coriell Cell Repository. Twenty-two single nucleotide polymorphisms (SNPs) were observed, including four nonsynonymous coding region SNPs (cSNPs) that altered the following amino acids: Glu10Lys, Met281Leu,Val291Met and Arg432Lys. We also observed four insertions/deletions, including one sample that was homozygous for an 81-bp deletion in the 5'-flanking region 286 bp upstream from the site of transcription initiation. Transient expression studies showed that two of the nonsynonymous cSNPS, those that resulted in Glu10Lys and Val291Met alterations in encoded amino acids, showed significant decreases in levels of PAPSS activity. In the case of Glu10Lys, decreased activity was paralleled by a decrease in immunoreactive protein, while the Val291Met allozyme displayed a significant decrease in affinity for both ATP and Na2SO4 when compared to 'wild-type' enzyme, but without a significant alteration in level of immunoreactive protein. It will now be possible to test the hypothesis that these common, functionally significant PAPSS2 genetic polymorphisms might contribute to variations in sulfate conjugation in vivo.

Animals↗
PubMedDate not supplied

Data mining as a tool for research and knowledge development in nursing.

The ability to collect and store data has grown at a dramatic rate in all disciplines over the past two decades. Healthcare has been no exception. The shift toward evidence-based practice and outcomes research presents significant opportunities and challenges to extract meaningful information from massive amounts of clinical data to transform it into the best available knowledge to guide nursing practice. Data mining, a step in the process of Knowledge Discovery in Databases, is a method of unearthing information from large data sets. Built upon statistical analysis, artificial intelligence, and machine learning technologies, data mining can analyze massive amounts of data and provide useful and interesting information about patterns and relationships that exist within the data that might otherwise be missed. As domain experts, nurse researchers are in ideal positions to use this proven technology to transform the information that is available in existing data repositories into useful and understandable knowledge to guide nursing practice and for active interdisciplinary collaboration and research.

Algorithms↗
PubMed1998

Research potentials and pitfalls in the use of an HIV clinical database: Chelsea and Westminster Hospital.

This article summarizes the various problems and pitfalls in using clinical databases for epidemiologic research, with particular reference to an HIV clinical database. The combined population of HIV-infected individuals attending the Chelsea and Westminster Hospital, the Charing Cross Hospital, and the Victoria Clinic in London is the largest cohort of HIV-positive individuals in the U.K. A computerized database was developed in the mid-1980s and was adapted into a clinically oriented observational database for approximately 6,653 HIV-1-positive registered patients from three hospital-based clinics within the Riverside Health Authority in London, U.K.: Chelsea and Westminster Hospital Clinic (n = 5,000); Charing Cross Hospital (n = 500); and the Victoria Clinic (n = 500). The majority (83%) of HIV-infected patients registered at these sites are homosexual or bisexual men. Of 2,078 patients seen within the last 6 months, 22% are asymptomatic and 33% have AIDS; 30% have a CD4 cell count of less than 100 cells/mm3 and 17% have a CD4 cell count of greater than 500 cells/mm3. Dates of seroconversion are known for approximately 285 patients. For each patient, information on demographic characteristics, clinical symptoms, and HIV-related diagnoses, outpatient pharmacy prescriptions, day care treatments and procedures, and enrollment into clinical trials is routinely collected at outpatient clinic visits and entered into the database. Inpatient diagnoses and treatments were integrated into the database in September 1995. Unused serum samples from routine AIDS antibody or antigen testing are stored in a local specimen repository. The main purpose of the HIV database is to provide a multipurpose resource for use by physicians, researchers, and managers for administration, clinical care, and research. The specific functions of the database are the following: to enhance patient management by providing access to a clinical summary sheet detailing up-to-date information; to serve as a research tool for clinical and epidemiologic research; to aid in the identification of patients eligible for planned or ongoing clinical trials; to provide a facility for local and regional AIDS surveillance and reporting; and to provide a facility for administration and resource management of HIV services. The major limitations of this database in the conduct of clinical research have been losses to follow-up and incomplete information about clinical outcomes, because physicians have failed to update the clinical information.

Acquired Immunodeficiency Syndrome↗
PubMedDate not supplied

A model "go-kit" for use at Strategic National Stockpile Points of Dispensing.

The Strategic National Stockpile (SNS) is a national repository of pharmaceuticals and other medical supplies forseeably needed during a medical disaster. In the event of SNS deployment, state and local public health authorities must be prepared to receive, distribute, and dispense the materials. We propose a cache of supplies, termed the "POD go-kit," prepared in advance and locally available prior to the establishment of Points of Dispensing (POD) for SNS material. Characteristics of the preassembled go-kit are its multiplicity of use, ease of storage and transportation, minimal redundancy with SNS material, and packaging in a manner consistent with POD function. The POD go-kit is assembled into 4 separate "subkits": administrative supplies, patient routing supplies, dispensing supplies, and POD staff protection supplies. Incorporating existing practices from the SNS Listserv, this article itemizes the contents of the POD go-kit and its subkits and provides a rationale for its packaging. The Division of Strategic National Stockpile (DSNS) has not certified the proposed "POD go-kit" as a standardized POD go-kit.

Disasters↗
PubMed2001

Tissue microarrays: what will they bring to molecular and anatomic pathology?

The analysis of a large number of tumor tissues with conventional techniques of molecular pathology is tedious and slow. The authors recently developed the tissue microarray technology that makes it possible to sample up to 1,000 tumors on one glass slide, which then can be analyzed by fluorescence in situ hybridization, RNA in situ hybridization, or immunohistochemistry. The tissue microarray technology has the potential to significantly accelerate molecular studies that seek associations between molecular changes and clinicopathologic features of the cancer. Examples of potential applications for tissue microarrays include testing and optimization of probes and antibodies, the organization of large tissue repositories, and the facilitation of multicenter studies. Further, tissue microarrays can be used for educational purposes as well as to improve quality control and standardization of staining methods and interpretation. Tissue microarrays have become one of the most promising tools for the molecular and anatomic pathologist and will have many applications in cancer research, as well as in other fields of pathology. This review article gives an overview of current applications of tissue microarrays as well as possible future development of the technology.

Female↗
PubMedDate not supplied

Consent for genetic research in a general population: the NHANES experience.

PURPOSE: To determine the sociodemographic factors associated with consent for storage of DNA for future genetic research. METHODS: Analysis of the characteristics of consenting individuals participating in the National Health and Nutrition Examination Survey, a nationally representative survey of the US household population. RESULTS: In 1999, 84% (95% confidence interval 82.4-85.6) of eligible participants consented to have their blood samples included in a national repository for genetic research. In 2000, 85.3% (95% confidence interval 84.0-86.6) consented. Females and black participants in both years were least likely to consent (1999, 82.2% and 73.2%; 2000, 83.6% and 81.3%, respectively). An assessment by logistic regression demonstrated that in both years only non-Hispanic black race/ethnicity was a significant independent predictor for not consenting to future genetic research. CONCLUSION: Although non-Hispanic black individuals have overall response rates similar to those of the other racial/ethnic groups, they are less likely to agree to have a blood sample saved for future genetic research. In balance, however, these findings demonstrate wide acceptance among survey participants for allowing storage of specimens for future genetic research across many demographic variables.

Adult↗
PubMed2005

Detection of cervical human papillomavirus infection by in situ hybridization in fetuses from women with squamous intraepithelial lesions.

OBJECTIVE: To evaluate for human papillomavirus (HPV) infection in the cervix of fetuses from mothers with documented squamous intraepithelial lesions. METHODS: Fetal cervical epithelium was obtained from the Human Fetal Tissue Repository as per Institutional Review Board protocol. Fetal cervical epithelium was dissected, fixed in formalin, and embedded in paraffin. Sections were tested by in situ hybridization using a wide-spectrum HPV DNA probe. Cases were specimens from mothers with low- and high-grade squamous intraepithelial lesions, and controls were specimens from women with no documented squamous intraepithelial lesions. RESULTS: A total of 14 controls and 10 cases were evaluated for HPV DNA. No reactivity was detected in the controls. Two cases showed focal intracellular reactivity with the HPV DNA probe. CONCLUSION: To our knowledge, this is the first study demonstrate fetal cervical HPV infection due to intrauterine exposure. These findings have important implications in understanding the pathogenesis of cervical neoplasia and its management.

Carcinoma, Squamous Cell↗
PubMed1989

Histologic and statistical studies on hyalin bodies in the human endolymphatic sac.

Hyalin bodies are amorphous, eosinophilic masses that protrude from the subepithelial connective tissue into the lumen of the endolymphatic sac. In this study, hyalin bodies were analyzed in two groups of temporal bones: normal bones and bones with cochlear otosclerosis. The results revealed that bones with cochlear otosclerosis had significantly more and larger hyalin bodies that did normal bones. In addition, the hyalin bodies in cochlear otosclerosis were denser and associated with more edema and loose connective tissue in the surrounding areas. Foamy macrophages, concentric calcific structures, and bony ingrowth were frequent features of the hyalin bodies in the cochlear otosclerosis. Our current hypothesis is that these hyalin bodies are repository of membranous cellular debris phagocytized by the macrophages. If this is true, the hyalin bodies may further support the proposed resorptive and phagocytic functions of the endolymphatic sac and the enzymatic concept in cochlear otosclerosis.

Adolescent↗
PubMed1989

Electron microscopy of hyalin bodies in the human intraosseous endolymphatic sac.

Hyalin bodies are amorphous, eosinophilic masses protruding from the subepithelial connective tissue into the lumen of the intraosseous endolymphatic sac (ES). We studied hyalin bodies at the electron microscopic level. Celloidin- embedded temporal bone sections known to have hyalin bodies were re-embedded into plastic and cut into thin sections appropriate for electron microscopy. The results revealed that the hyalin bodies are composed predominantly of thick bundles of collagenous fibers arranged in various directions. Fibroblasts and disintegrated macrophages were occasionally observed among the collagen fibers. Concentric calcific structures found within the hyalin bodies were composed of multiple smaller, concentric, lamellar calcifications. The results of this study support the hypothesis that the hyalin bodies are a repository of membranous cellular debris phagocytized by the macrophages.

Calcinosis↗
PubMed2002

Deoxyribonucleic acid contamination in archival human temporal bones: a potentially significant problem.

HYPOTHESIS: Contamination of archival human temporal bones with extraneous deoxyribonucleic acid may represent a potentially significant problem in the analysis of nucleic acids isolated from archival specimens. BACKGROUND: During the past decade, there has been growing interest in the development of molecular biologic techniques that can be applied to the investigation of pathologic changes in archival human temporal bones. The impetus for the development of these techniques is in part related to the fact that the temporal bone collections represent a repository of archival material compiled over decades, which is not available from living patients. METHODS: An archival human temporal bone specimen from a male patient with the Mohr-Tranebjaerg syndrome (formerly called DFN-1) and a well-characterized mutation was analyzed for the presence of the mutation by a standard method for extraction, isolation, amplification, and sequencing of deoxyribonucleic acid. The experiment was repeated four times. RESULTS: The deoxyribonucleic acid sequence from three of four extractions was normal. The known mutation was easily and repeatedly demonstrated in a blood sample from the same individual. Because Mohr-Tranebjaerg syndrome is X-linked, there is only one allele, and therefore there is no potential endogenous source to account for the normal sequence that was amplified. Contamination of the tissue sections by extraneous deoxyribonucleic acid presumably occurred during acquisition and processing of the temporal bone. CONCLUSIONS: Contamination of archival temporal bones with exogenous deoxyribonucleic acid is a significant potential problem that must be considered in the interpretation of the results of deoxyribonucleic acid retrieved from archival sections. The authors recommend collecting blood samples from temporal bone donors in the future to ensure the availability of a reliable source of deoxyribonucleic acid.

Aged↗
PubMed2005

Mitochondrial haplogroups and peripheral neuropathy during antiretroviral therapy: an adult AIDS clinical trials group study.

OBJECTIVE: HIV nucleoside reverse transcriptase inhibitors (NRTI) can cause peripheral neuropathy that is a result of mitochondrial injury. Polymorphisms in the mitochondrial genome define haplogroups that may have functional implications. The objective of this study was to determine if NRTI-associated peripheral neuropathy is associated with European mitochondrial haplogroups. DESIGN: Case-control study of Adult AIDS Clinical Trials Group (ACTG) study 384 and ACTG Human DNA Repository participants. METHODS: ACTG study 384 was a treatment strategy trial of antiretroviral therapy with didanosine (ddI) plus stavudine (d4T) or zidovudine plus lamivudine given with efavirenz, nelfinavir, or both. Subjects were followed for up to 3 years. Peripheral neuropathy was ascertained based on signs and symptoms. For this analysis, polymorphisms that define European mitochondrial haplogroups were characterized in a majority of ACTG 384 participants, and associations with peripheral neuropathy were assessed using logistic regression. RESULTS: A total of 509 subjects were included in this analysis of whom 250 (49%) were self-identified as white, non-Hispanic. Mitochondrial haplogroup T was more frequent in subjects who developed peripheral neuropathy. Among 137 white subjects randomized to receive ddI plus d4T, 20.8% of those who developed peripheral neuropathy belonged to mitochondrial haplogroup T compared to 4.5% of control subjects (odds ratio, 5.4; 95% confidence interval, 1.4-25.1; P = 0.009). Independent predictors of peripheral neuropathy were randomization to receive ddI plus d4T, older age, and mitochondrial haplogroup T. CONCLUSIONS: A common European mitochondrial haplogroup may predict NRTI-associated peripheral neuropathy. Future studies should validate this relationship, and evaluate non-European mitochondrial haplogroups and other NRTI toxicities.

Adolescent↗
PubMed2006

Hemochromatosis (HFE) gene mutations and peripheral neuropathy during antiretroviral therapy.

OBJECTIVE: Peripheral neuropathy (PN) often complicates nucleoside reverse transcriptase inhibitor (NRTI) therapy of HIV infection and may involve mitochondrial dysfunction. Since iron deficiency is associated with some types of PN, and iron is essential for mitochondrial function, we tested the hypothesis that hemochromatosis (HFE) gene mutations influence susceptibility to NRTI-induced PN. DESIGN: Case-control study involving multicenter, AIDS Clinical Trials Group (ACTG) protocol 384 and ACTG Human DNA Repository specimens. METHODS: Study participants were randomized to receive three- or four-drug antiretroviral therapy with didanosine (ddI) plus stavudine (d4T) or zidovudine plus lamivudine, given with efavirenz, nelfinavir, or both, with up to three years of follow-up. PN was ascertained based on signs and symptoms. HFE C282Y and H63D genotypes were determined, and associations with PN were assessed using logistic regression. RESULTS: : Of 509 participants, 147 (29%) developed PN, 73% of whom had been randomized to receive ddI plus d4T. Among ddI/d4T-ever-treated individuals, HFE C282Y heterozygotes developed PN on ddI/d4T significantly less often than C282Y non-carriers, adjusting for age, CD4 lymphocyte count and viral load at baseline, and concomitant antiretroviral drugs [6% vs. 35%, respectively, in whites; adjusted odds ratio (OR), 0.17; 95% confidence interval (CI) 0.03-0.83; P = 0.021]. Regardless of race/ethnicity, ddI/d4T-associated PN was uncommon in C282Y heterozygotes [race-adjusted OR, 0.30; 95% CI 0.09-0.96); P = 0.042]. CONCLUSIONS: Iron-loading HFE mutations such as C282Y are associated with a decreased risk of PN during antiretroviral therapy. This finding has potential implications for the prediction and prevention of NRTI-associated PN, particularly in populations at risk of iron deficiency.

Adolescent↗
PubMed2006

Sample bias among women with retained DNA samples for future genetic studies.

OBJECTIVE: To evaluate whether women who agree to future use of their biologic specimens for genetic studies reflect the larger study population from which they are derived. METHODS: Women were questioned as to the future disposition of their maternal and fetal DNA samples upon enrollment in a multicenter, observational study originally designed to identify factor V Leiden mutation carriers and prospectively ascertain the estimated rate of pregnancy-related venous thromboembolism and adverse pregnancy outcome. Univariate and multivariate analyses was carried out on the 5,003 of 5,188 enrolled women who indicated their desire regarding future disposition of their DNA samples. RESULTS: Among these 5,003 women, 20.1% desired that their samples be discarded and not available for future genetic studies. Multivariate analysis demonstrated that women who agreed to subsequent use of samples were less likely African-American (odds ratio [OR] 0.6, 95% confidence interval [CI] 0.4-0.7) or Hispanic (OR 0.4, 95% CI 0.3-0.5), and more likely to use tobacco (OR 1.2, 95% CI 1.0-1.6) than those who desired that their samples be discarded. CONCLUSION: Genetic samples from women agreeing to their use in a sample repository may not be representative of the index study cohort. This should be considered in their subsequent interpretation and generalizability. LEVEL OF EVIDENCE: III.

Adult↗
PubMed2003

Genetic determinants of diabetic nephropathy: The family investigation of nephropathy and diabetes (FIND).

Diabetes mellitus is the leading cause of ESRD in the United States. Family-based studies and segregation analyses suggest that inherited factors play a major role in susceptibility to diabetic renal complications, including albuminuria and chronic kidney failure. The Family Investigation of Nephropathy and Diabetes (FIND) study is a multicenter consortium established by the National Institute of Diabetes, Digestive and Kidney Diseases to identify the gene(s) responsible for diabetic nephropathy. Eight participating centers will enroll nearly 10,000 individuals by September 2004. Two independent strategies to detect causative genes will be used. These include family-based linkage analyses in African-American, American-Indian, Mexican-American, and European-American families (predominantly affected and discordant relative pair analyses) and mapping by admixture linkage disequilibrium (MALD) in African and Mexican Americans. Cell lines are being created from participants, and a repository containing stored urine and serum samples has been developed. This paper describes the enrollment criteria and methods used in FIND to allow for the detection of gene(s) predisposing to diabetic nephropathy.

Adult↗
PubMed2006

Does universal newborn hearing screening identify all children with GJB2 (Connexin 26) deafness? Penetrance of GJB2 deafness.

OBJECTIVE: Deafness is the most common neurosensory defect at birth, and GJB2 (connexin 26) mutations are the most frequent genetic cause of hearing loss in many populations. The hearing loss caused by GJB2 mutations is usually congenital in onset and moderate to profound in degree. Considerable phenotypic variation has been noted however, including two anecdotal cases of apparent non penetrance at birth. The objective of this study is to document nine additional children with two pathogenic GJB2 mutations who had non penetrance of hearing loss at birth. DESIGN: Subjects were identified through a national repository which includes deaf probands ascertained primarily from the United States through the Annual Survey of Deaf and Hard of Hearing Children and Youth conducted at the Research Institute at Gallaudet University. The hearing of each of these children had been screened at birth using standard audiologic techniques. Parents were interviewed and available medical records were reviewed. Testing for GJB2 mutations was performed by PCR and sequencing of the entire coding exon in all nine individuals. RESULTS: Using parent interviews and medical records, we documented that all nine children passed newborn audiologic hearing screening. The age at which the hearing loss was subsequently identified in these nine children ranged from 12-60 mo. Of these nine children, 3 were compound heterozygotes and six were homozygous for the 35delG mutation in the GJB2 gene. CONCLUSION: These nine cases demonstrate that current newborn hearing screening does not identify all infants with two GJB2 mutations. These cases suggest that the frequency of non penetrance at birth is approximately 3.8% or higher. It is important to consider connexin deafness in any child with recessive nonsyndromic hearing loss as well as simplex cases with no history of other affected family members even when the newborn hearing screening results were within the normal range.

Audiometry, Evoked Response↗
PubMed2005

METLIN: a metabolite mass spectral database.

Endogenous metabolites have gained increasing interest over the past 5 years largely for their implications in diagnostic and pharmaceutical biomarker discovery. METLIN (http://metlin.scripps.edu), a freely accessible web-based data repository, has been developed to assist in a broad array of metabolite research and to facilitate metabolite identification through mass analysis. METLINincludes an annotated list of known metabolite structural information that is easily cross-correlated with its catalogue of high-resolution Fourier transform mass spectrometry (FTMS) spectra, tandem mass spectrometry (MS/MS) spectra, and LC/MS data.

Biomarkers↗
PubMed2005

Developing a sustainable process to provide quality control materials for genetic testing.

PURPOSE: To provide a summary of the outcomes of two working conferences organized by the Centers for Disease Control and Prevention (CDC), to develop recommendations for practical, sustainable mechanisms to make quality control (QC) materials available to the genetic testing community. METHODS: Participants were selected to include experts in genetic testing and molecular diagnostics from professional organizations, government agencies, industry, laboratories, academic institutions, cell repositories, and proficiency testing (PT)/external Quality Assessment (EQA) programs. Current efforts to develop QC materials for genetic tests were reviewed; key issues and areas of need were identified; and workgroups were formed to address each area of need and to formulate recommendations and next steps. RESULTS: Recommendations were developed toward establishing a sustainable process to improve the availability of appropriate QC materials for genetic testing, with an emphasis on molecular genetic testing as an initial step. CONCLUSIONS: Improving the availability of appropriate QC materials is of critical importance for assuring the quality of genetic testing, enhancing performance evaluation and PT/EQA programs, and facilitating new test development. To meet the needs of the rapidly expanding capacity of genetic testing in clinical and public health settings, a comprehensive, coordinated program should be developed. A Genetic Testing Quality Control Materials Program has therefore been established by CDC in March 2005 to serve these needs.

Centers for Disease Control and Prevention, U.S.↗
PubMed2006

Consent for genetic research in a general population: an update on the National Health and Nutrition Examination Survey experience.

PURPOSE: The study determines the consent rates for storage of biologic samples for future research with and without genetic studies and describes trends in sociodemographic factors associated with consent. METHODS: We performed an analysis of the characteristics of consenting individuals participating in three data cycles of the National Health and Nutrition Examination Survey, a nationally representative survey of the U.S. population. RESULTS: In the 1999 to 2000 and the 2001 and 2002 surveys, 84.8% and 90.1% of eligible participants, respectively, consented to have their biologic samples including DNA stored in a national repository. Female and non-Hispanic black participants were least likely to consent when genetic studies and DNA were included. In the 2003 to 2004 survey, with the discontinuation of the DNA collection, 98.4% signed the consent document and these race/gender differences were no longer observed. CONCLUSION: Females and non-Hispanic blacks consistently had lower consent rates during the survey years when genetic studies were mentioned in the consent, but once DNA collection was discontinued these differences disappeared. These findings demonstrate wide acceptance among survey participants for allowing storage of specimens for future studies but indicate the need to explore race/gender issues with the collection and storage of DNA for genetic research.

Adult↗