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Biomedical subjects

R Long

Publications and source records attributed to R Long.

At least 19 recordsLinked to original sources
PubMed2006

Neuregulin 1 (8p12) and childhood-onset schizophrenia: susceptibility haplotypes for diagnosis and brain developmental trajectories.

Childhood-onset schizophrenia (COS), defined as onset of psychosis by the age of 12, is a rare and malignant form of the illness, which may have more salient genetic influence. Since the initial report of association between neuregulin 1 (NRG1) and schizophrenia in 2002, numerous independent replications have been reported. In the current study, we genotyped 56 markers (54 single-nucleotide polymorphisms (SNPs) and two microsatellites) spanning the NRG1 locus on 78 COS patients and their parents. We used family-based association analysis for both diagnostic (extended transmission disequilibrium test) and quantitative phenotypes (quantitative transmission disequilibrium test) and mixed-model regression. Most subjects had prospective anatomic brain magnetic resonance imaging (MRI) scans at 2-year intervals. Further, we genotyped a sample of 165 healthy controls in the MRI study to examine genetic risk effects on normal brain development. Individual markers showed overtransmission of alleles to affecteds (P=0.009-0.05). Further, several novel four-marker haplotypes demonstrated significant transmission distortion. There was no evidence of epistasis with SNPs in erbB4. The risk allele (0) at 420M9-1395 was associated with poorer premorbid social functioning. Further, possession of the risk allele was associated with different trajectories of change in lobar volumes. In the COS group, risk allele carriers had greater total gray and white matter volume in childhood and a steeper rate of subsequent decline in volume into adolescence. By contrast, in healthy children, possession of the risk allele was associated with different trajectories in gray matter only and was confined to frontotemporal regions, reflecting epistatic or other illness-specific effects mediating NRG1 influence on brain development in COS. This replication further documents the role of NRG1 in the abnormal brain development in schizophrenia. This is the first demonstration of a disease-specific pattern of gene action in schizophrenia.

Adolescent↗
PubMed2005

Multicolour FISH and quantitative PCR can detect submicroscopic deletions in holoprosencephaly patients with a normal karyotype.

Holoprosencephaly (HPE) is the most common structural malformation of the developing forebrain. At birth, nearly 50% of children with HPE have cytogenetic anomalies. Approximately 20% of infants with normal chromosomes have sequence mutations in one of the four main HPE genes (SHH, ZIC2, SIX3, and TGIF). The other non-syndromic forms of HPE may be due to environmental factors or mutations in other genes, or potentially due to submicroscopic deletions of HPE genes. We used two complementary assays to test for HPE associated submicroscopic deletions. Firstly, we developed a multicolour fluorescent in situ hybridisation (FISH) assay using probes for the four major HPE genes and for two candidate genes (DISP1 and FOXA2). We analysed lymphoblastoid cell lines (LCL) from 103 patients who had CNS findings of HPE, normal karyotypes, and no point mutations, and found seven microdeletions. We subsequently applied quantitative PCR to 424 HPE DNA samples, including the 103 samples studied by FISH: 339 with CNS findings of HPE, and 85 with normal CNS and characteristic HPE facial findings. Microdeletions for either SHH, ZIC2, SIX3, or TGIF were found in 16 of the 339 severe HPE cases (that is, with CNS findings; 4.7%). In contrast, no microdeletion was found in the 85 patients at the mildest end of the HPE spectrum. Based on our data, microdeletion testing should be considered as part of an evaluation of holoprosencephaly, especially in severe HPE cases.

Base Sequence↗
PubMed2004

Prognostic markers in node-negative breast cancer: a prospective study.

BACKGROUND: Despite years of research, it is still unclear which women with node-negative (N-) breast cancer will need adjuvant chemotherapy and which women are being treated unnecessarily. Our goal was to determine which factors best predicted disease free survival (DFS) or cancer-specific overall survival (OS) and, therefore, select the correct patients for treatment. A total of 11 parameters were measured: estrogen receptor (ER), progesterone receptor (PR), age, race, ploidy status, %G0/G1 (% non-DNA synthesis), %S (% S-phase), cathepsin D status, size, stage, and histologic grade. RESULTS: In this prospective study, we followed 556 N- patients diagnosed between 1991 and 1996. The tumors were 56% ER+, 51% PR+, 30% diploid, with a mean %S of 8.9%. The level of cathepsin D ranged from 0.50 to 155 pmol/mg of protein with a mean of 42.9 pmol/mg of protein. There were 87 recurrences (16%) and 72 cancer deaths (13%), with a median follow-up of 7.8 years. Ploidy status (p = 0.01), S-phase activity (p = 0.003), G1 phase activity (p = 0.02) and age (p = 0.01) were able to significantly predict DFS in a univariate manner. All of the measurable factors were significant or borderline significant in predicting OS in a univariate manner except for age, race, and ER status. In multivariate analysis with S-phase included, it was the only remaining factor in DFS and OS; with S-phase excluded, age and ploidy status remained as factors for DFS in stepwise regression, while PR, size, and cathepsin D were the remaining factors that predicted cancer-specific OS. The effect of adjuvant treatment on prognosis was also analyzed. CONCLUSIONS: Both biochemical and clinical parameters have the potential to predict prognosis for N- breast cancer. In this large prospective clinical trial, with a median follow-up of 7.8 years, no individual marker adequately predicted the prognosis for an individual patient. %S activity was the best independent marker, but only 77% of the tumors provided this value. Subset analysis provided improved prognostication, but there were limits to its utility. These data represents a definitive study starting in 1991 and ending in 2002.

Adult↗
PubMed2004

Transmission characteristics of tuberculosis in the foreign-born and the Canadian-born populations of Alberta, Canada.

SETTING: All notified cases of tuberculosis in the province of Alberta, Canada, 1994-1998. OBJECTIVE: To compare the transmission characteristics of tuberculosis among foreign-born and Canadian-born cases. DESIGN: Retrospective analysis using DNA fingerprinting (IS6110 restriction fragment length polymorphism and spoligotyping) and patient information from the Alberta Tuberculosis Registry. Transmission indexes were determined by calculating the average number of culture-positive pulmonary cases generated by a single source case. RESULTS: Of the 750 cases of active tuberculosis, 437 (58.3%) were in the foreign-born. DNA fingerprinting of Mycobacterium tuberculosis isolates from all 573 culture-positive cases over the 5 years from 1994 to 1998 showed that there was significantly less clustering among foreign-born isolates (9.8%) compared to Canadian-born non-Aboriginal (28.8%) and Aboriginal (44.7%) isolates. The transmission index was significantly higher for males, lower for those > or =65 years of age, and higher for Aboriginals. CONCLUSION: Although cases of tuberculosis in the foreign-born constitute the majority in Alberta, there is little transmission to other foreign-born or to Canadian-born individuals. Transmission of tuberculosis among the Aboriginal population remains a significant problem in Alberta.

Adult↗
PubMed2003

Attenuation characteristics of the fundamental modes that propagate in buried iron water pipes.

The attenuation of the fundamental non-torsional modes that propagate down buried iron water pipes has been studied. The mode shapes, mode attenuation due to leakage into the surrounding medium and the scattering of the modes as they interact with pipe joints and fittings have been investigated. In the low frequency region the mode predicted to dominate over significant propagation distances approximates a plane wave in the water within the pipe. The established acoustic technique used to locate leaks in buried iron water pipes assumes that leak noise propagates as a single non-dispersive mode at a velocity related to the low frequency asymptote of this water borne mode. Experiments have been conducted on buried water mains at test sites in the UK to verify the attenuation and velocity dispersion predictions.

Acoustics↗
PubMed2002

The emergency department is a determinant point of contact of tuberculosis patients prior to diagnosis.

SETTING: Metropolitan Edmonton, Canada. OBJECTIVES: To determine 1) the pre-diagnosis emergency department utilization history of urban tuberculosis patients, and 2) the resource and outcome implications of emergency department utilization by tuberculosis patients pre-diagnosis. DESIGN: Nested case (emergency department attendee) control (non-emergency department attendee) study of a retrospective cohort of tuberculosis patients. PATIENTS: All tuberculosis notifications, 1994 through 1998. MAIN OUTCOME MEASURES: Emergency department utilization during the 6 months antedating the diagnosis and emergency department attendee characteristics; for those notified in 1997 and 1998, hospitalizations, nosocomial infectiousness time, and health care costs. RESULTS: Of 250 cases of tuberculosis, 117 (47%) made a total of 258 pre-diagnosis emergency department visits. Emergency department use increased the nearer the patient was to diagnosis. Emergency department attendees were more likely to be older, to have smear and/or culture positive respiratory disease, to have a risk factor for progression of infection to disease, and to have a fatal outcome. In 1997 and 1998, emergency department throughput accounted for 70% of all hospitalization days, 95% of all source case nosocomial infectiousness time, and most health care costs of tuberculosis patients pre-diagnosis. CONCLUSIONS: The emergency department is heavily utilized by urban tuberculosis patients pre-diagnosis. Emergency department throughput of tuberculosis patients pre-diagnosis has major resource and outcome implications. The emergency department may present an opportunity for earlier diagnosis.

Adolescent↗
PubMed2002

The epidemiology of tuberculosis among foreign-born persons in Alberta, Canada, 1989-1998: identification of high risk groups.

BACKGROUND: To date, there have been no comprehensive epidemiological studies in Canada of the incidence rates of tuberculosis among foreign-born persons. Accurate rate estimates are needed to develop cost-effective strategies for the prevention, control, and ultimate elimination of tuberculosis. METHODS: Most new immigrants to Canada settle in one of four provinces: Ontario, British Columbia, Quebec and Alberta. Data from the provincial reporting system for tuberculosis, from Statistics Canada censuses and population estimates of Treaty Status Indians provided by the Department of Indian and Northern Affairs Canada, were used to estimate the rate of tuberculosis in Alberta's Canadian-born and foreign-born population between 1989 and 1998. RESULTS: Age-adjusted tuberculosis case rates per 100,000 person-years were 19.4 and 61.9 in the foreign-born and Canadian-born Treaty Indians-approximately 10 times and 30 times, respectively, higher than the rate in the remainder of the Canadian-born population (2.1/100,000 person-years). Age-specific rates in male and female foreign-born persons were highest at ages 15-34 and > or = 65 years, whereas rates in Canadian-born non-Treaty and Treaty males and females increased incrementally, with a single peak at > or = 65 years. Tuberculosis case rates in the foreign-born varied significantly according to World Bank region and country of birth. By far the highest rates were seen in immigrants to Canada from Asia, in particular Vietnam, the Philippines, China, Hong Kong and India. Most (90%) tuberculosis patients from these countries had not been identified as requiring medical surveillance in Canada after arrival. CONCLUSION: Immigrants to Alberta from Asia and Treaty Status Indians are at high risk for tuberculosis. Physicians in Alberta who care for foreign-born persons should be aware that their patients are at increased risk for tuberculosis, even if they have been medically cleared during the legal immigration process.

Adolescent↗
PubMed2001

Postsanatorium pattern of antituberculous drug resistance in the Canadian-born population of western Canada: effect of outpatient care and immigration.

Concurrent with the shift in tuberculosis case management from sanatorium to outpatient setting was a shift in the continent of origin (Europe to Asia) of most new immigrants to CANADA: To assess the impact of these two events on antituberculous drug resistance in the Canadian-born population, the authors reviewed the results of six drug resistance surveys conducted in the two westernmost provinces of Canada between 1963 and 1994. Survey data were complemented by new molecular diagnostic and contact tracing data collected over 5 years (1994--1998) in one of the three large urban centers of the region. Over the time spanned by the surveys, there was no increase in the proportion of all Canadian-born tuberculosis cases who relapsed or the proportion of all Canadian-born relapsed cases who were drug resistant (approximately 12--13%). In addition, the prevalence of primary drug resistance among Canadian-born cases did not increase; rates consistently averaged between 2% and 5% despite a doubling of primary resistance rates among foreign-born cases. Molecular diagnostic and contact tracing data strongly supported the survey findings. The authors concluded that outpatient care and immigration have thus far had no measurable impact on the pattern of antituberculous drug resistance in the Canadian-born population of western CANADA:

Adolescent↗
PubMed2001

Safety of intracoronary administration of c-myc antisense oligomers after percutaneous transluminal coronary angioplasty (PTCA).

We wished to assess the clinical safety and pharmacokinetics of ascending doses of a synthetic oligodeoxynucleotide (LR-3280) administered after coronary angioplasty. Antisense oligodeoxynucleotides designed to hybridize with target messenger ribonucleic acid (mRNA) in a complementary fashion to inhibit the expression of corresponding protein also have the ability to bind to extracellular growth factors. LR-3280 has been shown to reduce c-myc expression, inhibit growth and collagen biosynthesis in human vascular cells, and reduce neointimal formation in animal models of vascular injury. After successful percutaneous transluminal coronary angioplasty (PTCA), 78 patients were randomized to receive either standard care (n = 26) or standard care and escalating doses of LR-3280 (n = 52) (doses from 1 to 24 mg), administered into target vessel through a guiding catheter. Overall safety was evaluated by clinical adverse events, laboratory tests, and electrocardiograms. Patency was evaluated by quantitative coronary angiography. There were no clinically significant differences between treated and control patients. No adverse effects of LR-3280 on the patency of dilated coronary arteries were observed. Pharmacokinetic data revealed that peak plasma concentrations of LR-3280 occurred at 1 minute over the studied dose range and rapidly decreased after approximately1 hour, with little LR-3280 detected in the urine between 0-6 hours and 12-24 hours. The intracoronary administration of LR-3280 is well tolerated at doses up to 24 mg and produces no adverse effects in dilated coronary arteries. These results provide the basis for the evaluation of local delivery of this phosphorothioate oligodeoxynucleotide for the prevention of human vasculoproliferative disease.

Aged↗
PubMed2001

Non-Invasive monitoring of a bioartificial pancreas in vitro and in vivo.

Monitoring biochemical processes relevant to the function, survival, and longevity of tissue-engineered pancreatic constructs is important for the development of an optimum construct design as well as patient care management after implantation. In this report we demonstrate the ability of nuclear magnetic resonance (NMR) techniques to monitor aspects of intracellular metabolism, overall morphology, and distribution of a microencapsulation based bioartificial pancreas in vitro and in vivo.

Animals↗
PubMed2001

Evaluation of cytotoxic T-lymphocyte responses in human and nonhuman primate subjects infected with human immunodeficiency virus type 1 or simian/human immunodeficiency virus.

Cytotoxic T-lymphocyte (CTL) responses have been implicated as playing an important role in control of human immunodeficiency virus (HIV) infection. However, it is technically difficult to demonstrate CTL responses consistently in nonhuman primate and human subjects using traditional cytotoxicity assay methods. In this study, we systematically evaluated culture conditions that may affect the proliferation and expansion of CTL effector cells and presented a sensitive method for detection of cytotoxicity responses with bulk CTL cultures. We confirmed the sensitivity and specificity of this method by demonstration of vigorous CTL responses in a simian-HIV (SHIV)-infected rhesus macaque. The expansion of epitope-specific CTL effector cells was also measured quantitatively by CTL epitope-major histocompatibility complex tetramer complex staining. In addition, two new T-cell determinants in the SIV gag region are identified. Last, we showed the utility of this method for studying CTL responses in chimpanzee and human subjects.

Acquired Immunodeficiency Syndrome↗
PubMed2001

Pharmacogenetics research network and knowledge base: 1st annual scientific meeting.

The National Institute of General Medical Sciences of the National Institutes of Health recently established a collaborative group of scientists, called the Pharmacogenetics Research Network. Central to the network is a shared, state-of-the-art data repository, the Pharmacogenetics Knowledge Base (PharmGKB), which is housed at Stanford University. Network investigators deposit pharmacogenetic data into PharmGKB, after all individually identifying information has been removed. Contents of PharmGKB will be freely accessible to the scientific community, with the goal of forging new links between gene variation and drug response. An open scientific meeting was held recently to introduce the research community to the network and to invite academic and industry-based researchers to deposit data into PharmGKB. Featured at the meeting were summaries of research progress to date, as well as discussions of issues intimately related to pharmacogenetics research, namely ethics and relations with the biotechnology and pharmaceutical industries.

Animals↗