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Biomedical subjects

D Cohen

Publications and source records attributed to D Cohen.

At least 307 records · Page 17Linked to original sources
PubMed1994

Marginal analysis in practice: an alternative to needs assessment for contracting health care.

Prioritising health care services on the basis of total needs can lead to inefficient use of resources. A better option is to determine priorities by marginal analysis, which examines the effects of altering the existing balance of expenditure between health care programmes. Resources to support investment are released from disinvestments-that is, the strategy is resource neutral. Thus an increase in total health benefits is achieved independent of any gains that may result from increased spending on health. In 1989 the Welsh Health Planning Forum identified 10 health gain areas, outlining within each one where further investment was likely to produce health gains and where disinvestment might be considered. All Welsh districts then attempted, with varying degrees of success, to produce a resource neutral strategy. Mid Glamorgan further explored the possibility of using marginal analysis in producing its strategy and influencing its policy for contracting. Working groups for most health gain areas each proposed 10 programmes for investment and a further 10 for disinvestment, which were then evaluated by a core evaluation team. In the case of maternal and child health the team dropped 10 of the 20 proposals. The remainder were considered by the health authority, which dropped a further proposal. Nine of the original 20 proposals thus formally became policy for 1995.

Cost-Benefit Analysis↗
PubMed1994

Refined mapping of a gene (NPH1) causing familial juvenile nephronophthisis and evidence for genetic heterogeneity.

Familial juvenile nephronophthisis (NPH) is an autosomal recessive progressive tubulo-interstitial kidney disorder, responsible for 6-10% of end-stage renal failure in children, and is frequently associated with Leber amaurosis (termed Senior-Løken syndrome). The biochemical basis of NPH is unknown. We recently reported linkage of the purely renal form of NPH to three markers on chromosome 2. Our results also suggested the existence of genetic heterogeneity between NPH and SLS. To map this NPH gene more precisely, we have now tested the segregation of six new microsatellite markers and five additional families. Haplotype analyses show unequivocally that four NPH families are not linked to the chromosome 2 markers, although there are no clinical or pathological features discernible in these families that could separate them from the families linked to the chromosome 2 NPH locus (NPH1). This reveals genetic heterogeneity in the purely renal form of NPH. In situ hybridization of YAC clones isolated with two closely linked markers assigned the NPH1 region to 2q13. Furthermore, based on haplotype analysis and specific recombination events, the NPH1 gene has been placed between D2S293/D2S340 and D2S121, a genetic interval of about 5-7 cM.

Chromosomes, Human, Pair 2↗
PubMed1994

A YAC contig in 6p23 based on sequence tagged sites.

A yeast artificial chromosome (YAC) contig located in 6p23 and spanning roughly 2.5 Mb has been constructed from the content of 10 sequence tagged sites (STSs) for YAC clones in 66 yeast colonies. Nine of the STSs have been genetically mapped in CEPH families. The order of STSs mapped with the contig is consistent with that of the genetic map. The order of loci that did not recombine with each other on the genetic map was inferred from the contig. Various regions of the contig are covered by multiple YAC clones that complement observed STS deletions. The STS for the CAG repeat sequence contained in the gene for spinal cerebellar ataxia 1 (gene symbol SCA1) is localized in the contig. It is likely that this gene is located in 6p23. The frequency of chimeric YAC clones in this contig is 35%. Eleven yeast colonies were found to carry two or more YACs. YAC subclones from some of these colonies showed size variation, and for several subclones, evidence consistent with deletion of a sequence tagged site.

Base Sequence↗
PubMed1994

Enhanced stress responsivity of Tourette syndrome patients undergoing lumbar puncture.

Tourette's syndrome (TS) is a complex inherited neuropsychiatric disorder that is characterized by multiple motor and phonic tics. Stress-related fluctuations in symptom severity and medication responsiveness are common, and patients often report that tics are worsened by fatigue, emotional trauma, and anxiety. We examined the effects of lumbar puncture (LP) stress on plasma adrenocorticotropin (ACTH) and cortisol, urinary catecholamines, and self- and clinician ratings of anxiety in 13 medication-free TS patients and 10 normal controls, ages 17 to 41 years. The TS patients secreted significantly more ACTH than the normal controls in response to the stress of the lumbar puncture. Compared to the controls the TS patients had significantly greater postLP mean and postLP peak ACTH levels. The TS patients also excreted significantly more norepinephrine in the 20 hr preceding the lumbar puncture and reported higher levels of anxiety before and during the procedure than the controls. In addition, urinary norepinephrine excretion of the TS patients was significantly correlated with clinician ratings of tic severity. The results were not related to current levels of depression and anxiety. Taken together, these findings suggest that a subset of TS patients may be characterized by heightened reactivity of the hypothalamic-pituitary-adrenal axis and related noradrenergic sympathetic systems.

Adrenocorticotropic Hormone↗
PubMed1994

Insertion/deletion polymorphism of the angiotensin-converting enzyme gene is strongly associated with coronary heart disease in non-insulin-dependent diabetes mellitus.

Non-insulin-dependent diabetes mellitus (NIDDM) is considered a model of premature atherosclerosis with a strong genetic component. We have investigated the role of angiotensin-converting enzyme (ACE; EC 3.4.15.1) gene in 316 unrelated NIDDM individuals, 132 who had myocardial infarction or significant coronary stenoses and 184 with no history of coronary heart disease (CHD). A deletion-polymorphism in the ACE gene was recently reported to be associated with myocardial infarction especially in people classified as low risk. Here we report that the D allele of the ACE gene is a strong and independent risk factor for CHD in NIDDM patients. The D allele is associated with early-onset CHD in NIDDM, independently of hypertension and lipid values. A progressively increasing relative risk in individuals heterozygous and homozygous for the D allele was observed (odds ratios of 1.41 and 2.35, respectively; P < 0.007), suggesting a codominant effect on the cardiovascular risk. The percentage of CHD attributable to the ACE deletion allele was 24% in this NIDDM population. Identification of NIDDM patients carrying this putative CHD-susceptibility genotype would help early detection and treatment of CHD.

Alleles↗
PubMed1994

Targeted development of microsatellite markers from inter-Alu amplification of YAC clones.

Primary genetic maps based on highly informative markers are now available. The local density of these markers may, however, not be sufficient. There is thus a need for new means to generate polymorphic markers from targeted regions of the genome. This can be achieved by selectively cloning and sequencing (CA)n-positive human inter-Alu sequences from targeted YAC clones. This method was tested on 21 YACs and led to the development of seven new polymorphic microsatellite markers.

Base Sequence↗
PubMed1994

Effects of stem cell factor (kit-ligand) and interleukin-3 on the growth and serine proteinase expression of rat bone-marrow-derived or serosal mast cells.

The effects of rat stem-cell factor (SCF) and interleukin-3 (IL-3), alone or in combination, on the in vitro growth and serine proteinase expression of rat serosal/connective-tissue mast cells (CTMC) or bone marrow-derived mast cells (BMMC) were examined. Rat SCF stimulated the growth of both CTMC and BMMC. IL-3 stimulated BMMC growth to a lesser extent than did SCF, whereas CTMC numbers did not increase in IL-3. However, SCF and IL-3 had synergistic effects on the growth of both BMMC and CTMC. SCF favoured the maintenance of rat mast cell proteinase-I (RMCP-I) in CTMC, but did not induce detectable production of RMCP-I in BMMC. In contrast, when IL-3 or lymph node-conditioned medium (LNCM) was added to SCF, a subpopulation of CTMC expressed and stored the soluble proteinase RMCP-II. In BMMC, the RMCP-II content of cells maintained in SCF was significantly less than that of cells maintained in IL-3 or LNCM. RMCP-II also appeared in the supernatants of BMMC, especially when BMMC numbers were increasing rapidly in SCF with or without IL-3 or LNCM. Thus, SCF and IL-3 can regulate the growth of rat BMMC and CTMC, as well as influence their production and release of proteinases.

Animals↗
PubMed1994

Integrated YAC contig containing the 3p14.2 hereditary renal carcinoma 3;8 translocation breakpoint and the fragile site FRA3B.

An extended YAC contig has been developed for the 3p14 region containing the hereditary renal carcinoma 3;8 translocation breakpoint and the 3p14.2 fragile site FRA3B. This region of chromosome 3 has been implicated by chromosomal translocation, deletion, and loss of heterozygosity in the pathogenesis of several malignant diseases. The contig allows accurate positioning of candidate genes, polymorphic markers, and other 3p rearrangements within this region. The contig, spanning approximately 6 Mb of DNA, contains 51 YACs identified by 27 markers, including a subset of CA repeats located in the 3p14.1-14.2 interval. The order of CA microsatellites, derived from marker content of the YACs, is in agreement with the order previously determined by genetic linkage studies. We find that the protein-tyrosine phosphatase gamma gene, PTPRG, is located minimally 1 Mb proximal to the t(3;8) breakpoint. The more proximal 3p homozygous deletion in the small-cell lung cancer cell line, U2020, is more than 5 Mb from the site of the 3;8 translocation. This integrated physical and genetic map provides a framework for further investigations of malignant diseases associated with proximal 3p loss. In addition, the positioning of separate 3p14.2 aphidicolin-induced breakpoints suggests that FRA3B may represent a region rather than a single site.

Carcinoma, Renal Cell↗
PubMed1994

Induction of kidney epithelial morphogenesis by cells expressing Wnt-1.

During kidney development, unknown signals derived from the ureteric bud induce metanephric mesenchymal cells to differentiate into nephron epithelia. In addition to the ureteric bud, a number of other tissues can act as heterologous inducers of this process in vitro, including embryonic spinal cord. In this report we demonstrate that Wnt-1, a gene that encodes a secreted glycoprotein expressed in embryonic spinal cord, is capable of conferring nephron-inducing activity to fibroblast cell lines. When cocultured with cells expressing exogenous Wnt-1, metanephric mesenchyme differentiated into glomerular and renal tubular epithelia. No such effect was observed using control cells. These data imply that the ability of embryonic spinal cord to act as an inducer of nephrogenesis may result from its production of Wnt-1 protein and suggest that a member of the Wnt gene family may be a mediator of renal epithelial morphogenesis in vivo.

Animals↗
PubMed1994

Cloning the human major histocompatibility complex in YACs.

To clone the human major histocompatibility complex (MHC), 53 YACs, with an average size of 490 kb, were isolated and characterized from the CEPH YAC library. These YACs were organized in a single large contig covering more than 4000 kb. Furthermore, a complete physical map of the previously uncloned HLA class I region was established from partial and/or total digestions of 15 YACs spanning 2000 kb. This resulted in the establishment of the first YAC contig that spans the entire MHC region and constitutes an essential step in the isolation of all of the genes present in the region.

Animals↗
PubMed1994

Large human YACs constructed in a rad52 strain show a reduced rate of chimerism.

Current YAC libraries are plagued by a high frequency of chimeras--that is, clones containing fragments from multiple genomic regions. Chimeras are thought to arise largely through recombination in the yeast host cell. If so, the use of recombination-deficient yeast strains, such as rad52 mutants, might be expected to alleviate the problem. Here, we report the construction of megabase-sized human YACs in the rad52 strain MHY5201 and the determination of their rate of chimerism by fluorescence in situ hybridization analysis. Examination of 48 YACs showed a rate of chimerism of at most 8%, whereas YACs constructed in the wildtype host AB1380 showed a rate of about 50%. These results show that it is possible to significantly decrease the rate of YAC chimerism through the use of appropriate yeast host strains.

Base Sequence↗
PubMed1994

Long-term persistence of anti-diphtheria toxin antibodies among adults in Israel. Implications for vaccine policy.

Vaccination against diphtheria has essentially led to the disappearance of the disease in Israel. However, in other countries with high immunization coverage, isolated cases and small outbreaks have occurred in adults. Immunity following vaccination or natural exposure to toxigenic strains of C. diphtheriae is conferred by serum antibodies to diphtheria toxin. Since booster doses of diphtheria toxoid are recommended every ten years in adults, this raises the question of persistence of protective levels of anti-diphtheria toxin antibodies. In this study we assessed a possible age-related decline in anti-diphtheria toxin antibodies among adults in Israel. The study population comprised random samples in three age groups: 263 male recruits aged 18-19 years, 116 male reserve soldiers aged 25-35 years and 153 aged 41-51 years. Anti-diphtheria toxin antibody levels were measured by means of ELISA. Results indicate that 64.3% (95% CI = 58.5-70.1%) of those aged 18-19 had anti-diphtheria toxin levels in excess of 0.1 IU ml-1, whereas the corresponding figures for ages 25-35 and 41-51 were 32.8% (95% CI = 24.2-41.3%) and 15% (95% CI = 9.4-20.7%). However, even in the oldest age group, 95.4% (95% CI = 90.8-98.1%) had antibodies above the presumed protective level of 0.01 IU ml-1. Although these results indicate a significant age-related decline in anti-diphtheria toxin antibodies in vaccinated subjects, most had apparently protective levels. The absence of cases suggests that vaccine-induced immunity is long-lasting. However the immune status of the population should be carefully monitored.

Adolescent↗
PubMed1994

Identification of Shigella species in stool specimens by DNA amplification of different loci of the Shigella virulence plasmid.

The sensitivity and specificity of the polymerase chain reaction (PCR) for detection of DNA sequences specific to Shigella spp. and enteroinvasive Escherichia coli (EIEC) in stools was evaluated. Stool specimens were obtained from patients with acute gastroenteritis before and after antibiotic treatment. Fecal material was pre-incubated in phosphate-buffered saline, gram-negative broth or brain heart infusion (BHI) broth, and DNA was extracted and amplified. Primers complementary to the ial or the virF loci of the 140 MDa plasmid of Shigella were evaluated. The highest sensitivity for detection of Shigella DNA in stools (higher than that of culture) was reached by pre-incubation of the fecal material in BHI broth and use of virF primers for amplification. The specificity of this PCR protocol was documented by the negative results obtained with non-Shigella enteric organisms. These findings point out the important diagnostic and epidemiologic potential of the virF-specific PCR protocol in the investigation of Shigella infections.

Acute Disease↗