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Biomedical subjects

D Cohen

Publications and source records attributed to D Cohen.

At least 379 records · Page 21Linked to original sources
PubMed1993

Drug use patterns of persons with Alzheimer's disease and related disorders living in the community.

OBJECTIVE: To describe drug use patterns by persons with Alzheimer's disease, multi-infarct dementia, and mixed Alzheimer's disease and multi-infarct dementia. DESIGN: Multicenter, patient registry. SETTING: Community-living persons evaluated in primary care, geriatric, and Alzheimer ambulatory settings. PARTICIPANTS: Of the 930 persons in three diagnostic categories, there were 671 with probable or possible Alzheimer's disease by NINCDS/ADRDA criteria or Alzheimer's disease by DSM-III-R criteria, 162 multi-infarct cases by DSM-III-R criteria, and 97 mixed cases by DSM-III-R criteria. In each diagnostic category, 65% were women, and the majority were 70 years or older. MEASUREMENTS: The average number of all prescription and non-prescription drugs and selected therapeutic categories by age, sex, diagnosis, and mini-mental status score at the time of diagnosis or evaluation. RESULTS: Alzheimer patients average 2.3 drugs compared with multi-infarct (4.3; P < 0.0001) and mixed (3.7; P = 0.002) patients, and their pattern of drug use was different when stratified by therapeutic categories and drug classes. Drug use increased with age, and women used significantly more drugs than men in all three diagnostic categories. Women with Alzheimer's disease used significantly more cardiovascular drugs than men with Alzheimer's disease (P < 0.05). The lower the mini-mental status score in patients with any dementia, the greater the mean number of central nervous system agents used. The higher the mini-mental status score in a patient with multi-infarct or mixed dementia, the greater the use of cardiovascular drugs. CONCLUSION: Drug use by Alzheimer patients was lower than in multi-infarct and mixed patients, primarily due to a lower prevalence of cardiovascular drugs.

Age Factors↗
PubMed1993

Ultraviolet radiation-induced phospholipase A2 activation occurs in mammalian cell membrane preparations.

Ultraviolet erythema in human skin is mediated in part by membrane derivatives of arachidonic acid (AA). UVA (320-400 nm) and UVB (290-320 nm) have been shown to induce release of AA from intact mammalian cells in culture. In order to investigate the mechanism of this release we examined the effect of UVA and UVB on release of [3H] AA from membrane preparations of murine fibroblasts. C3H 10T1/2 cells were prelabelled for 24 h with [3H] AA. The membrane fractions of the cells were separated after lysis by differential centrifugation. The membranes were irradiated in suspension and the [3H] AA released from the membranes was determined by scintillation spectroscopy of supernatants 3-4 h after irradiation. Both UVA and UVB induced release of AA from the membrane preparations. The response to UVB was small but significant, reaching levels approximately 150% of control release at doses of 1,200-4,000 J/m2. The response to UVA was larger; doses of 2.5-5.0 J/cm2 induced release equal to twice control (200%) levels, while doses of 10-20 J/cm2 induced maximal release at levels approximately 400% of control. Time course studies with UVB and UVA showed maximal release at 4 h after irradiation. When the membrane preparations were incubated with a polyclonal anti-phospholipase A2 antibody the UV induced release of [3H] AA was completely inhibited in both UVB (1200 J/m2) and UVA (10 J/cm2) treated cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Immunogenicity and efficacy of oral or intranasal Shigella flexneri 2a and Shigella sonnei proteosome-lipopolysaccharide vaccines in animal models.

Immunity against shigellosis has been shown to correlate with the presence of antibodies specific for Shigella lipopolysaccharide (LPS). We here propose a new candidate vaccine for shigellosis composed of purified Shigella flexneri 2a or Shigella sonnei LPS hydrophobically complexed with group C type 2b Neisseria meningitidis outer membrane protein proteosomes. Immunization of mice either orally or intranasally with this complex induced specific homologous anti-LPS antibodies in both intestinal and respiratory secretions as well as in sera. Strong anamnestic responses were found after two or three immunizations. LPS alone, alkaline-detoxified LPS, or alkaline-detoxified LPS complexed with proteosomes was not effective. Oral or intranasal immunization of guinea pigs with two or more doses of this proteosome-LPS vaccine elicited homologous protection against Shigella keratoconjunctivitis (Serény test). These data demonstrate that proteosomes can be used as an effective mucosal vaccine delivery system and that orally or intranasally administered acellular vaccines can protect against Shigella infections.

Administration, Intranasal↗
PubMed1993

Synthesis, characterization, and clinical evaluation of conjugate vaccines composed of the O-specific polysaccharides of Shigella dysenteriae type 1, Shigella flexneri type 2a, and Shigella sonnei (Plesiomonas shigelloides) bound to bacterial toxoids.

The theoretic basis for developing conjugate vaccines, to induce immunoglobulin G (IgG) lipopolysaccharide (LPS) antibodies for the prevention of shigellosis, has been described (J. B. Robbins, C.-Y. Chu, and R. Schneerson, Clin. Infect. Dis. 15:346-361, 1992). The O-specific polysaccharides (O-SPs) of Shigella dysenteriae type 1, S. flexneri type 2a, and S. sonnei were covalently bound to carrier proteins. Alone, the O-SPs were not immunogenic in mice. Conjugates of these O-SPs, injected into young outbred mice subcutaneously as saline solutions containing 2.5 micrograms of saccharide, elicited serum IgG and IgM antibodies with booster responses; adsorption onto alum enhanced their immunogenicity. Injection of 25 micrograms of these conjugates into adult volunteers elicited mild local reactions only. Each conjugate induced a significant rise of the geometric mean serum IgG, IgM, and IgA LPS antibody levels. A second injection 6 weeks later did not elicit booster responses, and adsorption of the conjugates onto alum did not enhance their immunogenicity. Conjugate-induced levels of IgA, but not IgG or IgM, declined to preimmunization levels at day 56. The levels of postimmunization antibodies of the three immunoglobulin classes were similar to or higher than those of recruits in the Israel Defense Force following shigellosis caused by S. flexneri type 2a or S. sonnei. These data provide the basis for evaluating these conjugates to prevent shigellosis.

Adolescent↗
PubMed1993

Evidence of genetic heterogeneity in the autosomal recessive adult forms of limb-girdle muscular dystrophy following linkage analysis with 15q probes in Brazilian families.

The autosomal recessive limb-girdle muscular dystrophies (LGMD) represent a heterogeneous group of diseases which may be characterised by one or more autosomal loci. A gene at 15q has recently been found to be responsible for a mild form of LGMD in a group of families from the isolated island of Réunion, now classified as LGMD2. Based on results of eight out of 11 large Brazilian LGMD families of different racial background (which were informative for the closest available probe to the LGMD2 gene), we confirmed linkage to the LGMD2 gene at 15q in two of these families and exclusion in six others. These data provide the first evidence of genetic heterogeneity for the autosomal recessive limb-girdle muscular dystrophies.

Brazil↗
PubMed1993

A simple method for prenatal diagnosis of trisomy 21 on uncultured amniocytes.

Prenatal diagnosis of trisomy 21 would be easier if fluorescence in situ hybridization (FISH) could be applied to interphase nuclei. Therefore, we prepared a chromosome-21-specific probe by in vitro enzymatic amplification of inter-Alu sequences from YAC clones previously localized to this chromosome. This probe was used for FISH on 22 uncultured amniocyte samples. An easy, rapid, and safe technique is proposed for the prenatal diagnosis of trisomy 21.

Amniocentesis↗
PubMed1993

Deletion of the donor splice site of intron 4 in the glucokinase gene causes maturity-onset diabetes of the young.

Missense and nonsense mutations in the glucokinase gene have recently been shown to result in maturity-onset diabetes of the young (MODY), a subtype of non-insulin-dependent diabetes mellitus with early age of onset. Glucokinase catalyzes the formation of glucose-6-phosphate and is involved in the regulation of insulin secretion and integration of hepatic intermediary metabolism. Nucleotide sequence analysis of exon 4 and its flanking intronic regions of the glucokinase gene, in four hyperglycemic individuals of a MODY family, revealed a deletion of 15 base pairs, which removed the t of the gt in the donor splice site of intron 4, and the following 14 base pairs. This deletion resulted in two aberrant transcripts, which were analyzed by reverse transcription of RNA from lymphoblastoid cells obtained from a diabetic patient. In one of the abnormal transcripts, exon 5 is missing, while in the other, the activation of a cryptic splice site leads to the removal of the last eight codons of exon 4. This intronic deletion in a donor splice site seems to cause a more severe form of glucose intolerance, compared with point mutations described in glucokinase. This might be due to a more pronounced effect on insulin secretion.

Adult↗
PubMed1993

Phenotypic conversions in renal development.

The transporting epithelia of the kidney are derived from an embryonic rudiment containing two distinct cell populations: ureteric bud epithelia and mesenchymal cells of the metanephric blastema. The ureteric bud is a caudal outgrowth of the Wolffian Duct and gives rise to the renal collecting system by branching morphogenesis. The metanephric blastema gives rise to diverse cells of the nephron after receiving an inductive stimulus. It has been proposed that mesenchymal progenitors of the metanephric blastema derive directly from intermediate mesoderm, although this hypothesis has never been tested directly. Utilizing direct lineage analysis techniques we demonstrate, in an organ culture system, that mesenchymal nephron progenitors are immediate descendants of ureteric bud epithelia. Ureteric bud epithelia can give rise to mesenchymal nephron progenitors that populate the metanephric blastema by undergoing an epithelial-to-mesenchymal transition followed by delamination. If this process occurs in vivo, renal morphogenesis can be characterized by two phenotypic conversions: an epithelial-to-mesenchymal transition leading to the generation of mesenchymal-nephron progenitors, followed by a mesenchymal-to-epithelial transition leading to the generation of diverse nephron epithelial cell types. We have immortalized an embryonic renal mesenchymal cell line and demonstrate that the clonal cell line, RSTEM-1, undergoes phenotypic conversions in vitro, providing a suitable model to study the regulation of the epithelial phenotype.

Animals↗
PubMed1993

Lipoprotein(a) in diabetic patients and normoglycemic relatives in familial NIDDM.

OBJECTIVE: To compare lipoprotein(a) levels in diabetic patients and normoglycemic relatives in familial NIDDM and to assess whether Lp(a) is a risk factor for myocardial infarction in this population. RESEARCH DESIGN AND METHODS: We compared 577 patients and 261 normoglycemic relatives from 189 NIDDM multiplex families with 49 unrelated healthy individuals. Of the 577, 23 patients with previously documented myocardial infarction were further analyzed as a separate group. RESULTS: Lp(a) concentrations in diabetic patients, normoglycemic relatives, and the control group were not significantly different. Variance of Lp(a) in a given individual could not be accounted for by any clinical or biological parameter, but was strongly related to the mean Lp(a) value in his or her family. Diabetic patients with previous myocardial infarction (and their relatives) had significantly higher levels of Lp(a) than patients without coronary heart disease complaints. CONCLUSIONS: Lp(a) concentration in familial NIDDM was not related to the degree of glucose intolerance, but presented a strong familial aggregation. High Lp(a) levels seem to be an independent risk factor for myocardial infarction in this NIDDM cohort.

Adult↗
PubMed1993

A prospective population-based study of microalbuminuria as a predictor of mortality in NIDDM.

OBJECTIVE: To assess prospectively the relationship between microalbuminuria and mortality in a geographically defined population of NIDDM patients and to determine the relative importance of microalbuminuria as a risk factor for mortality. RESEARCH DESIGN AND METHODS: A survey of known diabetes undertaken in 1982 identified a cohort of 249 NIDDM patients. Follow-up information was available for 246 patients who contributed 1498 person-yr exposure and were followed up for a mean period of 6.1 yr. The median age of the cohort at entry was 68 yr (range 28-89 yr), and the median duration of diabetes was 7 yr (range 1-41 yr). At baseline, a clinical examination was performed and a random daytime urine specimen was obtained for measurement of urinary albumin concentration. RESULTS: UAC results were available for 236 patients: 45 (19%) patients had a UAC > 15- < 40 mg/L; 36 (15%) had a UAC 40-200 mg/L; 10 (4%) had a UAC > 200 mg/L; and 145 (61%) had a normal UAC < or = 15 mg/L. During the follow-up period, 93 patients died. All-causes mortality, expressed as standardized mortality ratio (SMR = 149) and coronary heart disease mortality (CHD SMR = 166) were significantly increased. This excess mortality was significant in women (all-causes SMR = 194, CHD SMR = 234) but not in men (all-causes SMR = 118, CHD SMR = 128). On univariate analysis, systolic blood pressure was the only significant association with albumin concentration (P = 0.0002). An age-stratified log-rank test was conducted to determine the effect of potential explanatory variables on survival. Survival distributions were significantly different for known duration of diabetes (P = 0.045), intermittent claudication (P = 0.012), severity of retinopathy, lens opacity (P < 0.001) and UAC (P = 0.013) and diastolic blood pressure approached significance (P = 0.051). After adjusting for the effects of these potentially confounding variables identified by the log-rank analysis, significant predictors of early mortality on multivariate survival analysis were age, UAC of 40-200 mg/L (relative risk = 2.2, 95% confidence interval 1.3-3.7), more severe retinopathy (relative risk = 3.4, 95% confidence interval 1.9-6.0), and lens opacity (relative risk = 2.4, 95% confidence interval 1.6-3.8). CONCLUSIONS: The findings from this population-based cohort confirm the predictive power of microalbuminuria as a risk factor for mortality in NIDDM. In contrast to prospective studies of conventional cardiovascular risk factors in NIDDM, consistent evidence indicates that microalbuminuria is an independent predictor of excess mortality regardless of the collection procedure used.

Adolescent↗
PubMed1993

Knowledge-based generation of machine learning experiments: learning with DNA crystallography data.

Though it has been possible in the past to learn to predict DNA hydration patterns from crystallographic data, there is ambiguity in the choice of training data (both in terms of the relevant set of cases and the features needed to represent them), which limits the usefulness of standard learning techniques. Thus, we have developed a knowledge-based system to generate machine learning experiments for inducing DNA hydration pattern classifiers. The system takes as input (1) a set of classified training examples described by a large set of attributes and (2) information about a set of learning experiments that have already been run. It outputs a new learning experiment, namely a (not necessarily proper) subset of the input examples represented by a new set of features. Domain specific and domain independent knowledge is used to suggest subsets of training examples from suspected subpopulations, transform attributes in the training data or generate new ones, and choose interesting ways to substitute one experiment's set of attributes with another. Automatic hydration pattern predictors are of both theoretical and practical interest to DNA crystallographers, because they can speed up a labor intensive process, and because the extracted rules add to the knowledge of what determines DNA hydration.

Artificial Intelligence↗
PubMed1993

Probenecid-resistant J774 cell expression of enhanced organic anion transport by a mechanism distinct from multidrug resistance.

Macrophages possess organic anion transporters that carry membrane-impermeant fluorescent dyes, such as lucifer yellow (LY) and carboxy-fluorescein, from the cytoplasm into endosomes and out of the cells. Probenecid, an organic anion transport inhibitor, blocks these processes. Prolonged incubation of J774 cells in medium containing 2.5 mM probenecid eventually kills most of these cells. To identify J774 variants that express increased organic anion transport activity, we selected probenecid-resistant (PBR) J774 cells by growing them in medium containing increasing concentrations of probenecid. When PBR and unselected J774 cells were loaded with LY by ATP4- permeabilization, the amount of LY accumulated by the PBR cells was about half that in the unselected cells. This difference was abolished by adding 10 mM probenecid to the medium in which the cells were loaded, suggesting that the diminished LY accumulation in PBR cells was due to enhanced LY secretion and that the PBR cells expressed increased organic anion transport activity. Direct comparison of LY efflux from J774 and PBR J774 cells showed a faster initial rate of secretion of LY from PBR J774 cells than from unselected J774 cells. To determine whether LY efflux is mediated by P-glycoprotein, we compared LY efflux in unselected J774 cells, PBR J774 cells, and multidrug-resistant J774 cells (J7.C1). LY efflux from J7.C1 cells was not sensitive to verapamil, which inhibits multidrug-resistance transporters, and reverses the multidrug-resistant phenotype of J7.C1 cells. The rates of LY efflux from unselected J774 and J7.C1 cells were virtually identical.(ABSTRACT TRUNCATED AT 250 WORDS)

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1993

Taxol: mechanisms of action and resistance.

Information on the mechanisms of action and of resistance to Taxol, as well as new data from our laboratory on the promoter regions of the genes that encode P-glycoprotein in a murine Taxol-resistant cell line, is discussed. Taxol induces the formation of stable bundles of microtubules, thereby interfering with the normal function of cellular microtubules. The drug can induce the multidrug-resistance (MDR) phenotype that includes the overproduction of P-glycoprotein, a membrane glycoprotein that acts as a drug efflux pump. In human tumors resistant to Taxol, P-glycoprotein could be responsible for maintaining the drug below cytotoxic levels. Analyses of the MDR promoters that are involved in P-glycoprotein expression and overproduction revealed an interesting recombination event in a Taxol-resistant cell line. As an important new clinical agent for the treatment of malignancies, Taxol requires further mechanistic investigations at the preclinical level.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1993

Use of neoadjuvant androgen deprivation therapy in clinically localized prostate cancer.

Radical prostatectomy is an excellent form of treatment of pathologically organ-confined prostatic carcinoma. However, most clinically localized prostatic cancers have pathologic evidence of extracapsular spread, limiting the effectiveness of radical surgery in curing this disease. To improve the organ-confined rate of prostate cancer, we studied the effect of preoperative or neoadjuvant androgen deprivation therapy (ADT). Our initial attempts focused on downstaging locally advanced tumors (T3) with neoadjuvant diethylstilbestrol (3 mg/d). Our study of 59 patients revealed that although there were significant clinical signs of downstaging, most patients still had extraprostatic disease. However, a subset of patients demonstrated marked pathologic regression, so we initiated a nonrandomized but controlled study of neoadjuvant ADT (goserelin acetate and flutamide for 3 months) followed by radical prostatectomy in patients with clinically localized prostate cancer. Of 72 control and 69 study patients, the rate of organ-confined disease was 48% and 74% (including 4% with no detectable residual carcinoma), respectively. In addition, the margin-positive rate was 33% and 10%, respectively. As demonstrated in the previous study, changes in serum prostate-specific antigen, transrectal ultrasonographic evaluations, and digital rectal examinations could not predict those patients with favourable pathology. Our results suggest that neoadjuvant ADT may improve the pathologic stage in some prostatic carcinomas and is worthy of further investigation in the efforts to augment the effectiveness of radical prostatectomy.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1993

[First generation of the physical map of the human genome].

Sets of ordered overlapping cloned genomic fragments, spanning each of the human chromosomes are urgently needed for identification of human disease genes. Such a physical map provides also a unique source of material to study structure and function of the genome. To achieve this goal we exhaustively analyzed the CEPH yeast artificial chromosome (YAC) library containing 33,000 clones, which insert sizes were individually measured. With 0.9 Mb average lengths these YACs cover an equivalent of 10 haploid genomes. Then, several mapping techniques were combined to generate multiple structural information for most of these clones. Finally, the library was screened with more than 2,000 genetic markers quasi-uniformly distributed along 90% of the genome. These results should allow the scientific community to construct detailed chromosomic maps. Moreover, we propose a data analysis strategy that produces a first generation integrated map covering most of the human genome.

Chromosome Mapping↗
PubMed1993

[Ablation of the internal limiting membrane, macular unfolding and visual outcome in surgery of idiopathic epimacular membranes].

The files of 40 patients operated on for epimacular membranes were reviewed in order to correlate the functional and anatomical results with the presence or absence of internal limiting membrane on histological specimens. Only the eyes with idiopathic membranes were considered for the study. Visual acuity and fluorescein angiography were obtained preoperatively and at the 6 months postoperative visit. The surface of the posterior pole was measured on fluorescein angiogram pre and postoperatively by computerized image analysis. Light microscopy looked for the presence of significant segments of internal limiting membrane. In 28 cases (group 1) long segments of internal limiting membrane were adherent to the epimacular membrane and in 12 cases (group 2) no internal limiting membrane fragments or only small fragments were present. Mean postoperative visual acuity was the same in the two groups; 64% of eyes from group I and 50% from group 2 had visual acuity superior or equal to 0.5 (NS). Image analysis showed that the posterior pole surface area increased by 25% in group 1 but only by 15% in group 2 (p < 0.025). Internal limiting membrane ablation does not preclude good visual recovery and is correlated with improved unfolding of the posterior pole.

Fluorescein Angiography↗
PubMed1993

Loss of telomeric DNA during aging of normal and trisomy 21 human lymphocytes.

The telomere hypothesis of cellular aging proposes that loss of telomeric DNA (TTAGGG) from human chromosomes may ultimately cause cell-cycle exit during replicative senescence. Since lymphocytes have a limited replicative capacity and since blood cells were previously shown to lose telomeric DNA during aging in vivo, we wished to determine: (a) whether accelerated telomere loss is associated with the premature immunosenescence of lymphocytes in individuals with Down syndrome (DS) and (b) whether telomeric DNA is also lost during aging of lymphocytes in vitro. To investigate the effects of aging and trisomy 21 on telomere loss in vivo, genomic DNA was isolated from peripheral blood lymphocytes of 140 individuals (age 0-107 years), including 21 DS patients (age 0-45 years). Digestion with restriction enzymes HinfI and RsaI generated terminal restriction fragments (TRFs), which were detected by Southern analysis using a telomere-specific probe (32P-(C3TA2)3). The rate of telomere loss was calculated from the decrease in mean TRF length, as a function of donor age. DS patients showed a significantly higher rate of telomere loss with donor age (133 +/- 15 bp/year) compared with age-matched controls (41 +/- 7.7 bp/year) (P < .0005), suggesting that accelerated telomere loss is a biomarker of premature immunosenescence of DS patients and that it may play a role in this process. Telomere loss during aging in vitro was calculated for lymphocytes from four normal individuals, grown in culture for 10-30 population doublings. The rate of telomere loss was approximately 120 bp/cell doubling, comparable to that seen in other somatic cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗