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Biomedical subjects

K Gottlieb

Publications and source records attributed to K Gottlieb.

At least 37 records · Page 2Linked to original sources

A novel interferon-inducible domain: structural and functional analysis of the human interferon regulatory factor 1 gene promoter.

We have cloned and functionally characterized the human interferon regulatory factor 1 (IRF-1) gene promoter. The promoter contains a CpG island, with several GC boxes, a CAAT box, but no TATA box. IRF-1 mRNA is strongly induced by gamma interferon (IFN-gamma) but more weakly and transiently by IFN-alpha. There are several putative kappa B motifs and numerous AA(G/A)G(G/T)A and GAAANN motifs throughout the promoter. The IRF-1 promoter is not autoregulated by the IRF-1 gene product. IFN inducibility of the promoter was studied with 5' deletion mutants linked to a heterologous reporter gene. Gel mobility shift assays were used to show IFN-inducible factor binding to the IRF-1 promoter. These studies showed that IFN inducibility is conferred by a novel imperfect inverted-repeat arrangement of two GAAANN motifs within a domain, 130 nucleotides upstream of transcription initiation. This inverted repeat binds a factor upon induction with IFN and can confer IFN inducibility on a heterologous promoter. Conversely, point mutations of the inverted repeat are not IFN inducible when linked to the same heterologous promoter.

Base Sequence↗

Identification of a complex formed between nuclear proteins and the transcriptional enhancer of interferon-inducible genes that is present in the peripheral blood myeloid cells of CML but not normal individuals.

Interferon-alpha (INF-alpha) induces cytogenetic remissions in 20% of chronic myelogenous leukemia (CML) patients. To clarify the mechanisms through which this antiproliferative action of IFN is mediated in the CML cell, a modification of the mobility-shift assay was used to follow the formation of complexes between nuclear proteins and IFN-inducible transcriptional enhancers involved in mediating the cellular effects of IFN-alpha. These studies identified a complex that was present in the myeloid cells of 18/24 (75%) of chronic-phase CML patients tested whose cells contained 100% Philadelphia chromosome positive (Ph+) cells, while the proteins of none of the samples tested from normal peripheral blood samples and only 22% (2/9) of the CML patients in an IFN-induced major cytogenetic remission (less than 30% Ph+ cells) contained these complexes. These studies suggest that the mobility-shift assay detects changes in the CML myeloid cell that distinguish it from the normal myeloid cell.

Base Sequence↗

Nutrition in acute pulmonary disease.

Acutely stressed patients with chronic pulmonary disease have a particular need for accurate nutritional assessment and appropriate nutritional therapy. Loss of skeletal muscle, often extensive, can be paralleled by dramatic alterations in cellular function; inadvertent provision of excessive calories or of individual substrates may produce more harm than benefit. In the absence of a single "gold standard" for nutritional assessment and monitoring, no single value should take precedence over the entire clinical picture, which should be thoughtfully assessed and reassessed, with both the patient's nutritional needs and the consequences of their provision kept in mind. In the future, assessments of the impact of nutritional intervention will probably rely more heavily on functional tests of specific organs and of the immune system. Intervention will be based not only on provision of calories, individual substrates, vitamins, and minerals, but also on control of the inflammatory response in order that the nutrients may be properly utilized.

Acute Disease↗

Patterned selection of mates in St. Ouen, Jersey, and the Scilly Isles examined by isonymy.

Within-lineage repeated-pair isonymy is calculated as RPW = sigma [Sij(Sij - 1)]/sigma [Si(Si - 1)], in which Sij is the number of a combination of two surnames in marriages (for total RPW, in both orders, brides first and also grooms first) and Si is the corresponding number of individuals of each surname (for total RPW of both sexes). In St. Ouen the 3479 native Jersey marriages between 1634 and 1914 yield a mean total RPW of 0.03314, which can be compared with a random isonymy (Ir) of 0.02205 and a marital isonymy (Im) of 0.04942. In the most recent time periods (1830-1914) there was an increase in RPW, but the increase is small if all marriages are considered rather than only native Jersey ones. In the Scilly Isles 2827 marriages between 1725 and 1975 yield a mean total RPW of 0.05127, which compares with a mean Ir of 0.01960 and an Im of 0.05238. In each kind of isonymy there is a decline over 1850-1975 caused by increased migration to the Scilly Isles. In the Scilly Isles RPW consistently approximately equals Im, so the nonrandom component of inbreeding is fully accounted for by factors that affect marital choice in the whole lineage. In St. Ouen, however, RPW is intermediate in value between Ir and Im, so the nonrandom component of inbreeding is only partly a lineage phenomenon and is also affected by other (individual) factors in choice of spouses.

Channel Islands↗

Twin study methodology and variability in xenobiotic placental metabolism.

The present study assesses the contribution of genetic and environmental factors to variability in placental aryl hydrocarbon hydroxylase and glutathione transferase activities using twin study methodology. Twin placentas were collected at the time of delivery. The placenta, except for a single layer of maternal decidua, consists of fetal tissue exhibiting fetal genotype. Microsomal and cytosolic fractions were prepared under stringent protocols to prevent enzyme activity loss. There were two monozygotic-monochorionic pairs, five monozygotic-dichorionic pairs, and 21 dizygotic-dichorionic pairs that showed measurable aryl hydrocarbon hydroxylase activity using the direct fluorometric assay. Most of the mothers were smokers. Aryl hydrocarbon hydroxylase activity was measured with two different substrates, benzo(a)pyrene and 7-ethoxyresorufin. Glutathione transferase activity was measured using glutathione and 1-chloro-2,4-dinitrobenzene as substrates for a spectrophotometric assay that follows the conversion of the aromatic substrate. Twin pair similarity was calculated with intraclass correlation coefficients. There is a high correlation between the activities of the two aryl hydrocarbon hydroxylase substrates (r = .814), but no correlation between aryl hydrocarbon hydroxylase and glutathione transferase activity levels. There is little evidence of genetic variability underlying the variation in the enzyme activities because monozygotic-dichorionic twins are no more similar to each other for the three substrate activities than are the dizygotic twins. To delineate the prenatal environmental influences on placental enzyme variability, dichorionic placentation was subdivided further into contiguous and noncontiguous placental position. Lower intraclass correlation coefficients are obtained for the dizygotic twins whose placentas were noncontiguous compared with dizygotic twins with contiguous placentas. The results suggest that most of the variability seen in these placental enzyme systems is due to environmental differences within uteri, rather than genetic variability in the population. This does not negate the possibility that between-pair, or population, variability may have a genetic component, because even dizygotic twins share a large proportion of their genes. This study points out that a significantly variable environment exists within the human uterus.

Aryl Hydrocarbon Hydroxylases↗

Monoclonal antibody phenotyping of interindividual differences in cytochrome P-450-dependent reactions of single and twin human placenta.

Cytochromes P-450 are a family of enzymes responsible for metabolism of drug and xenobiotics, such as carcinogen, and certain physiological compounds, such as steroids and prostaglandins. We prepared a monoclonal antibody (MAb 1-7-1) to a polycyclic hydrocarbon-induced rat cytochrome P-450 that antigenically defines and inhibits a type of cytochrome P-450 responsible for aryl hydrocarbon hydroxylase (AHH) and 7-ethoxycoumarin deethylase (ECD) activity in human placenta. We examined the placentas from single and twin births from mothers who smoked cigarettes and nonsmokers. The MAb 1-7-1 inhibited the smoking-induced AHH activity of essentially the entire population of placentas by 70 to 95%. Thus, up to 95% of the AHH in a population of human placentas is catalyzed by a type of cytochrome P-450 that contains an antigenic site recognized by MAb 1-7-1. A second type of cytochrome P-450, which is insensitive to MAb 1-7-1, is responsible for the ECD activity in the placentas of nonsmokers. In the placentas from smokers, both types of P-450 contribute to ECD activity. Their ratios can be determined by the amount of inhibition by MAb 1-7-1 which ranges from 0 to 70%. The placentas from both dizygotic and dichorionic monozygotic twins show extraordinarily high intrapair concordance for both the absolute amounts of AHH and ECD and their inhibition by MAb 1-7-1 compared with unrelated individuals, indicating that interindividual differences in these parameters of biological activity are not due to random variation or experimental error. Our results show that the amount of activity of antigenically unique types of cytochrome P-450 responsible for different drug and carcinogen reactions can be measured in different individuals by the amount of their inhibition by highly specific monoclonal antibodies. These findings may have general application to studies on the relationship cytochrome P-450 phenotype to population differences in drug and carcinogen biotransformation.

7-Alkoxycoumarin O-Dealkylase↗

Population distribution of placental benzo(a)pyrene metabolism in smokers.

Human placental microsomes isolated from term placentas derived from nonsmoking women and women smoking 1 to 40 cigarettes a day were analyzed for the metabolism of benzo(a)pyrene measured as various metabolites by HPLC and/or as aryl hydrocarbon hydroxylase (AHH)6 activity. In accordance with other reports, AHH activity was several times higher in smokers than in nonsmokers. Regression analysis on 13 different placental tissues from women smoking from 1 to 40 cigarettes demonstrated a high correlation (r = 0.8 to 0.9) between AHH activity (or the formation of benzo(a)pyrene phenols resolved by HPLC) versus the formation of the procarcinogenic benzo(a)pyrene-7,8-diol. Subsequent studies on placentas derived from 67 women who smoked 10 to 40 cigarettes per day demonstrated a definite dose-response relationship between AHH activity and the number of cigarettes smoked/day. The dose-response curve was sigmoidal in shape; however, when the data were plotted on a semi-log scale the curve assumed a linear shape, reaching saturation of AHH induction beyond 20 to 25 cigarettes/day. While mean AHH activity was dependent upon the number of cigarettes smoked/day, considerable interindividual variability in AHH (ranging more than 1,000-fold in some cases) was observed among individuals with comparable smoking histories, i.e. smoking the same number of cigarettes. Population distribution suggested clustering of the population in the low-AHH-activity region while cord-blood thiocyanate analysis and twin studies suggested that genetic factors contributed to a major portion of the inter-individual variability in AHH activity observed among smokers.

Aryl Hydrocarbon Hydroxylases↗

Gametic equilibrium of four loci on chromosome 1.

The present study is the first to investigate gametic disequilibrium of loosely linked loci (recombination greater than 22%) of known map distance in humans. The study population consisted of 302 healthy unrelated individuals of whit mixed-European ancestry living in the Denver, Colorado area. Pair-wise combinations of four loci on chromosome 1 (Rhesus, Duffy, phosphoglucomutase-1, and amylase-2) were examined for nonrandom association of alleles at different loci. Observed and expected values were compared with chi-square goodness-of-fit tests. There was no evidence of first-order interaction, i.e., gametic disequilibrium. From these findings it seems that gametic disequilibrium may not be important in the genetic organization of chromosome 1.

Amylases↗

Artificial cranial deformation and the increased complexity of the lambdoid suture.

Studies examining an association between artificial cranial deformation and the presence of wormian bones in the lambdoid suture have been inconclusive. Cranial deformation, however, does not seem to have a direct effect of increasing the sutural complexity of the pars lambdica of the lambdoid suture and also increasing the mean number of lambdoidal wormian bones, given their presence.

Humans↗

Median arcuate ligament syndrome with multivessel involvement: diagnosis with spiral CT angiography.

Intestinal angina may be caused by compression of the celiac artery by the median arcuate ligament of the diaphragm. Aortography can suggest the diagnosis, but the diaphragm cannot be visualized by this examination. We report a symptomatic woman in whom spiral computed tomography-guided angiography demonstrated stenosis of the celiac artery, superior mesenteric artery, and both renal arteries due to diaphragmatic compression. Surgery was beneficial.

Celiac Artery↗

Intraluminal fungal colonization of gastrostomy tubes.

Percutaneous endoscopic gastrostomy tubes are frequently colonized with fungal and bacterial organisms. This has not been previously reported. In our sample of 10 patients, nine percutaneous endoscopic gastrostomy tubes were colonized with fungi. This occurred as early as 1 week after placement. Candida tropicalis was isolated in five patients. It is hypothesized that a variety of fungi use components of the gastrostomy tube polymer, such as polymer additives, which contribute to the structural deterioration of the tube.

Aged↗

Blood lead levels in children from lower socioeconomic communities in Denver, Colorado.

We measured blood lead levels and inquired about environmental exposure pathways in 443 children aged 6 mo to 6 y in four lower socioeconomic Denver, Colorado, neighborhoods. Two neighborhoods were adjacent to a cadmium refinery. Eight percent of the children had blood lead levels > or = 10 micrograms/dl and 45% were below the detection limit of 4 micrograms/dl. Statistical analyses specific to the problem of below-detection values (i.e., dichotomization of variables, the probability plot method of estimation, and the bootstrap estimate of the standard error) were conducted to detect neighborhood differences. A child who lived in Globeville, the neighborhood surrounding the refinery, had a slightly higher probability of having a blood lead level > or = 5 micrograms/dl. Yet, the results as a whole documented the striking decline in blood lead levels in urban children after the deleading of gasoline.

Child↗

Oral Candida colonizes the stomach and gastrostomy feeding tubes.

The lumen of gastrostomy tubes is frequently colonized with Candida. To investigate the source of this contamination, 20 consecutive malnourished patients undergoing placement of a percutaneous endoscopic gastrostomy tube and ten ambulatory controls having routine upper endoscopy performed had both their oral cavity and gastric antrum swabbed and cultured. Percutaneous endoscopic gastrostomy tube recipients who after several weeks were still under our care (9 of 20) had the lumen of their tubes cultured. Fungi were isolated from the stomach in 13 (65%) of 20 patients undergoing percutaneous endoscopic gastrostomy tube placement but in only 1 of 10 ambulatory patients (p < .01). The species isolated from the oral cavity, the stomach, and later the gastrostomy tube were identical in most cases. We conclude that gastrostomy tubes are probably colonized by oral organisms that have made their way into the stomach.

Aged↗

Use of midazolam--an alternative for controlled sedation.

Midazolam hydrochloride (midazolam) is a short-acting central nervous system depressant that allows controlled sedation of the patient after open-heart surgery. Use of an intravenous (IV) loading dose induces sleep rapidly, and can be supplemented by a titratable infusion to allow variations in the sleep-wake cycle. A loading dose of 0.1 mg/kg is given slowly IV. A continuous infusion with the dose based on mcg/kg calculation allows the nurse to titrate the infusion based on the desired therapeutic response.

Cardiac Surgical Procedures↗