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Biomedical subjects

B Paigen

Publications and source records attributed to B Paigen.

At least 55 records · Page 3Linked to original sources
PubMed1997

High plasma HDL concentrations associated with enhanced atherosclerosis in transgenic mice overexpressing lecithin-cholesteryl acyltransferase.

A subset of patients with high plasma HDL concentrations have enhanced rather than reduced atherosclerosis. We have developed a new transgenic mouse model overexpressing human lecithin-cholesteryl acyltransferase (LCAT) that has elevated HDL and increased diet-induced atherosclerosis. LCAT transgenic mouse HDLs are abnormal in both composition and function. Liver uptake of [3H]cholesteryl ether incorporated in transgenic mouse HDL was reduced by 41% compared with control HDL, indicating ineffective transport of HDL-cholesterol to the liver and impaired reverse cholesterol transport. Analysis of this LCAT-transgenic mouse model provides in vivo evidence for dysfunctional HDL as a potential mechanism leading to increased atherosclerosis in the presence of high plasma HDL levels.

Animals↗
PubMed1997

Phenotypic characterization of Lith genes that determine susceptibility to cholesterol cholelithiasis in inbred mice: physical-chemistry of gallbladder bile.

Lith genes control susceptibility to cholesterol gallstone formation in inbred strains of mice on a lithogenic diet containing high fat, high cholesterol and 0.5% cholic acid. Our study defines the physical-chemical phenotypes of C57L, AKR, and (C57L x AKR) F1 mouse gallbladder biles during 56 days on the lithogenic diet. We found enhanced cholesterol supersaturation, accumulation of mucin gel, and larger gallbladders in all C57L and F1 mice, as well as more frequent gallstone formation in male C57L and F1 mice (80%) compared to females (40%) or AKR mice (15%). In male C57L and F1 mice, mucin gel accumulated at 3 days, followed by cholesterol supersaturation and phase separation of liquid crystals, solid monohydrate crystals, and, in 43% of mice, anhydrous cholesterol crystals; whereas, in females, phase separations were delayed 2 to 9 days, and anhydrous crystals did not form. In AKR mice, cholesterol supersaturation and phase separations were infrequent and delayed, and gender did not influence the phenotype. Taurocholate invariably replaced endogenous bile salts, especially tauro-beta-muricholate, with crystallization sequences matching taurocholate-containing model bile systems. We conclude: i) Lith genes determine biliary cholesterol supersaturation, mucin gel accumulation, gallbladder size, phase-separation, and prevalence of cholesterol gallstones. ii) Identical phenotypes in C57L and F1 mice indicate susceptibility to cholesterol gallstones is genetically dominant, favoring males 2:1. iii) Mucin gel accumulation, crystallization, and stone formation are rare in AKR mice. This definition of the physical chemistry of lithogenesis should aid in further elucidation of the Lith genes and the proteins they encode.

Animals↗
PubMed1996

Transgenic mice expressing human phospholipid transfer protein have increased HDL/non-HDL cholesterol ratio.

The role of plasma phospholipid transfer protein (PLTP) in lipoprotein metabolism is poorly understood. In vitro studies suggest that PLTP influences HDL size and composition and transfers phospholipids among lipoproteins. To provide an in vivo model for studies of PLTP physiology, transgenic mice that express human PLTP were generated. Human PLTP transcripts were detected in total RNA from adipose tissue, lung, heart, and spleen of the two distinct lines (A and C) of transgenic mice. Despite minimal expression of human PLTP in the liver of these transgenic mice and similar plasma phospholipid transfer activity in transgenic and non-transgenic mice (19.1 +/- 3.1 vs 18.9 +/- 2.7 mumol/ml/h), differences in lipoprotein levels were observed between transgenic and control mice receiving the same chow diet. Male transgenic mice of line C had significantly higher HDL cholesterol than control mice (76.4 +/- 4.6 vs 71.9 +/- 7.0 mg/dl, p < 0.05) and the male transgenic mice of lines A and C had a significantly lower non-HDL cholesterol (15.1 +/- 4.1 and 15.6 +/- 4.7 vs 20.9 +/- 5.5 mg/dl, P < 0.01 and P < 0.02) and a significantly higher HDL cholesterol/non-HDL cholesterol ratio than the control mice (5.3 +/- 1.3 and 5.5 +/- 2.2 vs 3.9 +/- 1.9 mg/dl, P < 0.01 and P < 0.02). Female mice from transgenic line C had higher HDL cholesterol than control mice (64.6 +/- 4.8 vs 57.4 +/- 5.1 mg/dl, P < 0.01) while female mice from line A tended to have higher HDL cholesterol/non-HDL cholesterol ratio than control mice (5.5 +/- 3.7 vs 3.8 +/- 1.4). These observations suggest that expression of PLTP in peripheral tissues play an important role in lipoprotein metabolism. Expression of human PLTP produced a more favorable lipoprotein profile and thus, enhanced expression of PLTP could potentially retard atherosclerosis.

Animals↗
PubMed1996

Strain distribution pattern for SSLP markers in the SWXJ recombinant inbred strain set: chromosomes 7 to X.

The SWXJ recombinant inbred (RI) set was developed for genetic analysis of heritable ovarian tumors. In this report we present data for 223 simple sequence length polymorphisms spanning Chromosomes (Chrs) 7-X to complete the genetic marking of this RI set. The strain distribution patterns (SDP) for these loci were combined with data from 19 other polymorphic genes, resulting in densely marked maps for Chrs 7-X. Combined with the 165 loci for Chr 1-6 reported previously (Svenson et al., Mamm. Genome 6, 867, 1995), the SWXJ RI set represents a powerful tool for mapping genes in neoplastic as well as other heritable disorders.

Animals↗
PubMed1996

Air quality in an animal facility: particulates, ammonia, and volatile organic compounds.

Concentrations of ammonia, volatile organic compounds, particles, and mouse allergen were measured in an animal facility. Ammonia concentrations averaged less than 1 ppm, below any health-based standards. The concentrations of volatile organic compounds were in the 5-15 micrograms/m3 range. Among the volatile organic compounds found, only the terpenes a-pinene and a-terpinol (which may be derived from the pine shavings used as bedding) were consistently present in concentrations greater than outdoor air. The primary air contaminant present at concentrations high enough to be of known physiological significance was the mouse allergen, Mus ml. To determine which activities in an animal room generated the highest concentrations of airborne Mus ml, a monitor that counted particles continuously was used. The particle counts were correlated with allergen levels in the worker's breathing zone (r50.83,p,0.05). Thus, a particle counter can be used effectively in an animal facility to identify specific activities that generate high levels of both particles and allergen. Such activities included changing mice from soiled to clean cages, cleaning floors, and changing foam inserts in pressurized individually ventilated cages. To reduce exposure to allergen during cage changing, which is the major activity for an animal caretaker, a capture-type ventilated changing table was designed and tested. Use of such a table reduced exposure to allergen in the worker's breathing zone from 4.961.1 to 2.160.3 ng Mus ml/m3, a level comparable to background levels.

Air Pollutants, Occupational↗
PubMed1995

Lith1, a major gene affecting cholesterol gallstone formation among inbred strains of mice.

The prevalence of cholesterol gallstones differs among inbred strains of mice fed a diet containing 15% (wt/wt) dairy fat, 1% (wt/wt) cholesterol, and 0.5% (wt/wt) cholic acid. Strains C57L, SWR, and A were notable for a high prevalence of cholelithiasis; strains C57BL/6, C3H, and SJL had an intermediate prevalence; and strains SM, AKR, and DBA/2 exhibited no cholelithiasis after consuming the diet for 18 weeks. Genetic analysis of the difference in gallstone prevalence rates between strains AKR and C57L was carried out by using the AKXL recombinant inbred strain set and (AKR x C57L)F1 x AKR backcross mice. Susceptibility to gallstone formation was found to be a dominant trait determined by at least two genes. A major gene, named Lith1, mapped to mouse chromosome 2. When examined after 6 weeks on the lithogenic diet, the activity of hepatic 3-hydroxy-3-methylglutaryl-CoA reductase (EC 1.1.1.88) was downregulated as expected in the gallstone-resistant strains, AKR and SJL, but this enzyme failed to downregulate in C57L and SWR, the gallstone-susceptible strains. This suggests that regulation of the rate-limiting enzyme in cholesterol biosynthesis may be pivotal in determining the occurrence and severity of cholesterol hypersecretion and hence lithogenicity of gallbladder bile. These studies indicate that genetic factors are critical in determining gallstone formation and that the genetic resources of the mouse model may permit these factors to be identified.

Animals↗
PubMed1995

Strain distribution pattern for SSLP markers in the SWXJ recombinant inbred strain set: chromosomes 1 to 6.

We typed 147 simple sequence length polymorphisms in the SWXJ recombinant inbred (RI) strain set spanning Chromosomes (Chrs) 1-6. The strain distribution pattern for these loci was combined with data from 18 previously typed loci for SWXJ, resulting in new chromosome maps for this RI set, with an average density of 3.5 cM between loci. This is the first systematic effort to develop a more highly resolved genetic map for the SWXJ RI set and thereby improves the usefulness of this genetic tool for mapping genes underlying both simple and complex genetic disorders.

Animals↗
PubMed1995

The effect of relative humidity on mouse allergen levels in an environmentally controlled mouse room.

To determine the effect of humidity on the levels of the mouse allergen Mus m 1, an experimental animal room was constructed to control environmental variables. The sex, strain, age, and number of mice was constant in the room, so that the average daily production of Mus m 1 would not vary greatly. Six different levels of relative humidity from 15% to 65% were maintained for a minimum of a week each. Daily collections of airborne particulates were eluted from filters and Mus m 1 content measured by immunological assay. Increasing relative humidity caused a decrease in Mus m 1 levels from a high of 3 ng/m3 at 15% humidity to a low of 0.5 ng/m3 at 65% humidity. Thus, reduction of airborne allergen levels can be achieved by careful attention to humidity control, especially during the winter heating season when humidity levels may be low. This experimental room can be used to measure the effect of other variables such as ventilation rate, caging, bedding, and work practices on the levels of mouse allergen in an animal facility.

Allergens↗
PubMed1995

Genetics of responsiveness to high-fat and high-cholesterol diets in the mouse.

The natural variation among inbred strains of mice was used to elucidate the genetic factors underlying the responsiveness to high-fat and high-cholesterol diets. The nine strains examined are the progenitors of recombinant inbred strain sets: C57BL/6J, C57L/J, SWR/J, SJL/J, SM/J, A/J, AKR/J, C3H/HeJ, and DBA/2J. Plasma lipids, liver lipids, the prevalence of cholesterol gallstones, and the size of aortic fatty streak lesions were examined after 18 wk of consumption of the diet containing 15% fat and 1% cholesterol. The variation in aortic lesions found among inbred strains provided the basis for several additional studies that demonstrated the existence of eight genes affecting atherosclerosis. These genes, named Ath1 to Ath8, are briefly described. The genetic analysis of variation in gallstone formation demonstrated that more than one gene affects this phenotype.

Animals↗
PubMed1995

Apolipoprotein E deficiency in mice: gene replacement and prevention of atherosclerosis using adenovirus vectors.

Apolipoprotein E (apoE)-deficient mice develop marked hyperlipidemia as well as atherosclerosis and thus are an excellent animal model for evaluating the potential for gene therapy in human genetic dyslipoproteinemias. Recombinant adenovirus containing either human apoE (rAdv.apoE) or the reporter gene luciferase (rAdv.luc) were generated and infused intravenously in apoE-deficient mice with preinfusion plasma total cholesterol of 644 +/- 149 mg/dl an cholesterol rich VLDL/IDL. After a single infusion of rAdv.apoE, plasma concentrations of human apoE ranging from 1.5 to 650 mg/dl were achieved. Adenovirus-mediated apoE replacement resulted in normalization of the lipid and lipoprotein profile with markedly decreased total cholesterol (103 +/- 18mg/dl), VLDL, IDL, and LDL, as well as increased HDL. Measurement of aortic atherosclerosis 1 mo after adenoviral infusion demonstrated a marked reduction in the mean lesion area of mice infused with rAdv.apoE (58 +/- 8 x 10(3) microns2) when compared with control mice infused with rAdv.luc (161 +/- 10 x 10(3) microns2; P < 0.0001). Thus, apoE expression for 4 wk was sufficient to markedly reduce atherosclerosis, demonstrating the feasibility of gene therapy for correction of genetic hyperlipidemias resulting in atherosclerosis. The combined use of adenovirus vectors and the apoE-deficient mouse represents a new in vivo approach that will permit rapid screening of candidate genes for the prevention of atherosclerosis.

Adenoviridae↗
PubMed1994

New murine polymorphisms detected by random amplified polymorphic DNA (RAPD) PCR and mapped by use of recombinant inbred strains.

Oligonucleotide primers of random sequence that were 12 bases in length, 58% in GC content, and lacking internal palindromes were designed. By random amplified polymorphic DNA (RAPD) PCR, these primers were used to survey for DNA variations between the progenitors of the mouse AXB and BXA recombinant inbred sets (A/J and C57BL/6J). We identified 17 DNA variants detected by 10 primers. Map positions for these variants were determined by comparing their strain distribution patterns in the AXB, BXA recombinant inbred sets with strain distribution patterns of previously published loci. When necessary, BXD and NXSM recombinant inbred sets were also used. These 17 new loci mapped to 12 chromosomes. The 10 primers were also used to survey 20 inbred mouse strains including the progenitors of other recombinant inbred sets and four mouse strains recently inbred from the wild (CAST/Ei, MOLF/Ei, PERA/Ei, and SPRET/Ei).

Animals↗
PubMed1994

Characterization of plasma lipids in genetically obese mice: the mutants obese, diabetes, fat, tubby, and lethal yellow.

Plasma lipid levels were measured in control strains C57BL/6J (B6) and C57BL/KsJ (BKs) and in the mutants obese (ob), diabetes (db), fat (fat), tubby (tub), and lethal yellow (Ay), which are considered models of non-insulin-dependent diabetes mellitus (NIDDM), to determine if perturbations in plasma lipids were similar to those observed in the obese or diabetic human population. Compared with control mice, obese, diabetes, tubby, and lethal yellow mice had triglyceride levels that were elevated 1.5-fold to twofold, but fat mice had triglyceride levels similar to those of controls. Elevated plasma cholesterol levels, which were also observed in most mutant mice, were mainly due to an increase in high-density lipoprotein cholesterol (HDL-C). The degree of hypercholesterolemia appeared to be related to the age of onset and severity of the obesity and diabetes phenotype, with the greatest elevations occurring in obese and diabetes, milder elevations in fat mice of both sexes, male tubby, and male yellow mice, and no apparent changes in female tubby or lethal yellow mice. Plasma HDL-C and glucose levels and body weight in B6-db/db mice and their normal littermates were measured at intervals between 2 and 12 weeks of age to determine when the changes in cholesterol occurred in relationship to hyperglycemia and obesity. An elevation in HDL-C in B6-db/db mice was apparent by 3 weeks of age, a time concurrent with the elevation in blood glucose but before any weight differences.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Atherosclerosis in genetically obese mice: the mutants obese, diabetes, fat, tubby, and lethal yellow.

Mice with five different mutations conferring an obese or diabetic phenotype were evaluated for fatty streak lesions after consuming an atherogenic diet containing 15% fat and 1.25% cholesterol (wt/wt) for 14 weeks. The five mutations, fat, obese, tubby, diabetes, and lethal yellow, are maintained as congenic strains with C57BL/6J (B6) or C57BL/KsJ (BKs) as genetic backgrounds. None of the mutants exhibited accelerated fatty streak lesion formation; the mutant fat had aortic lesions comparable in size to those of its control strain, and the mutants obese, diabetes, tubby, and lethal yellow had significantly reduced lesion area in comparison to controls. Although B6 and BKs are closely related strains, we observed that the BKs strain was more prone to early-stage atherogenesis. Fatty streak lesion area was twice as large in BKs mice than those found in B6 mice; likewise, in comparison, the mutants obese and diabetes had larger lesions if they were carried as congenic strains in the BKs rather than the B6 genetic background. Plasma triglycerides, total cholesterol, high-density lipoprotein cholesterol (HDL-C), and combined low-density and very-low-density lipoprotein cholesterol (LDL-C and VLDL) levels were also measured in the mice. Lipid profiles differed among the mutant mice, but in general, elevations in plasma total cholesterol, triglycerides, and HDL-C were observed. Whereas the hypertriglyceridemia and hypercholesterolemia are consistent with an atherogenic lipid profile, HDL-C levels, which are normally decreased in individuals with non-insulin-dependent diabetes mellitus, were increased in the mouse mutants.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗