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M Beeson

Publications and source records attributed to M Beeson.

12 recordsLinked to original sources
PubMed2002

Reciprocal congenics defining individual quantitative trait Loci for sedative/hypnotic sensitivity to ethanol.

BACKGROUND: We have identified four major genes or quantitative trait loci (QTLs) that determine duration of loss of righting reflex (LORR), induced by sedative doses of ethanol: Lore1, Lore2, Lore4, and Lore5. Together these genes explain more than 50% of the phenotypic variance for sensitivity to the sedative/hypnotic effects of ethanol between the Inbred Long Sleep (ILS) and Inbred Short Sleep (ISS) strains of mice. The derivation of these strains is reviewed here. METHODS: Each QTL has been bred onto the opposite background (ILS or ISS) through 10 rounds of backcrossing by using QTL-marker-assisted counter selection to produce reciprocal congenic strains. Mice were genotyped for markers that flanked each of the QTLs. Selection for the donor at the desired QTL, and against donor markers at the other four QTLs, allowed rapid fixation of the genetic background. Phenotypic assessment in the ISS-recipient congenic strains was conducted throughout the backcross. RESULTS: By the N5 generation, phenotypic assessments failed to detect significant effects in some sublines; these sublines were discarded and positive lines split to create new replicate sublines. In the N10, all sublines retained the phenotypic difference between heterozygotes and ISS homozygotes; however, the expected additive effect was not found in the Lore1 congenics. On the ILS background, each Lore was captured, as shown by the expected differential LORR. Two strains on the ILS background, and one on the ISS, exhibited the differential effect on blood ethanol concentration associated with the donor strain. CONCLUSIONS: Congenic strains represent an important resource for confirmation of previously identified QTLs, for identification and mapping of additional phenotypes, and for exclusion of candidate genes. QTL-marker-assisted selection rapidly stabilized the genetic background within four generations (based on phenotypic assessments); however, phenotypic selection during the backcrossing to generate congenic strains did not contribute to the successful capture of the ISS QTLs.

Animals↗
PubMed2001

High-throughput sequence identification of gene coding variants within alcohol-related QTLs.

Low initial response to alcohol has been shown to be among the best predictors of development of alcoholism. A similar phenotypic measure, difference in initial sensitivity to ethanol, has been used for the genetic selection of two mouse strains, the Inbred Long-Sleep (ILS) and Inbred Short-Sleep (ISS) mice, and for the subsequent identification of four quantitative trait loci (QTLs) for alcohol sensitivity. We now report the application of high throughput comparative gene sequencing in the search for genes underlying these four QTLs. To carry out this search, over 1.7 million bases of comparative DNA sequence were generated from 68 candidate genes within the QTL intervals, corresponding to a survey of over 36,000 amino acids. Eight central nervous system genes, located within these QTLs, were identified that contain a total of 36 changes in protein coding sequence. Some of these coding variants are likely to contribute to the phenotypic variation between ILS/ISS animals, including sensitivity to alcohol, providing specific new genetic targets potentially important to the neuronal actions of alcohol.

Alcoholism↗
PubMed1997

Confirmation of quantitative trait loci for ethanol sensitivity in long-sleep and short-sleep mice.

Initial insensitivity to alcohol is a strong predictor of human alcoholism, a widespread and heritable health problem. The Long Sleep and Short Sleep lines of mice were developed by genetic selection for high or low alcohol sensitivity. We have identified seven quantitative trait loci (QTLs) specifying differences in alcohol sensitivity using intercross progeny from these selected strains. These QTLs (Lorel-Lore7) together account for approximately 60% of the total genetic variance for this trait. This represents the first report of linkages for genes influencing alcohol action in any mammalian system using stringent, genome-wide mapping criteria.

Alcoholic Intoxication↗
PubMed1997

Anesthesia for trauma during wartime.

Trauma during wartime has been the scourge of the ages. Conventional anesthesia with ether has been available since 1846 when it was demonstrated in Boston by a dentist named William Morton. Subsequently, ether was used during the Mexican-American War in 1847, and chloroform was used during the Crimean War from 1854 to 1856. Nurse anesthetists have made substantial contributions to care of the war-injured by initiating acute airway management and resuscitation efforts and by the administration of anesthesia care for critically injured war casualties undergoing surgical procedures. They have further contributed to goodwill in war-torn areas by providing anesthesia care to many civilian children and adults living in these areas of conflict. The evolution of nurse anesthesia contributions to the treatment of traumatized war casualties is the central focus of this article.

Anesthesia↗
PubMed1997

Quick method for confirmation of quantitative trait loci.

Numerous algorithms for the identification and genetic mapping of quantitative trait loci (QTL) have been developed. Methods for confirming QTL maps involve either examination of independent segregating populations or the construction of congenic lines differing only in the QTL of interest. Because these projects require a minimum of several years or thousands of marker assessments in laboratory mice, an alternative, faster congenic method has been proposed. In a preliminary study, we tested this method for confirming QTLs identified in crosses between the ILS and ISS selected lines of mice for differential sensitivity to the hypnotic effects of ethanol. Herein, we report the construction of "segregating congenic" strains in which each QTL is made homozygous in a single generation, whereas the remainder of the genetic background is allowed to segregate. Sensitivity to ethanol among the progeny of such mice is consistent with predictions. Phenotypic variation is high, as expected, due to the background segregation, and statistical significance was attained in only 2 of 7 comparisons. Such segregating congenic populations may be a valuable research tool for confirming QTL map positions and for subsequent assessment of individual pathways and mechanisms of action of individual QTLs.

Alcoholism↗
PubMed1990

Failure to phosphorylate the retinoblastoma gene product in senescent human fibroblasts.

Heterokaryon studies suggest that senescent and quiescent human diploid fibroblasts (HDF) contain a common inhibitor of entry into S phase. DNA synthesis can be induced in senescent and quiescent HDF by fusing them with cells containing DNA viral oncogenes such as SV40 T antigen, adenovirus E1A, or human papillomavirus E7. Both senescent and quiescent HDF contained the unphosphorylated form (p110Rb) of the retinoblastoma protein, a putative inhibitor of proliferation. After serum stimulation, senescent HDF did not phosphorylate p110Rb and did not enter S phase, whereas quiescent HDF phosphorylated p110Rb and entered S phase. These findings, combined with the observations that T antigen, E1A, and E7 form complexes with, and presumably inactivate, unphosphorylated p110Rb, suggest that failure to phosphorylate p110Rb may be an immediate cause of failure to enter S phase in senescent HDF.

Adenovirus Early Proteins↗
PubMed1986

Quiescent human diploid fibroblasts. Common mechanism for inhibition of DNA replication in density-inhibited and serum-deprived cells.

The mechanism for cessation of proliferation in density-inhibited quiescent human diploid fibroblasts (HDF) and serum-deprived quiescent HDF was compared in two ways. Density-inhibited HDF were fused to either replicating HDF or SV40-transformed HDF and DNA synthesis was measured in the resulting heterokaryons. DNA synthesis was inhibited in the replicating HDF nuclei in heterokaryons in a way that suggested that entry into S phase was blocked, but ongoing DNA synthesis was not inhibited. In contrast, DNA synthesis was induced in the quiescent nuclei in heterokaryons formed with SV40-transformed HDF. Previous experiments had shown that serum-deprived HDF also behave in this way in heterokaryons. To test this similarity further, we examined the inhibitory activity of cell membranes prepared from both types of quiescent HDF. We found that both types of quiescent HDF contain DNA synthesis-inhibitory activity that is (1) effective on replicating HDF; (2) ineffective on SV40-transformed HDF; (3) sensitive to heat and trypsin. Thus, these results support the hypothesis that both density-inhibited HDF and serum-deprived HDF share a common mechanism for arrest in G1 phase. They also suggest that a membrane-bound protein plays a role in the inhibition of DNA synthesis in quiescent HDF.

Blood↗
PubMed1982

Carcinogen-transformed human cells are inhibited from entry into S phase by fusion to senescent cells but cells transformed by DNA tumor viruses overcome the inhibition.

Senescent human diploid cells (HDC) were fused to replicative transformed cells of different types, and DNA synthesis was monitored in the resulting heterodikaryons. Human cells transformed by simian virus 40 or adenovirus serotype 5 were able to induce DNA synthesis in senescent HDC nuclei in heterodikaryons. In contrast, carcinogen-transformed cells were not able to induce DNA synthesis in senescent HDC nuclei; rather, the transformed nuclei in these heterodikaryons were inhibited from entering S phase. Cells transformed by Rous sarcoma virus and most human tumor cells tested are similarly inhibited by fusion to senescent HDC. These results suggest that the mechanism for transformation by DNA tumor viruses may be fundamentally different from that of other viruses and carcinogens and from that of most human tumor cells. A simple model to explain these results is that (i) senescent HDC contain an inhibitor of entry into S phase; (ii) cells transformed by DNA tumor viruses have gained a transforming factor, perhaps large tumor antigen, that is capable of overriding the normal inhibitor; and (iii) cells transformed by carcinogens or RNA viruses have lost or altered the mechanism for expression of the normal inhibitor yet are still sensitive to it. We propose that this inhibitor is produced in normal cells when they experience conditions that are inadequate for proliferation and that it plays a role in putting the cells into a distinct quiescent state with long-term viability. The override of this inhibitor function in simian virus 40-transformed HDC can explain why they have low viability in plateau-phase cultures and why they die during crisis.

Carcinogens↗
PubMedDate not supplied

Generalized resistance to thyroid hormone associated with possible selective cardiac nonresistance.

OBJECTIVE: To review the condition of generalized resistance to thyroid hormone and to report a case of generalized thyroid hormone resistance associated with atrial fibrillation. METHODS: A case report is presented of a 52-year-old man with atrial fibrillation who was referred by a cardiologist for thyroid ablation because of "hyperthyroidism," when his free thyroxine was found to be 4.35 ng/dL (normal, 0.55 to 2.46) and his free triiodothyronine was 6.5 pg/mL (normal, 1.4 to 4.4). RESULTS: This clinically euthyroid man with no signs or symptoms of hyperthyroidism except for the possibly related atrial fibrillation had a thyrotropin level of 3.45 mIU/L (normal, 0.46 to 4.7) in conjunction with the aforementioned increased levels of thyroid hormones. Further evaluation revealed normal 6-hour (11.7%) and 24-hour (27.6%) (123)I uptakes. Magnetic resonance imaging of the pituitary revealed a normal-sized gland with no masses. CONCLUSION: This is a rare case of generalized resistance to thyroid hormone in a patient with only atrial fibrillation. Whether the heart was selectively nonresistant to thyroid hormone as the cause of his atrial fibrillation or whether his atrial fibrillation was due to his mitral valve prolapse documented on echocardiography could not be determined with certainty. His ventricular rate of 83 per minute and laboratory evaluation suggest that thyroid hormone was not the cause of the atrial fibrillation.

Atrial Fibrillation↗