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Biomedical subjects

R C Davis

Publications and source records attributed to R C Davis.

At least 73 records · Page 4Linked to original sources
PubMed1991

Assessment of chronic gamma radiosensitivity as an in vitro assay for heterozygote identification of ataxia-telangiectasia.

Ataxia-telangiectasia (A-T) is a rare human autosomal recessive disorder characterized by, among other symptoms, catastrophic reaction to conventional radiotherapy. A-T heterozygotes are clinically asymptomatic and their fibroblasts are intermediate in radiosensitivity between homozygotes and normals. We have attempted to identify heterozygotes by assaying for cellular hypersensitivity to chronic gamma irradiation. Cultured dermal fibroblast strains from 13 control subjects and 55 members from a large Amish pedigree segregating for A-T were assayed for loss of colony-forming ability (CFA) in response to 137Cs gamma radiation delivered at a dose rate of 0.8 cGy/min. For each strain, multiple dose-response curves were summarized in a composite D10 value (dose, in cGy, reducing colony survival to 10%). The D10's of the clinically normal controls and of those pedigree members with known A-T genotype formed a trimodal distribution, with the seven obligate heterozygotes displaying an average value (516 cGy) intermediate between that of the 10 healthy controls (797 cGy) and that of the two affected patients (154 cGy). The D10's were modeled statistically using Gaussian penetrance functions. The most parsimonious model yielded a significant difference in D10 means for heterozygotes and normal homozygotes, a significant donor age effect, but no sex effect. We compared probabilistic identification of heterozygotes based on D10 values with identification based on linkage data for two markers, THY1 and D11S144, closely linked to the A-T gene. This comparison revealed that the D10 data were appreciably less informative than the linked markers. Indeed, the extensive overlap between D10 values for heterozygotes and normal homozygotes precludes the use of postirradiation CFA for either accurate identification of heterozygotes or chromosomal mapping of the A-T gene.

Ataxia Telangiectasia↗
PubMed1991

Effect of N-linked glycosylation on hepatic lipase activity.

Hepatic lipase (HL) is a secretory protein synthesized in hepatocytes and bound to liver endothelium. Previous studies have suggested that HL N-linked glycans are required for catalytic activity. To directly test this hypothesis, Xenopus laevis oocytes were used to express native rat HL or HL lacking one or both N-linked glycosylation sites. The expressed and secreted native HL had an apparent molecular mass of 53 kDa, consistent with purified rat liver HL. The mutant lacking both glycosylation sites, while poorly secreted, had an apparent molecular mass of 48 kDa, the same size observed for HL after enzymatic removal of N-linked oligosaccharides. Mutants lacking one of the two sites were intermediate in size and showed reduced secretion. Each of these expressed and secreted proteins had full catalytic activity that was inhibited by antisera to rat HL. Thus, N-linked glycosylation of rat HL, while important to lipase secretion, is not essential for the expression of lipase activity.

Animals↗
PubMed1990

The effect of ursodiol on the efficacy and safety of extracorporeal shock-wave lithotripsy of gallstones. The Dornier National Biliary Lithotripsy Study.

BACKGROUND: In the treatment of gallstones with extracorporeal shock-wave lithotripsy, the bile acid ursodiol is administered to dissolve the gallstone fragments. We designed our study to determine the value of administering this agent. METHODS: At 10 centers, 600 symptomatic patients with three or fewer radiolucent gallstones 5 to 30 mm in diameter, as visualized by oral cholecystography, were randomly assigned to receive ursodiol or placebo for six months, starting one week before lithotripsy. RESULTS: The stones were fragmented in 97 percent of all patients, and the fragments were less than or equal to 5 mm in diameter in 46.8 percent. On the basis of an intention-to-treat analysis of all 600 patients, 21 percent receiving ursodiol and 9 percent receiving placebo (P less than 0.0001) had gallbladders that were free of stones after six months. Among those with completely radiolucent solitary stones less than 20 mm in diameter, 35 percent of the patients receiving ursodiol and 18 percent of those receiving placebo (P less than 0.001) were free of stones after six months. Biliary pain, usually mild, occurred in 73 percent of all patients but in only 13 percent of those who were free of stones after three and six months (P less than 0.01). There were few adverse events. Only diarrhea occurred with a significantly different frequency in the two groups: 32.6 percent were affected in the ursodiol group, as compared with 24.7 percent in the placebo group (P less than 0.04). Severe biliary pain occurred in 1.5 percent of all patients, acute cholecystitis in 1.0 percent, and acute pancreatitis in 1.5 percent; endoscopic sphincterotomy was performed in 0.5 percent, and cholecystectomy in 2.5 percent. CONCLUSIONS: Extracorporeal shock-wave lithotripsy with ursodiol was more effective than lithotripsy alone for the treatment of symptomatic gallstones, and equally safe. Treatment was more effective for solitary than multiple stones, radiolucent than slightly calcified stones, and smaller than larger stones.

Blood Pressure↗
PubMed1990

Combined lipase deficiency in the mouse. Evidence of impaired lipase processing and secretion.

Newborn combined lipase-deficient (cld) mice have severe hypertriglyceridemia associated with a marked decrease of lipoprotein lipase (LPL) and hepatic lipase (HL) activities. Since the cld mutation and lipase genes reside on separate chromosomes, combined lipase deficiency cannot result from defects occurring within the LPL or HL structural genes. To elucidate the biochemical basis of this trans-acting defect, cld mice were compared to unaffected littermates for changes in lipase mRNA levels, rates of synthesis, and posttranslational processing and secretion. LPL and HL mRNA levels in cld liver and LPL in cld heart were comparable to controls; corresponding lipase synthetic rates were modestly decreased by about 30%. However, these reduced synthetic rates were not lipase-specific, since the rates of apolipoprotein (apo) A-I and apoA-II synthesis in cld liver were similarly decreased. Despite LPL synthetic rates that were 70% of controls, LPL mass in cld postheparin plasma was markedly reduced to only 7% of control values, suggesting that the majority of LPL is not secreted but remains intracellular. Consistent with a lipase secretory defect, neither the LPL nor HL oligomannosyl forms were converted to their respective complex forms in cld tissues, indicating that the lipases had failed to move from the endoplasmic reticulum/cis-Golgi to the medial/trans-Golgi network. In addition, the majority of intracellular LPL was catalytically inactive, since LPL specific activity (units/mg LPL protein) in cld heart, kidney, and brain was reduced 80-97%. In contrast to the severe impairment of lipase posttranslational processing and secretion, cld mouse plasma contained normal levels of another secretory N-linked glycoprotein, adipsin, with its oligosaccharide chains fully processed to the complex form. Thus, the cld mutation appears not to globally disrupt the secretion of all N-linked glycoproteins, but rather selectively impairs LPL and HL at points essential to their normal intracellular transport and secretion.

Animals↗
PubMed1990

Hepatic lipase: site-directed mutagenesis of a serine residue important for catalytic activity.

Hepatic lipase (HL) is a member of the lipoprotein lipase/pancreatic lipase gene family and is believed to function in processing of intermediate and high density lipoproteins. As a lipase, HL is presumed to have a lipid interfacial binding domain, distinct from the esterase catalytic site, orienting the enzyme at aqueous-lipid interfaces and resulting in activation of esterase activity. However, the structural domains responsible for these separate functions have not been identified. Amino acid sequence homology to serine proteases, thioesterases and other lipases, identified Ser147 of rat HL as part of a highly conserved element in an esterase gene family. In order to better define the function of this domain in HL, site-directed mutagenesis was utilized to produce mutant cDNAs with amino acid substitutions for Ser147, Ser133, or Ser228. Following injection of Xenopus oocytes with SP6 transcripts for normal or mutant HL, media from the oocytes were assayed for lipolytic activity and immunoprecipitable HL protein. Mutations of Ser133 and Ser228 produced no decrease in activity whereas the mutant protein in which Ser147 was replaced with glycine had little, if any activity against emulsified triolein substrates. Replacing HL Ser147 with glycine also resulted in a protein with little or no measurable activity for tributyrin, a substrate which does not provide a lipid interface. These results suggest that Ser147 in rat HL is either located at the catalytic site or is required for maintaining the structural integrity of the catalytic site.

Animals↗
PubMed1989

In situ bypass to the dorsalis pedis and tibial arteries at the ankle.

Over a three-year period (1984-1987), we performed 98 in situ saphenous vein bypasses to the tibial arteries in 89 patients. In 68 of these grafts, the distal anastomoses were above ankle level. All but one of these grafts were performed for limb salvage indications. Seven (10%) of these grafts were done in patients on chronic renal dialysis. In 30 grafts, the distal anastomoses were to the ankle level. Indications for surgery were risk of limb loss in all these patients, with tissue loss in 29 (97%). Six (20%) were done in patients on chronic renal dialysis. Operative mortality was 3% in both groups. Late mortality was 13% in the above-ankle group, and 27% in the ankle level group. Secondary patency for the above-ankle group was 97%, 85%, 81%, and 81% at 30 days, one year, two years, and three years. Primary patency was 91%, 67%, and 58% at 30 days, one year, and two years, after which the standard error is greater than 10%. Secondary patency for the grafts at the ankle level was 100% and 82% at 30 days and one and one-half years. Primary patency rates were 93% and 68% at 30 days and one year. In situ bypass grafts at the ankle level had patency rates equivalent to grafts with distal anastomoses above the ankle. Patients with distal bypasses usually presented with tissue loss and had a higher late mortality rate. Careful follow-up and operative intervention when changes in graft velocities or indices are recognized, markedly improves the durability of the in situ saphenous vein bypass.

Anastomosis, Surgical↗
PubMed1987

mRNA species regulated during the differentiation of HL-60 cells to macrophages and neutrophils.

Using cDNA clone banks from differentiated and undifferentiated HL-60 promyelocytic leukemia cells, we have selected clones for genes which are regulated during this differentiation. Regulation of the corresponding mRNAs in HL-60 cells during both monocytic and neutrophilic differentiation was measured for 21 of these clones. The levels of mRNA hybridizing to some of these clones changed by more than 100-fold during differentiation. Unlike erythropoiesis or myogenesis, in which the synthesis of a few new proteins is synchronously regulated, mRNAs in differentiating HL-60 cells are asynchronously regulated, suggesting a complex series of regulatory events. About half of these regulation-selected clones contained repeat sequences, including both Alu and novel repeat families. Most of the regulated genes are members of extensive gene families.

Cell Differentiation↗
PubMed1987

Gamma-actin: unusual mRNA 3'-untranslated sequence conservation and amino acid substitutions that may be cancer related.

beta-Actin mutations in chemically transformed human cell lines have been associated with tumorigenicity, an association consistent with other evidence suggesting that altered cytoskeletal proteins may have an important role in cancer initiation or progression. From a human promyelocytic leukemia cell line, we have isolated a gamma-actin cDNA clone with amino acid substitutions in a region highly conserved in the many actins analyzed. To our knowledge, this is the first example of a variant gamma-actin in a human neoplasm. A separate finding from the analysis of this clone is that the gamma-actin 3'-untranslated region is among the most highly conserved of all 3'-untranslated sequences so far reported, but is entirely different from the beta-actin 3'-untranslated region. The high degree of evolutionary conservation suggests that the 3'-untranslated regions of these two mRNAs have important and distinct functional roles that were already fully differentiated more than 100 million years ago. Mutations affecting four major cytoskeletal components have now been identified in human neoplastic cells. These findings suggest that mutated cytoskeletal genes may be members of a class of oncogenes, fundamentally different from both the nuclear-acting (e.g., myc and simian virus 40 large tumor antigen) and growth factor/receptor/protein kinase-related (e.g., sis, erbB, and ras) types of oncogenes.

Actins↗
PubMed1987

Patient management after endoscopic removal of the cancerous colon adenoma.

The subject of management of patients after endoscopic removal of cancerous adenomas is controversial. A retrospective review of 126 lesions in 121 patients who had had colonoscopic polypectomy of malignant lesions between 1971 and 1985 was used to determine the criteria for colon resection. Invasive cancer was identified in 80 patients, while 41 patients had carcinoma in situ. A synchronous colon cancer was found in five of the 121 patients. The patients who had carcinoma in situ had no evidence of residual tumor or metastatic disease on subsequent follow-up (colon resection in three patients and endoscopic surveillance in 38 patients). Of the 80 patients with invasive cancer, 44 had subsequent colon resection, and 34 of these had no evidence of tumor in the resected bowel or mesenteric lymph nodes. Ten patients had residual tumor, metastatic cancer to regional lymph nodes, or both. Each of the 10 had at least one of the following indications of inadequate resection or dissemination of disease to local lymph nodes (the first indication is a macroscopic evaluation, while the remaining four are all microscopic): incomplete excision, poorly differentiated tumor, invasion of the line of resection, invasion of the polyp stalk, and invasion of venous or lymphatic channels. Present recommendations for patient management after endoscopic removal of an invasive malignant adenoma should include colon resection with regional lymphadenectomy for patients with one or more of these five criteria. Patients without any of these risk factors should have early repeat endoscopic examination 3 months after initial polypectomy to evaluate the polypectomy site. Total colonoscopic examination is repeated at 1 year to ensure the surveillance program is begun with a colon without neoplasms.

Adenoma↗
PubMed1987

Synthesis of hepatic lipase in liver and extrahepatic tissues.

Immunoprecipitations of hepatic lipase from pulse-labeled rat liver have demonstrated that hepatic lipase is synthesized in two distinct molecular weight forms, HL-I (Mr = 51,000) and HL-II (Mr = 53,000). Both forms are immunologically related to purified hepatic lipase, but not to lipoprotein lipase. HL-I and HL-II are also kinetically related and represent different stages of intracellular processing. Glycosidase experiments suggest that HL-I is the high mannose microsomal form of the mature, sialylated HL-II enzyme. Hepatic lipase activity was detected in liver and adrenal gland but was absent in brain, heart, kidney, testes, small intestine, lung, and spleen. The adrenal and liver lipase activities were inhibited in a similar dose-dependent manner by hepatic lipase antiserum. Immunoblot analysis of partially purified adrenal lipase showed an immunoreactive band co-migrating with HL-II at 53,000 daltons which was absent in a control blot treated with preimmune serum. Adrenal lipase and authentic hepatic lipase yielded similar peptide maps, confirming the presence of the lipase in adrenal gland. However, incorporation of L-[35S]methionine into immunoprecipitable hepatic lipase was not detected in this tissue. In addition, Northern blot analysis showed the presence of hepatic lipase mRNA in liver but not adrenal gland. The presence of hepatic lipase in adrenal gland in the absence of detectable synthesis or messenger suggests that hepatic lipase originates in liver and is transported to this extrahepatic site.

Adrenal Glands↗
PubMed1987

Genetic linkage studies of ataxia-telangiectasia: phenotypic blood markers.

We have tested thirty-two phenotypic blood markers on sixteen families with with ataxia-telangiectasia (AT) in an attempt to identify the chromosomal location of the AT gene(s). Although at least five complementation groups have been defined, it is not known whether the corresponding AT genes are clustered or dispersed in the genome. Both clustered and dispersed genetic models were considered in linkage analyses. No significant linkages were found. The data exclude approximately 7 per cent of the autosomal genome for a 'clustered' model and 2 per cent of the autosomal genome for a 'dispersed' model. Several genomic areas were identified which warrant further study.

Ataxia Telangiectasia↗
PubMed1986

Structure and expression of ferritin genes in a human promyelocytic cell line that differentiates in vitro.

HL-60 is a human promyelocytic cell line with the capability of differentiating in vitro to give neutrophils, macrophages, or eosinophils. We screened libraries of HL-60 cDNA clones representing different time points during these differentiation processes to isolate clones corresponding to mRNAs whose expression is regulated during terminal differentiation. Upon sequencing this group of regulated clones, one clone encoding the heavy subunit and two clones encoding the light subunit of human ferritin were identified by reference to published amino acid sequences. Southern blot analyses showed that these clones are encoded by distinct multigene families. These clones identify two mRNAs whose ratios vary in a complex manner during both neutrophil and macrophage differentiation.

Amino Acid Sequence↗
PubMed1985

Comparison of a quantitative treadmill exercise score with standard electrocardiographic criteria in screening asymptomatic young men for coronary artery disease.

A computer-derived treadmill exercise score that quantifies the electrocardiographic response to exercise has been reported to have a high sensitivity (87 per cent) and specificity (92 per cent) in patients with a high prevalence of coronary artery disease. To test its accuracy in young, asymptomatic men with a low prevalence of coronary artery disease, we evaluated the responses of 377 military officers (mean age, 36.6 years) by two independent methods. According to standard electrocardiographic criteria, 45 of the subjects (12 per cent) had positive tests, whereas the treadmill exercise score indicated that only 3 (less than 1 per cent) had positive tests. Since two of these three had left ventricular hypertrophy and met only the criteria for the latter without associated coronary artery disease, the treadmill exercise score predicted that only 1 of 377 subjects would have clinically important coronary artery disease. Coronary arteriography, performed in 10 persons with the most positive scores on standard treadmill tests and the highest scores for risk factors, showed that nine subjects did not have coronary artery disease and that one had single-vessel disease (the same subject who the treadmill score predicted would have mild disease). The treadmill exercise score appears to improve the diagnostic specificity of exercise electrocardiography and may be more useful than values on standard stress tests in screening asymptomatic populations for coronary artery disease.

Adult↗
PubMed1985

A non-fluorescent complex of chlorophyll a with plastocyanin.

A complex between chlorophyll a and plastocyanin has been prepared by dialysis of mixtures of chlorophyll in Triton X-100 micellar solution with the protein. The complex appears to contain no more than one chlorophyll per plastocyanin molecule, and is non-fluorescent, whether the protein is in the oxidized or reduced state. The lack of fluorescence suggests that the chlorophyll is adsorbed very close to the Cu center.

Chlorophyll↗
PubMed1983

Maintenance of nutritional competence after gastric partitioning for morbid obesity.

Can normal nutritional status, as indicated by albumin, transferrin and lean body mass values, be maintained during a 100 lb weight loss after gastric partitioning? Fifteen morbidly obese patients with normal nutritional status were fed three diets before (diet A) and after (diets B and C) gastric partitioning, and changes in albumin, transferrin, and lean body mass were monitored. Diets A and C were compositionally equal and contained 40 to 60 g of protein and 600 to 900 calories administered in six to eight equally divided portions per day. Diet B contained 20 to 40 g of protein and 600 to 800 calories per day and was given through a gastrostomy tube for three months after surgery while oral input was limited to noncaloric liquids. Results showed that weight loss was more rapid before surgery with diet A, than after surgery with diet B or C (diet A versus diet B, p less than 0.05; diet A versus diet C, p less than 0.05). Lean body mass was maintained with each diet, but transferrin (p less than 0.01) and albumin (p less than 0.05) decreased while patients were fed diet B. When gastrostomy tube feedings were discontinued, diet C restored albumin and transferrin to preoperative values (diet C versus diet B, p less than 0.05, diet C versus diet A, p greater than 0.1). Total postoperative weight loss averaged 106 +/- 20 lb after 2 years. These data show that in carefully selected patients with morbid obesity who demonstrate compliance to diet A before surgery, a 100 lb weight loss may be achieved while nutritional competence is maintained.

Adult↗
PubMed1983

The effect of heat and radiation on the initiation and elongation processes of DNA synthesis.

The pH step alkaline elution and alkaline sucrose gradient techniques were utilized to evaluate alterations in DNA replication (initiation and elongation) induced by heat and low dose X-irradiation is synchronized Chinese hamster ovary cells. The initiation and elongation process of DNA synthesis were radioresistant at the G1/S boundary (4 hours after mitosis) while in mid S phase (9 hours after mitosis) DNA initiation and elongation were sensitive to X-irradiation. The initiation and elongation processes of DNA synthesis which were radiation resistant at the G1/S boundary could be inhibited by a hyperthermia treatment (43 degrees C for 1 hour beginning at 4 hours after mitosis). The impairment of initiation in the heated cells was maintained through late S phase while that of elongation was reversible as judged by full recovery at 15 hours after mitosis. These data suggest that the known synergistic lethality of heat and radiation may be mediated by an impairment of initiation of DNA synthesis.

Animals↗