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Biomedical subjects

P O'Brien

Publications and source records attributed to P O'Brien.

At least 163 records · Page 9Linked to original sources
PubMed1986

Effort angina with adequate beta-receptor blockade: comparison with diltiazem alone and in combination.

Calcium channel blockers and beta-receptor blockers improve symptoms of myocardial ischemia by potentially different mechanisms. Accordingly, combination therapy may entail additive benefits. Twenty-four patients with symptomatic stable effort angina despite full beta-blockade were randomized to a double-blind Latin square protocol in which they received propranolol in a dose producing full beta-receptor blockade, diltiazem, 240 mg/day, in divided doses and a combination of propranolol and diltiazem, 240 or 360 mg/day. Treadmill testing (Bruce protocol) was utilized to assess exercise tolerance, radionuclide ventriculography to assess left ventricular function and clinical follow-up to assess adverse effects and overall clinical response. Comparable treadmill exercise times were observed with monotherapy (344 +/- 83 seconds with propranolol and 341 +/- 87 seconds with diltiazem) and the lower dose combination (361 +/- 87 seconds). With propranolol and diltiazem, 360 mg/day, however, there was a significant increase in treadmill time (393 +/- 106 seconds; p less than 0.05). In five patients whose treadmill exercise was limited by angina on all therapies, there was a significant improvement in the time to onset of chest pain with both low dose and high dose combinations (311 +/- 71 seconds, p less than 0.05 and 336 +/- 76 seconds, p less than 0.01, respectively). Improved treadmill performance was supported by the clinical response, while an increase in adverse effects was not observed. Thirteen of 24 patients blindly selected the higher dose diltiazem combination as their optimal therapy. Left ventricular dilation was observed (by radionuclide ventriculography) in response to exercise in each phase of therapy; this was related to stress-induced ischemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Antagonists↗
PubMed1986

An approach to analyzing UV mutagenesis in E. coli.

UV mutagenesis of single-strand DNA phage can be divided into three types: induced untargeted; induced targeted; and uninduced targeted. We report the development of new tools to determine the number of processes which contribute to these types of mutagenesis. An E. coli tRNA gene, glyU, has been cloned using M13 derivatives mp8 and mp9 as vectors. The nucleotide sequence of glyU and its flanking regions is presented. In this paper, phage glyU anticodon mutants are detected by their ability to suppress GAA and GAT missense mutations in trpA. We used phage carrying GAG and CTC at the anticodon position and found results consistent with the hypothesis that two processes act to produce the transition to GAA suppression: an uninduced regionally targeted process; and an induced locally targeted process with some untargeted activity. The transversion frequency to GAT suppression on the other hand responded as if only an uninduced locally targeted process was involved. Thus, we hypothesize that the new tools have discriminated three different processes of mutagenesis and we discuss further work designed to test this hypothesis.

Anticodon↗
PubMed1986

Morphological and biochemical studies of canine progressive rod-cone degeneration. 3H-fucose autoradiography.

Visual cell pathology and rod outer segment renewal were investigated in normal and PRCD-affected miniature poodles using 3H-fucose autoradiography. Twenty-four hours following the intravitreal injection of 3H-fucose, label accumulated diffusely over cone OS and in a banded pattern at the rod OS base. In normal rods, the band of 3H-label was displaced sclerad with time. PRCD-affected rods in the early stages of the disease (stages 0-1) also showed a similar 3H-label pattern but a significantly (P less than 0.001) reduced renewal rate (control = 2.35 +/- 0.43 mu/24 hr; affected = 0.99 +/- mu/24 hr). This abnormal renewal rate was present in central, equatorial, and peripheral visual cells and was not associated with the presence or density of pigment in the RPE cell layer. Biochemical studies indicated that the 3H-label was present as an integral membrane component in the rod OS and confirmed that canine rhodopsin is a fucosylated glycoprotein. The 3H-band in the rod OS layer disappeared in stage 2 of the disease; diffuse label now was present over rod OS that had decreased length and were reduced in number. At this stage of the disease, interphotoreceptor space was invaded by phagocytic cells, and photoreceptor nuclei were lost from the outer nuclear layer. These late degenerative changes were more extensive in the superior and inferior retinal meridians.

Animals↗
PubMed1986

Effects of in vivo treatment with ibuprofen on macrophage function in breast and colon cancer patients.

In this study, the capacity of macrophages from breast and colon cancer patients to become cytotoxic for tumor cells after in vivo administration of the prostaglandin inhibitor, Ibuprofen, has been investigated. Prior to the administration of the drug, each patient's macrophages were tested for their ability to kill tumor cells in the presence and absence of 10(-7) M Ibuprofen. The patients were given 400 mg Ibuprofen 4 times daily for 28 days. At days 14 and 28 after commencing the study, blood samples were drawn and the macrophages were tested for their ability to kill tumor cells in vitro. The patients were divided into 3 groups: Category I, patients possessing non-cytotoxic macrophages in the presence and absence of Ibuprofen; Category II, patients possessing non-cytotoxic macrophages in the absence of the drug and cytotoxic macrophages in the presence of the drug; and Category III, patients possessing cytotoxic macrophages in the absence of the drug and non-cytotoxic macrophages in the presence of the drug. Category I cancer patients generally responded the most effectively to in vivo administration of Ibuprofen at day 28 whereas Category II patients responded the most effectively at day 14. Category II patients became non-responsive when tested again at day 28 and Category I patients became non-responsive when the study was extended to day 42. Category III patients were generally non-responsive at all time points studied.(ABSTRACT TRUNCATED AT 250 WORDS)

Breast Neoplasms↗
PubMed1985

Specific labeling and partial inactivation of cytochrome oxidase by fluorescein mercuric acetate.

Addition of 1 eq of fluorescein mercuric acetate (FMA) to beef heart cytochrome oxidase was found to inhibit the steady-state electron transfer activity by 50%, but further additions up to 10 eq had no additional effect on activity. The partial inhibition caused by FMA is thus similar to that observed with other mercury compounds (Mann, A. J., and Auer, H. E. (1980) J. Biol. Chem. 255, 454-458). The fluorescence of FMA was quenched by a factor of 10 upon binding to cytochrome oxidase, consistent with the involvement of a sulfhydryl group. However, addition of mercuric chloride to FMA-cytochrome oxidase resulted in an increase in fluorescence, suggesting that FMA was displaced from the high affinity binding site. Cytochrome c binding to FMA-cytochrome oxidase resulted in a 10% decrease in the fluorescence, possibly caused by Forster energy transfer from FMA to the cytochrome c heme. The binding site for FMA in cytochrome oxidase was investigated by carrying out sodium dodecyl sulfate gel electrophoresis under progressively milder dissociation conditions. When FMA-cytochrome oxidase was dissociated with 3% sodium dodecyl sulfate and 6 M urea, FMA was predominantly bound to subunit II following electrophoresis. However, when the dissociation was carried out at 4 degrees C in the absence of urea with progressively smaller amounts of lithium dodecyl sulfate, the labeling of subunit II decreased and that of subunit I increased. These experiments demonstrate that mercury compounds bind to a high affinity site on cytochrome oxidase, possibly located in subunit I, but then migrate to subunit II under the normal sodium dodecyl sulfate gel electrophoresis conditions. A definitive assignment of the high affinity binding site in the native enzyme cannot be made, however, because it is possible that mercury compounds can migrate from one sulfhydryl to another under even the mildest electrophoresis conditions.

Animals↗
PubMed1985

Identification of the binding site on cytochrome c1 for cytochrome c.

The reagent 1-ethyl-3-(3-[14C]trimethylaminopropyl)carbodiimide (ETC) was used to identify specific carboxyl groups on the cytochrome bc1 complex (ubiquinol-cytochrome c reductase, EC 1.10.2.2) involved in binding cytochrome c. Treatment of the cytochrome bc1 complex with 2 mM ETC led to inhibition of the electron transfer activity with cytochrome c. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis indicated that both the cytochrome c1 heme peptide and the Mr = 9175 "hinge" peptide were radiolabeled by ETC. In addition, a new band appeared at a position consistent with a 1:1 cross-linked cytochrome c1-hinge peptide species. Treatment of a 1:1 cytochrome bc1-cytochrome c complex with ETC led to the same inhibition of electron transfer activity observed with the uncomplexed cytochrome bc1, but to decreased radiolabeling of the cytochrome c1 heme peptide. Two new cross-linked species corresponding to cytochrome c-hinge peptide and cytochrome c-cytochrome c1 were formed in place of the cytochrome c1-hinge peptide species. In order to identify the specific carboxyl groups labeled by ETC, a purified cytochrome c1 preparation containing both the heme peptide and the hinge peptide was dimethylated at all the lysines to prevent internal cross-linking. The methylated cytochrome c1 preparation was treated with ETC and digested with trypsin and chymotrypsin, and the resulting peptides were separated by high pressure liquid chromatography. ETC was found to label the cytochrome c1 peptides 63-81, 121-128, and 153-179 and the hinge peptides 1-17 and 48-65. All of these peptides are highly acidic and contain one or more regions of adjacent carboxyl groups. The only peptide consistently protected from labeling by cytochrome c binding was 63-81, demonstrating that the carboxyl groups at residues 66, 67, 76, and 77 are involved in binding cytochrome c. These residues are relatively close to the heme-binding cysteine residues 37 and 40 and indicate a possible site for electron transfer from cytochrome c1 to cytochrome c.

Amino Acid Sequence↗
PubMed1985

Recurrent aneurysms and late vascular complications following repair of abdominal aortic aneurysms.

Between 1970 and 1976, 1,112 patients underwent abdominal aortic aneurysm repair. Follow-up, ranging from six to 12 years, was complete in 1,087 patients (97.7%). The most frequent cause of late deaths was coronary artery disease (45.6%), but significant morbidity related to the peripheral vascular system had developed in 94 patients, and led to 8.4% (48 patients) of all late deaths. Forty-nine true, 14 anastomotic, and five dissecting aneurysms were detected in 59 patients (5.4%) a mean (+/- SD) of 5.2 +/- 3.1 years after the initial aneurysm repair. These aneurysms were located in the thoracic (24), thoracoabdominal (five), or abdominal aorta (11), and in the iliac (six), femoral (17), popliteal (four), and renal arteries (one). Only one of 26 patients presenting with a rupture of one of these secondary aneurysms survived. There was a significant association between preoperative hypertension and recurrent aneurysm. These findings suggest that subsequent vascular disease, including recurrent aneurysms and graft complications, cause significant late morbidity and mortality after repair of abdominal aortic aneurysm. Careful follow-up and adequate control of hypertension may allow reduction in morbidity and an improvement in late survival.

Adult↗
PubMed1985

Homozygosity in a population of variable size and mutation rate.

A formula is obtained for the probability that two genes at a single locus, sampled at random from a population at time t, are of particular types. The model assumed is a diffusion approximation to a neutral Wright-Fisher model in which mutation is not necessarily symmetric and the population size is a function of time. It is shown that for symmetric mutation in a population undergoing a step-function type bottleneck, homozygosity increases with decreasing population size. A formula is given for the distribution of the number of segregating sites occurring in two randomly sampled sequences of completely linked sites, with general mutation at a site and identical mutation structure between sites. We give similar results for a population of fixed size but for which the mutation rate is a function of time, and not necessarily symmetric. We confirm the intuitively clear effect that increasing the mutation rate decreases homozygosity.

Alleles↗
PubMed1985

Pathology of colposcopic findings in 2635 diethylstilbestrol-exposed young women.

An analysis of 6055 colposcopically directed biopsy specimens from 2635 diethylstilbestrol (DES)-exposed women and 445 biopsy specimens from 277 nonexposed women was undertaken to correlate microscopic findings with colposcopic patterns. All examinations were performed using a standardized protocol which required that each participant have colposcopy, cytologic smears, and biopsy of abnormal colposcopic lesions. The findings of colposcopic "columnar epithelium, gland openings, and Nabothian cysts" correlated most often with glandular epithelium in the biopsy specimen. "White epithelium," which includes three related colposcopic patterns, mosaicism, punctation, and white epithelium, was associated most frequently (82-93% of cases) with squamous metaplasia, but occasionally with dysplasia and carcinoma in situ (CIS)(0-6%). The presence of dysplasia or CIS in any individual biopsy specimen occurred most frequently with the observation of higher graded lesions by colposcopy or a prior diagnosis of dysplasia.

Carcinoma in Situ↗
PubMed1985

Capillary number and percentage closed in human diabetic sural nerve.

The number of capillaries per mm2, minimum intercapillary distance, number of endothelial nuclei per capillary section, and percentage of capillaries closed were evaluated in transverse sections of fascicles of 45 control and 36 diabetic sural nerves. All controls and patients were prospectively studied to ascertain their diabetic and neuropathic status. An index of pathology was introduced and it was found to provide a sensitive and reliable measurement of the presence and severity of neuropathy. The number of capillaries and minimum intercapillary distance of diabetic nerves were not significantly different from those of controls (P greater than 0.05). Diabetic nerves exhibited a small but statistically significant increase in the number of endothelial nuclei per capillary that was positively correlated with the severity of neuropathy. The most striking abnormality was the statistically significant increase in the percentage of capillaries closed in patients with neuropathy as compared to those without neuropathy and controls. Among diabetics, this percentage increased with the severity of neuropathy (P = 0.008). The two capillary abnormalities that have been demonstrated may play a role in the development of diabetic polyneuropathy.

Adult↗
PubMed1985

Clinical and neuropathological criteria for the diagnosis and staging of diabetic polyneuropathy.

Scored symptoms, neurological deficits, detection threshold of cutaneous sensation and parameters of nerve conduction were compared with quantitated neuropathological abnormalities in the sural nerve in 47 healthy subjects and 36 diabetic patients, 32 with and 4 without neuropathy. The fifth percentile line of a new Index of Pathology, which combines loss of myelinated fibres and abnormality of the remaining fibres, was found to provide a sensitive and reliable minimum neuropathological criterion for the diagnosis of polyneuropathy. Abnormality, as assessed by two clinical evaluations, similarly separated healthy subjects and diabetic patients into those with and without neuropathy. For the detection of diabetic polyneuropathy, vibration sense was more sensitive than touch-pressure or thermal cooling. Abnormalities of nerve conduction were found to be both sensitive and reliable in the detection of polyneuropathy. Velocity was most frequently abnormal, but only slightly more often than F wave latency and amplitude. We conclude that abnormality, as judged independently from two different types of evaluation, provides a sensitive and reliable minimal criterion for the diagnosis of neuropathy. Although symptoms, neurological deficits and abnormalities of nerve conduction are statistically associated, they should be evaluated separately to provide adequate characterization.

Adolescent↗
PubMed1985

The Fontan procedure.

The Fontan procedure has afforded improved surgical repair for several complex congenital cardiac defects, including tricuspid atresia and single ventricle. Through surgical creation of a connection between the RA and the RV or PA, adequate pulmonary perfusion can be achieved without an RV. Although it is not an anatomic connection, the Fontan procedure is a more physiologic approach than the previously used shunt procedures. Systemic venous return and PVR are effectively separated within the heart, pulmonary blood flow is assured through an RA-to-PA connection, and ventricular volume overload is avoided. The procedure has been effective in relieving cyanosis and has resulted in improved levels of exercise tolerance after surgery.

Blood Vessel Prosthesis↗
PubMed1984

Increased incidence of cervical and vaginal dysplasia in 3,980 diethylstilbestrol-exposed young women. Experience of the National Collaborative Diethylstilbestrol Adenosis Project.

The incidence rates of dysplasia and carcinoma in situ (CIS) of the cervix and vagina were determined in 3,980 young women exposed prenatally to diethylstilbestrol. Strict criteria were developed to minimize selection bias among the subset of 744 pairs of matched exposed and unexposed (control) cohort participants, all of whom were identified through review of prenatal obstetrical records. A high degree of compliance was achieved throughout the seven-year study period since in each group about 90% of the women remained as active participants, kept 77% of the annual anniversary examinations, and had separate Papanicolaou smears of the cervix and vagina performed in 99% of the anniversary examinations. The incidence rate for dysplasia and CIS was significantly higher in the women exposed to diethylstilbestrol than in those not exposed in the matched cohort (15.7 v 7.9 cases per 1,000 person-years of follow-up). The rates were higher in the exposed women if squamous metaplasia extended to the outer half of the cervix or onto the vagina. In other respects, the matched cohorts were strikingly similar.

Adult↗
PubMed1984

Identification of specific carboxylate groups on adrenodoxin that are involved in the interaction with adrenodoxin reductase.

Modification of bovine adrenodoxin with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) dramatically inhibited the reaction with adrenodoxin reductase (EC 1.18.1.2). The modification did not cause any change in the visible spectrum of adrenodoxin, indicating that the iron-sulfur center was not perturbed. Furthermore, the anomalous fluorescence of Tyr 82 was not changed in either intensity or wavelength. The inhibition was accompanied by the covalent incorporation of 14C-labeled EDC into adrenodoxin. The sites modified by EDC were determined by hydrolyzing adrenodoxin with either trypsin or Staphylococcus aureus protease and separating the resulting peptides by reverse phase high pressure liquid chromatography. The major carboxyl groups modified were found to be at Glu 74, Asp 79, and Asp 86, which are located in a sequence containing a high negative charge density. We propose that the conversion of negatively charged carboxylate groups at these residues to bulky, positively charged EDC-carboxyl groups inhibits the reaction with the reductase. EDC was also found to cross-link adrenodoxin to cytochrome c in yields up to 90%. The cross-links were found to involve the formation of amide linkages between carboxyl groups on adrenodoxin and the lysine amino groups surrounding the heme crevice of cytochrome c.

Adrenodoxin↗