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Biomedical subjects

A L White

Publications and source records attributed to A L White.

34 records · Page 2Linked to original sources
PubMed1995

Current status of coronary artery bypass grafting in patients 70 years of age and older.

One hundred and seventy patients 70 years of age and older underwent isolated coronary artery bypass grafting (CABG) from January 1990 to December 1991 at St. Vincent's Hospital, Melbourne, Australia. The clinical records of these patients were analysed to investigate whether elderly patients could undergo safe coronary artery surgery and to determine the factors affecting the outcome. The 30 day or in-hospital mortality was 2.9% (5/170), with 80% (4/5) of the deaths due to cardiac causes. Major postoperative complications occurred in 22.3% (38/170) patients. The median postoperative hospital stay for the patients was 8 days (range 3-103 days). Univariate analysis identified hypertension and female gender as pre-operative risk factors and intraaortic balloon pump, prolonged ventilation, infarct, tamponade, need for inotropes, renal failure and a high APACHE II scores in the intensive care unit as postoperative significant risk factors for operative mortality. There was a trend towards increased mortality with emergency operations; the operative mortality was 2.1% (2/97) for elective operations, 3.1% (2/64) in urgent cases and 11.1% (1/9) for emergencies. Multivariate logistic regression analysis identified prolonged mechanical ventilation, perioperative infarct and APACHE II score as significant independent predictors of mortality. The low operative mortality indicates that elderly patients can undergo safe revascularization. A high incidence of complications necessitates careful monitoring but age per se should not be considered a contraindication to isolated CABG.

Age Factors↗
PubMed1995

High prevalence of colorectal cancer in HLA-B27 transgenic F344 rats with chronic inflammatory bowel disease.

BACKGROUND/AIMS: Transgenic rats expressing the human major histocompatibility class I molecule HLA-B27 develop a spontaneous multisystem disease that includes a chronic colitis resembling ulcerative colitis. The availability of this phenotype in B27 transgenic rats of 2 different inbred strains provided the opportunity to inquire whether colorectal neoplasia, which occurs with increased frequency in humans with inflammatory bowel disease (IBD), would develop in either or both rat genetic backgrounds. METHODS: Clinical and histologic evaluation of B27 transgenic rats with chronic inflammatory bowel disease (IBD) on the F344 and LEW inbred backgrounds. RESULTS: In B27 transgenic rats on an inbred F344 background, hyperplastic lesions evolved in the setting of chronic colitis, with a high frequency of colorectal polyp formation and frequent histologic progression from adenoma to adenocarcinoma. In contrast, no neoplasia occurred in B27 transgenic rats on an inbred LEW background, despite similar colitis. CONCLUSION: A high incidence of spontaneous colorectal neoplasia occurs in a line of B27 F344 rats that shares some features of both sporadic and inflammatory bowel disease-associated human colorectal cancer. This represents a novel example of spontaneous colorectal neoplasia in rodents that is not based on germline modification of one or more already-identified cancer-related genes.

Animals↗
PubMed1994

Cell surface assembly of lipoprotein(a) in primary cultures of baboon hepatocytes.

Lipoprotein(a) (Lp(a)) consists of a low density lipoprotein particle in which apolipoprotein(a) (apo(a)), is disulfide linked to apoB. Lp(a) is produced by the liver, and high plasma levels represent an independent risk factor for cardiovascular diseases. However, pathways of production and metabolism of Lp(a) are poorly understood. We used primary cultures of baboon hepatocytes to analyze the steps involved in Lp(a) biogenesis. The results demonstrated that Lp(a) assembly was extracellular, since it was inhibited when anti-apo(a) antiserum was present in the culture medium. In addition, free apo(a) produced by hepatocytes could associate extracellularly with apoB in either very low density or low density lipoproteins. Lp(a) assembly required lysine-binding pockets in apo(a) kringles, as it was inhibited by the lysine analog, 6-amino hexanoic acid. A portion of apo(a) was also bound to the cell surface via its kringle domains and could be released into the medium by 6-amino hexanoic acid or proline. In add-back experiments, apo(a), but not Lp(a), bound to the cell surface. Addition of low density lipoprotein or very low density lipoprotein to hepatocyte cultures released apo(a) from the cell surface into the lipoprotein fraction of culture medium. We conclude that assembly of Lp(a) can occur at the cell surface. This represents one potential mechanism of Lp(a) production in vivo.

Animals↗
PubMed1994

Molecular basis for "null" lipoprotein(a) phenotypes and the influence of apolipoprotein(a) size on plasma lipoprotein(a) level in the baboon.

High plasma levels of lipoprotein(a) (Lp(a)) and its unique apolipoprotein, apo(a), are an independent risk factor for cardiovascular disease. Plasma Lp(a) levels vary over a 1000-fold range and are determined by the apo(a) locus, which has at least 34 alleles expressing apo(a) isoforms with molecular weights from < 300,000 to > 800,000. In addition, "null" apo(a) alleles produce no detectable plasma apo(a). We used primary cultures of baboon hepatocytes to investigate the molecular basis for null apo(a) phenotypes. Immunoprecipitation of apo(a) after radiolabeling of hepatocytes revealed that some null alleles gave rise to intracellular protein products that were not secreted. Pulse-chase analysis and endoglycosidase digests demonstrated that these proteins were retained in the endoplasmic reticulum. We also examined the molecular basis for the documented inverse correlation between apo(a) size and plasma Lp(a) concentration. Steady-state labeling and pulse-chase analysis of hepatocytes from animals expressing two isoforms of apo(a) revealed that the endoplasmic reticulum residence time of secreted apo(a) isoforms was determined by their size. This accounted for the inverse relationship between isoform size and level of secretion. We conclude that the efficiency of post-translational processing of apo(a) is a major determinant of plasma Lp(a) concentration.

Animals↗
PubMed1994

Intracellular processing of apo(a) in primary baboon hepatocytes.

We have developed a serum-free medium for the long-term culture of highly differentiated primary baboon hepatocytes. Hepatocytes isolated from animals with defined plasma Lp(a) levels and apo(a) glycoprotein phenotypes were used to study the assembly of Lp(a). A combination of steady-state and pulse-chase labeling studies and endoglycosidase digests demonstrated that apo(a) was synthesized as a lower molecular weight precursor. After a prolonged period of time in the endoplasmic reticulum, apo(a) was converted to a mature form and secreted. A proportion of mature apo(a) also had a prolonged residence time in the trans Golgi apparatus. In all experiments, apoB co-immunoprecipitated with apo(a) from the culture medium but not from the cell lysates, supporting an extracellular association of the proteins for the formation of Lp(a). Analysis of hepatic RNA from 29 'null' Lp(a) phenotype baboons revealed that one-third of the animals had detectable apo(a) transcripts, whereas the remainder had no detectable apo(a) mRNA. The baboon hepatocyte system therefore represents a valuable model to examine the effect of allelic variation at the apo(a) locus on Lp(a) assembly.

Alleles↗
PubMed1993

Pathological lesions associated with Anoplocephala perfoliata at the ileo-caecal junction of horses.

The intestinal tracts of 20 horses, killed at a local abattoir and of unknown age, sex and previous clinical history were examined for the presence of Anoplocephala perfoliata attached to the ileo-caecal junction. Four horses had no tape-worms, nine had one to 20 tapeworms attached to the mucosa and seven had more than 100 attached to the mucosa. The histological changes of thickening, ulceration and eosinophil infiltration of the mucosa at the ileo-caecal junction were more severe when more than 100 parasites were present.

Abattoirs↗
PubMed1993

Intracellular maturation of apolipoprotein[a] and assembly of lipoprotein[a] in primary baboon hepatocytes.

The glycoprotein apolipoprotein[a] (apo[a]) is present in plasma at highly variable concentrations and appears as a number of genetically determined size isoforms (400-800 kDa), disulfide linked to apoB-100 in low density lipoprotein to produce lipoprotein [a](Lp[a]). Apo[a] is synthesized by the liver, but the site of association of apo[a] and apoB and factors that regulate its production are unknown. To examine the morphogenesis of the Lp[a] particle, baboon hepatocytes expressing a single, low molecular weight isoform of apo[a] were labeled with [35S]cysteine and methionine, and apo[a] was analyzed by immunoprecipitation and SDS-PAGE. Steady-state labeling revealed two molecular weight forms of apo[a] inside the cell. Only the large form was recovered from the culture medium. Pulse-chase studies and endoglycosidase treatment revealed that the lower molecular weight form of apo[a] represented a precursor with a prolonged residence time in the endoplasmic reticulum or an early Golgi compartment, after which it was processed to the mature form. A proportion of the mature form of apo[a] was rapidly secreted after synthesis, whereas the remainder had a prolonged residence time in a late Golgi compartment. In all experiments, apoB co-precipitated with apo[a] from the culture medium, but not from cell lysates. Density gradient ultracentrifugation and immunoblot analysis revealed that the majority of apo[a] was secreted into the medium in a free form, suggesting that the association between apo[a] and apoB occurred after secretion. Regulation of the movement of apo[a] between intracellular compartments may be one mechanism by which the plasma levels of Lp[a] are influenced.

Amidohydrolases↗
PubMed1992

Oleate-mediated stimulation of apolipoprotein B secretion from rat hepatoma cells. A function of the ability of apolipoprotein B to direct lipoprotein assembly and escape presecretory degradation.

Physiological concentrations of oleate stimulate apolipoprotein (apo) B-containing lipoprotein secretion from HepG2 cells without increasing apoB mRNA levels. The purpose of this study was to determine whether oleate acts by increasing translation of apoB mRNA or through posttranslational effects on the apoB protein. To address the mechanism of oleate-stimulated secretion of apoB, a series of carboxyl terminally truncated apoB constructs was made. Each contained the SV40 early promoter, the apoB 5'-untranslated region, and SV40 polyadenylation signals. Any difference in the response to oleate between endogenous apoB and the proteins encoded by the constructs or between the constructs themselves should thus depend on the protein sequence. Stable transformants were established for each of the constructs in the rat hepatoma cell line McArdle-RH7777. The effect of oleate on secretion of the apoB protein products was determined by labeling with [35S]methionine, immunoprecipitation, and sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Carboxyl-terminal truncation of apoB41 resulted in a loss of the ability of apoB secretion to respond to oleate. Ultracentrifugation of secreted proteins on continuous CsCl gradients from 1.0-1.4 g/ml revealed that this correlated with a decrease in the ability of apoB to be recovered as a buoyant lipoprotein particle. Addition of oleate decreased the densities at which the short forms of apoB secreted as lipoproteins were recovered. Pulse-chase analysis of the secretion of apoB100 and of the truncated proteins revealed that they all underwent rapid posttranslational intracellular degradation. We conclude that oleate has no effect on the translation of apoB mRNA but promotes the secretion of apoB-containing lipoproteins by reducing presecretory degradation of those forms of apoB that can produce buoyant lipoproteins.

Animals↗
PubMed1989

Early and late survival after coronary-artery surgery.

Between 1970 and 1985, 1801 patients underwent coronary-artery surgery without associated valvular surgery. Eighty-four per cent of patients were male and the mean (+/- SD) age was 55.7 +/- 8.3 years. Of the patients, 18.7% were from the Coronary Care Unit and 6.5% had diabetes. The hospital mortality rate for the whole group was 3.5%. Patients from the Coronary Care Unit had the highest (8.9%) hospital mortality rate compared with those patients who were not from the Coronary Care Unit (2.1%; P less than 0.001). Other factors which increased the hospital mortality rate significantly were the number of diseased vessels (P less than 0.01), the degree of left main coronary-artery stenosis (P less than 0.001), an earlier year of surgery (P less than 0.01) and female sex (P less than 0.01). After these were taken into account, no other factors (for example, age, preoperative infarction, presence of left-ventricular aneurysm, left-ventricular end-diastolic pressure, diabetes, use of mammary-arterial grafts or the need for endarterectomy) affected the mortality rate. Patients were followed-up for a mean (+/- SD) of 4.4 +/- 2.8 years. The five-year survival rate for all patients was 88% and the 10-year survival rate was 65%. Cox regression analysis showed that the significant indicators of decreased long-term survival were undergoing operation directly from the Coronary Care Unit (P less than 0.001), left main coronary-artery stenosis (P less than 0.01), the number of grafted vessels (P less than 0.01), concomitant surgery for aneurysm (P less than 0.001), year of surgery (P less than 0.01). Seventy-nine per cent of patients were free of angina pectoris at five years after operation. The year of surgery (P less than 0.001) and preoperative myocardial infarction (P less than 0.05) were the best predictors of recurrent angina. In the long term, recurrent angina remains a problem, although this may change with the increased use of mammary-arterial grafts.

Actuarial Analysis↗
PubMed1987

Open heart surgery in the elderly.

Of 3254 open heart surgical cases performed since 1972, 126 patients (3.9%) were 70 years of age or older. The mean age was 72 years, the oldest being 82. Sixty-seven per cent were male. The following procedures were performed: coronary artery bypass grafting (CABG) 51, aortic valve replacement (AVR) 44, AVR + CABG 16, mitral valve replacement (MVR) 3, MVR + CABG 6, MVR + AVR 4, and other, 2. Of those undergoing CABG, 33% came from the Coronary Care Unit and 24% had left main coronary artery stenosis. There was one peri-operative death (2.0%). Of those undergoing AVR, 43% had coronary artery disease and 13% triple vessel disease. Operative mortality for AVR, and AVR + CABG was 11.4% (5/44) and 18.8% (3/16), respectively. Twenty-six per cent of operative survivors had significant postoperative complications (excluding atrial arrhythmias). The postoperative hospital stay for CABG, AVR and other cases was 11, 13 and 16 days, respectively. Seven year survival of all patients was 61.2 +/- 6.5% (+/- 1 SE) and for AVR +/- CABG was 51.5 +/- 8.6%. Five year survival for CABG was 83.9 +/- 6.3%. We conclude that, in selected cases, CABG can be performed safely in the elderly. Although valvular and combined surgery may result in significant morbidity and mortality, the satisfactory long term results in survivors justifies surgery in this group of patients.

Aged↗
PubMedDate not supplied

The relationship of rat brain weight and pituitary weight to postnatal growth after prenatal exposure to methylazoxymethanol.

Teratogens can affect body weight in various ways, but the association of brain damage with postnatal growth abnormalities suggests a role for neuroendocrine growth-controlling systems. Growth deficiencies follow methylazoxymethanol (MAM) exposure during the period when the growth hormone releasing factor (GRF) cells of the hypothalamus form, and the pattern of growth of the animals is like that of animals deficient in growth hormone. The present studies were designed to examine the growth, body proportions, brain weight, and pituitary weight of animals treated with 20 mg/kg MAM on the 13th day of gestation, a peak period for production of GRF neurons. Among the offspring, this treatment produced about 25% dwarfs (animals smaller than the smallest control of the same sex). Significantly more females than males were categorized as dwarfs. The weight effect occurred long after birth, as is characteristic of animals and humans with growth hormone deficiency. Analyses of weights over the course of development indicated that prenatal factors, rather than factors operating between birth and weaning, predicted the adult body weight of dwarfs, while both sets of factors were significant in other animals. The growth reduction was symmetrical, as would be expected if the animals were growth hormone deficient, with an 18% reduction in weight reflecting a 6% reduction in bone length. The remaining treated animals were similar to controls in absolute weight, body proportions, and rate of growth. Neither pituitary weight nor brain weight appears to play the key role in determining which animals will exhibit growth deficiency.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗
PubMedDate not supplied

A comparison of hypothalamic cell numbers in dwarf and normal weight rats exposed prenatally to methylazoxymethanol (MAM).

Growth deficiencies follow MAM exposure during the period when the growth hormone releasing factor (GRF) cells of the hypothalamus form, while animals exposed slightly later in gestation when the inhibitors of growth hormone release are forming, exhibit giantism. Counts of sample regions of the hypothalamus have shown that rats treated in utero on the 14th day of gestation have reductions in the number of GRF cells, increases in the number of SRIF (somatotropin release inhibiting factor) cells, and alterations of pituitary structure. These effects occurred in all treated subjects, even though obvious effects on body size were present in a small fraction of the treated animals. The present study was designed to examine the effect of 20 mg/kg MAM on the 13th day of gestation (a peak period for production of GRF cells) on GRF and SRIF cell numbers, in a large sample of dwarf-treated rats, normal weight-treated rats, and controls. The results of total counts of hypothalamic cells identified by immunocytochemistry demonstrated significant reductions in GRF cells in both dwarf and normal weight rats exposed to MAM, compared to controls, with no difference between the two treated groups. Like pituitary weights, the neuron counts were significantly correlated with body weight only in dwarf animals. SRIF cell numbers were equivalent to those in controls, suggesting that the increase reported earlier may have been due to a rebound effect in proliferation rather than some response of SRIF cells to GRF cell reduction.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗