The injuries to JFK.
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Craniocerebral Trauma↗
Biomedical subjects
A White
Publications and source records attributed to A White.
Altered cell cycle arrest and gene amplification potential accompany loss of wild-type p53.
Gene amplification occurs at high frequency in transformed cells (10(-3)-10(-5)), but is undetectable in normal diploid fibroblasts (less than 10(-9)). This study examines whether alterations of one or both p53 alleles were sufficient to allow gene amplification to occur. Cells retaining one wild-type p53 allele mimicked the behavior of primary diploid cells: they arrested growth in the presence of drug and failed to demonstrate amplification. Cells losing the second p53 allele failed to arrest when placed in drug and displayed the ability to amplify at a high frequency. Thus, loss of wild-type p53 may lead to amplification, possibly caused by changes in cell cycle progression. Other determinants can by-pass this p53 function, however, since tumor cells with wild-type p53 have the ability to amplify genes.
Animals↗
Length regulation in the Dictyostelium discoideum slug is a late event.
Time-lapse video light microscopy was used to study the emergence and maturation of the migratory slug from a D. discoideum aggregate. The anterior part, the tip of this simple multicellular organism, establishes migration prior to the definition of the rear, and hence the length of the slug. It was found that newly formed slugs of wild-type strain WS380B can reach lengths greater than 1 cm, yet mature slugs of this strain are rarely longer than 2-3 mumm. Often the tip extended out of the aggregation mound upon an arching pillar of cells. After the tip first touched the substratum, it commenced migration with a rapid succession of movement steps. Here we show that at the initiation of migration, a differential rate of cell movement along the developing slug axis results in a series of complicated changes, before the stable and mature shape of the slug is formed. Our results lead to new conclusions about D. discoideum slug formation and shape maintenance. Evidence is presented for regulation of slug length.
Animals↗
The assembly and secretion of ApoB 100-containing lipoproteins in Hep G2 cells. ApoB 100 is cotranslationally integrated into lipoproteins.
The possibility that apoB 100 is cotranslationally translocated to the endoplasmic reticulum lumen and integrated into lipoproteins has been investigated. ApoB 100 nascent polypeptides were shown to be secreted from pulse-labeled Hep G2 cells after treatment with puromycin and chase for 1 or 2 h in the presence of puromycin and cycloheximide. These nascent polypeptides banded during sucrose gradient ultracentrifugation between the position of the high (HDL) and the low (LDL) density lipoproteins, revealing an inverse relationship between the length of the polypeptide and the density of the fraction. ApoB 100 occurred in the position of LDL and very low density lipoproteins (VLDL). Electronmicroscopy studies of the apoB-containing particles from the gradient indicated an increase in size with increasing length of the polypeptide. Furthermore, labeling studies indicated that the triglyceride load increased with the length of the polypeptide. An inverse relationship between the size of C-terminally truncated apoB polypeptides and the density of the assembled lipoproteins was also observed in experiments with transfected minigenes coding for apoB 41, apoB 29, and apoB 23. These proteins appeared on HDL particles. Pulse-chase experiments indicated that 80-200-kDa apoB nascent polypeptides on particles with HDL density, with time, were converted into larger polypeptides on lighter particles, to be fully replaced by apoB 100 on LDL-VLDL particles. The formation of these LDL-VLDL particles could be blocked by cycloheximide. Sixty-five percent of pulse-labeled apoB nascent polypeptides present in the microsomal fraction was released by sodium carbonate treatment, and 77% of these polypeptides could be recovered on the immature particles (banding between HDL and LDL) after sucrose gradient ultracentrifugation. Pulse-chase experiments indicated that these nascent polypeptides, on the immature lipoproteins, had the capacity to be precursors for all the apoB 100-containing LDL and VLDL particles formed in the cell. The obtained results indicate that a major portion of the apoB nascent polypeptides in the cell form lipoproteins cotranslationally during the translocation to the lumen of the endoplasmic reticulum.
Apolipoprotein B-100↗
Missed neuroleptic malignant syndrome.
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Antipsychotic Agents↗
Suppression of gene amplification in human cell hybrids.
Gene amplification, one example of genetic instability, is of prognostic and clinical importance in neoplasia. In tumorigenic cells, gene amplification occurs at a very high frequency, whereas in normal diploid fibroblasts the event is undetectable by the clonogenic assay. To investigate genetic control of gene amplification, amplification frequency was measured in hybrids of tumorigenic cells and normal diploid cells. The ability to amplify an endogenous gene behaved as a recessive genetic trait, and control of gene amplification potential segregated independently of tumorigenicity and immortality.
Aspartate Carbamoyltransferase↗
Detection of messenger RNA from O6-methylguanine-DNA methyltransferase gene MGMT in human normal and tumor tissues.
BACKGROUND: The level of the DNA repair protein O6-methylguanine-DNA methyltransferase is an important determinant of the response of tumor cells in culture to alkylating nitrosoureas. In these cells, the abundance of messenger RNA (mRNA) is directly correlated with repair activity. PURPOSE: Our purpose was to compare transferase mRNA levels with the repair activity in primary human tumors. METHODS: Human transferase mRNA was measured in tissue samples from brain tumors, normal lung, lung tumors, ovarian tumors, and normal human liver by use of an RNA protection assay with an antisense probe prepared from the cloned gene. RESULTS: Normal and tumor tissue samples from the same patient had similar transferase activity levels, but transferase expression varied widely among tissue samples from different patients. Brain and lung samples, on average, had transferase mRNA levels closer to those in liver samples than their transferase activity levels. In two cases, tissue samples which were transferase deficient by the activity assays were found to lack transferase mRNA. CONCLUSIONS: Deficiencies in transferase activity are due to reduced or absent mRNA transcription or processing. In brain and lung, there may be post-transcriptional control of mRNA expression. The wide interindividual variation in transferase expression is also seen at the transcription level. IMPLICATIONS: These are among the first measures of transferase mRNA expression in primary human tissue. More samples should be examined to extend these observations.
Brain Neoplasms↗
Elevated plasma insulin-like growth factor binding protein-1 levels in type 1 (insulin-dependent) diabetic patients with peripheral neuropathy.
Previous studies have suggested that nerve regeneration may be defective in patients with diabetic polyneuropathy. Since insulin-like growth factor I (IGF-I) has been shown to stimulate nerve regeneration, and IGF binding protein-1 is acutely regulated by plasma insulin we have investigated the relationships between plasma IGF-I, IGFBP-1, glucose and insulin in Type 1 (insulin-dependent) diabetic patients with peripheral polyneuropathy. Plasma samples were taken at hourly intervals over an 11-h period (08.00-19.00 hours) in order to characterise secretory profiles for 15 Type 1 diabetic patients (eight neuropathic and seven non-neuropathic) and eight non-diabetic control subjects. In the non-diabetic subjects, mean plasma IGF-I levels were stable throughout the 11-h period with a range of 97 micrograms/l-169 micrograms/l. In contrast, mean plasma IGFBP-1 levels declined steadily from a high level of 1.99 micrograms/l at 08.00 hours to approximately one half (0.86 microgram/l) at 15.00 hours. Comparison of areas under the curves revealed significant negative correlations between IGFBP-1 and glucose (-0.88, p = 0.01), IGFBP-1 and insulin (-0.75, p = 0.016), and IGFBP-1 and IGF-I (-0.68, p = 0.03). A significant positive correlation was found between insulin and IGF-I (+0.89, p = 0.001). The diabetic patients had markedly elevated plasma IGFBP-1 levels (area under curve, p = 0.01) and lower plasma IGF-I levels (p = 0.033) even though these patients were hyperinsulinaemic throughout the study period.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Antibodies to neuropeptides as alternatives for peptide receptor antagonists in studies on the physiological actions of neuropeptides.
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Adrenal Glands↗
Outpatient management of pyelonephritis.
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Acute Disease↗
The removal of morphologically abnormal sperm forms by phagocytes: a positive role for seminal leukocytes?
A preliminary investigation was undertaken further to determine the function of the leukocytic cells found in semen. We performed semen analysis and quantified leukocyte subsets using immunocytochemical staining techniques in ejaculates of 351 patients. Leukocyte profiles were examined in relation to sperm morphological data for evidence of a sperm removal/selection process. Three types of seminal phagocytic cell were found to contain spermatozoa: small polymorphonuclear leukocytes (approximately 10-12 microns), monocytes of similar size and much larger (30-40 microns) macrophages capable of engulfing multiple sperm heads. The total leukocyte count (P less than 0.01), the numbers of phagocytic cells i.e. polymorphonuclear leukocytes (P less than 0.05), monocyte/macrophages (P less than 0.01) and HLA-DR positive cells (P less than 0.01), were significantly higher in those samples with greater than 50% ideal sperm forms. Significantly fewer of these same cell types were observed in samples with greater than 50% head defects. There was no difference in the number of tail or midpiece defects between leukocytospermic (greater than 10(6)/ml) and non-leukocytospermic semen samples. Oligozoospermic samples contained significantly fewer leukocytes (P less than 0.005), although above a concentration of 5 x 10(6)/ml, the sperm number was not correlated with leukocyte number. These data, along with repeated observation of spermatozoa or sperm fragments within phagocytic cells, support the hypothesis that leukocytes have a role in the removal of abnormal spermatozoa from the ejaculate.
Alkaline Phosphatase↗
Childhood psychological trauma correlates with unsuccessful lumbar spine surgery.
In a retrospective study of 86 patients who underwent lumbar spine surgery, patients who had three or more of a possible five serious childhood psychological traumas (risk factors) had an 85% likelihood of an unsuccessful surgical outcome. Conversely, in patients with a poor surgical outcome, the incidence of these traumas was 75%. In the group of 19 patients with no risk factors, there was only a 5% incidence of failure. This study shows that a highly significant correlation exists between unsuccessful lumbar spine surgery and a history of childhood traumas. Although recognition of predictors for unsuccessful outcome can be useful in avoiding surgery in patients whose indications for surgery are borderline, the greater challenge is to help the patient who, despite being at high psychological risk for negative outcome, has severe spinal pathology that will likely require surgery. In such cases, psychiatric treatment is critical. In the group of 19 patients with no risk factors, single-level laminectomies and discectomies were performed on 6 patients. The other 13 cases were complex, involving a combination of repeat surgeries (n = 4) fusions (n = 3), and/or multilevel laminectomies and discectomies (n = 11).
Adult↗
Clinical efficacy of spinal instrumentation in lumbar degenerative disc disease.
In review of 871 lumbar fusion procedures performed during the last 8 years, the theoretical advantages of lumbar spinal instrumentation are not borne out in simple discogenic disease. Four groups of 30-35 patients without previous surgery who underwent fusion by different techniques were matched for age, sex, length of follow-up, surgeons, number of levels fused, duration of preoperative symptoms, diagnosis, and type of third party payer. At least for the diagnoses of herniated disc with segmental instability and the instrumentation systems used in this study, results were superior with no internal fixation. This is in keeping with the higher complication rates and frequent need for implant removal reported by many authors.
Adult↗
Salvage laryngectomy after radical radiotherapy for laryngeal carcinoma.
Of 376 patients who were treated by radical radiotherapy for squamous carcinoma of the larynx, 56 subsequently underwent total laryngectomy. Residual or recurrent tumour was identified in 43 of the resection specimens, and necrosis alone in 13 cases, although a positive biopsy had been obtained in 3 of these prior to salvage laryngectomy. No disease related factors such as site or stage of the original tumour, or treatment related factors such as radiation type or dose, were found to be predictive of whether or not tumour was present. The clinical opinion of an experienced surgeon was found to have a positive predictive value of 0.86 for the presence of tumour. The fistula rate of salvage laryngectomy, 15 out of 56, was similar to that of other series. The actuarial cause specific 5-year survival for patients with tumour was 0.589, and for patients with necrosis only was 0.923. Intercurrent, smoking related disease was the cause of death in 16 of the 33 patients who have died.
Biopsy↗
Discrimination between painful and painless diabetic neuropathy based on testing of large somatic nerve and sympathetic nerve function.
The syndromes of painful diabetic neuropathy and painless foot ulceration are distinct clinical entities. To investigate whether there is a pattern of nerve fibre involvement that could clearly discriminate between them, we have studied three groups of diabetic patients, 19 with painful neuropathy, 14 with painless foot ulceration, and 19 with no clinical neuropathy. Large somatic nerve fibre function was assessed by nerve conduction studies and vibration thresholds, small somatic nerve function by cooling and warming thresholds, the parasympathetic system by heart-rate dependent cardiac autonomic reflexes, and the sympathetic system by postural drop in blood pressure and plasma noradrenaline (supine and erect). Normal ranges were obtained from 25 age-matched healthy subjects. Painful neuropathy was characterized by uniform dysfunction of small somatic fibres and preserved sympathetic nerve activity (plasma noradrenaline) with a wide range of large somatic fibre and autonomic reflex abnormalities. By contrast, in painless foot ulceration there was universal severe dysfunction of all nerve fibre populations. Discriminant analysis identified peroneal motor conduction velocity as the best single variable for distinguishing between painful and painless neuropathy (81% of cases). A combination of peroneal motor conduction velocity with vibration threshold and plasma noradrenaline discriminated completely between the two clinical syndromes. These findings suggest that the key differences between painful and painless diabetic neuropathy are in large somatic and sympathetic fibre function.
Diabetic Neuropathies↗
Dietary nonprotein calories and cerebral infarction size in rats.
BACKGROUND AND PURPOSE: Conventional diets may cause hyperglycemia in patients with neurological injuries. The purpose of this study was to examine the effect on the severity of cerebral infarction of replacing carbohydrates as the primary dietary source of nonprotein calories. METHODS: Sixty-nine Long-Evans rats were either fasted for 24 hours, fed isocaloric amounts of a control diet containing 51.5% of the calories as carbohydrates, or fed one of five experimental diets before middle cerebral artery occlusion for 45 minutes. In the experimental diets, 60% of the carbohydrate calories were replaced with one or more of the following substrates: 1,3-butanediol, triacetin, tributyrin, and long- and medium-chain triglycerides. RESULTS: The plasma glucose concentration in the fasted animals was 6.4 +/- 1.1 mumol/ml. In the animals receiving the control diet, which contained the greatest number of carbohydrate calories, plasma glucose was 9.1 +/- 1.4 mumol/ml. The 1,3-butanediol diet resulted in an intermediate plasma glucose concentration averaging 7.8 +/- 1.3 mumol/ml. Plasma beta-hydroxybutyrate levels were elevated in the fasted group and with the 1,3-butanediol diet. Plasma acetate levels were increased with the diets supplemented with triacetin. The smallest infarct volume (53 +/- 43 mm3) was found in the fasted group and the largest (162 +/- 56 mm3) in the control diet group. Infarct volumes that were significantly smaller were found with the 1,3-butanediol diet (98 +/- 41 mm3) and with the triacetin/tributyrin diet (105 +/- 53 mm3). The volume of the infarct was directly related to the plasma glucose concentration before ischemia (n = 69, r = 0.47, p less than 0.01), but not to plasma lactate, ketone body, or acetate levels. CONCLUSIONS: It may be possible to develop a diet for patients with neurological injuries using noncarbohydrate calorie sources, such as 1,3-butanediol, triacetin, or tributyrin, that would supply systemic caloric and protein requirements without the adverse effect of conventional diets.
Animals↗
Bromocriptine inhibits pro-opiomelanocortin mRNA and ACTH precursor secretion in small cell lung cancer cell lines.
We have previously reported that a human small cell lung cancer (SCLC) cell line (COR L103) that expresses the proopiomelanocortin (POMC) gene and secretes ACTH precursor peptides is relatively resistant to glucocorticoid regulation. Using this model, we have now examined alternative regulatory mechanisms of the POMC gene and found that both the mRNA and ACTH precursor peptides were stimulated four- and two-fold, respectively, after 48 h incubation with db-cAMP. Next, we examined the dopamine agonist, bromocriptine, which acts predominantly through D2 receptors linked to adenyl cyclase to cause a reduction in intracellular cAMP. Bromocriptine suppressed cAMP levels and inhibited precursor peptide secretion within 24 h in a dose-dependent manner (0.15-15 microM). At the highest dose, peptide secretion was inhibited from 95 to 53 pmol/mg protein, and POMC mRNA was reduced by 50%, while beta-actin mRNA remained unchanged. This effect could not be mimicked by incubation of cells with the alpha-adrenergic antagonist, phenoxybenzamine, suggesting that the alpha-adrenergic effects of bromocriptine were not responsible for this observation. These cells also secrete estradiol, but the secretory rate was unaffected by bromocriptine, suggesting, with the beta-actin data, that the POMC inhibition was not a cytotoxic effect. No recovery in precursor peptide secretion was seen in a 48-h period after the removal of bromocriptine. However, when the postchallenge incubation was extended to 8 d, there was a recovery in secretory potential between day 3 and day 8 and normal growth kinetics in the 4 d after removal of the drug. In contrast to these findings, the mouse corticotroph cell line, AtT20, showed no response to bromocriptine, in keeping with reports that this agonist has no effect on anterior lobe corticotrophs. We conclude that bromocriptine effectively inhibits POMC expression in SCLC cells, and that this phenomenon might be of useful clinical application.
Adrenocorticotropic Hormone↗
A simple bioassay for epidermal growth factor using pig thyrocytes.
A bioassay for epidermal growth factor (EGF) is described using an eluted stain assay (ESTA) of dehydrogenase activity in pig thyrocytes. Optimal responsiveness to EGF was obtained in confluent cultures of primary pig thyrocytes cultured with EGF or biological samples containing EGF for either 24 or 48 h. Dehydrogenase activity was determined by measuring the production and then the release of a coloured formazan product produced by reduction of a 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide substrate added to the cells. The assay responded equally to mouse, human and recombinant EGF and was suitable for measuring EGF activity in some but not all biological fluids. Specificity of detection of EGF activity was confirmed using antibody to EGF. The ESTA assay compared favourably with the radioreceptor assay for EGF in terms of sensitivity to EGF with half-maximal activation at 0.24 +/- 0.06 nmol/l (mean +/- S.E.M., n = 22 experiments) for the ESTA assay and 0.60 +/- 0.13 nmol/l (n = 7 experiments) for the radioreceptor assay.
Animals↗