Valvular heart disease in women: the surgical perspective.
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Aortic Valve↗
Biomedical subjects
A J Carpenter
Publications and source records attributed to A J Carpenter.
A 'select and swap' strategy for the isolation of clones with tightly regulated transgenes.
Increasing numbers of biological problems are being addressed by genetic approaches that rely on inducible expression of transgenes. It is desirable that expression of such a transgene is tightly regulated, from close to zero expression in the 'off' state, to appreciable (at least physiological) expression in the 'on' state. Although there are many examples where tight regulation has been achieved, certain factors, including chromosomal position effects due to random integration of the transgene, often cause suboptimal inducibility and make the isolation of tightly regulated clones difficult and/or laborious. Here we describe a 'select and swap' strategy for the isolation, from a population of stable transfectants, of clones with tightly regulated transgenes. In this approach, a positively and negatively selectable, inducible marker gene is used to select for clones with optimal transgene regulation. After isolation of such clones, the marker gene is swapped with a linked gene of interest by the use of site-specific recombination. To test this strategy we introduced into human cells a plasmid with a tetracycline-inducible bacterial gpt gene linked to a promoterless luciferase gene, isolated clones with tight gpt expression and used the Cre/loxP site-specific recombination system to swap the gpt gene with the luciferase gene. We discuss ways for refining and developing the system and widening its applicability.
Blotting, Southern↗
Repression of CDK1 and other genes with CDE and CHR promoter elements during DNA damage-induced G(2)/M arrest in human cells.
Entry into mitosis is controlled by the cyclin-dependent kinase CDK1 and can be delayed in response to DNA damage. In some systems, such G(2)/M arrest has been shown to reflect the stabilization of inhibitory phosphorylation sites on CDK1. In human cells, full G(2) arrest appears to involve additional mechanisms. We describe here the prolonged (>6 day) downregulation of CDK1 protein and mRNA levels following DNA damage in human cells. This silencing of gene expression is observed in primary human fibroblasts and in two cell lines with functional p53 but not in HeLa cells, where p53 is inactive. Silencing is accompanied by the accumulation of cells in G(2), when CDK1 expression is normally maximal. The response is impaired by mutations in cis-acting elements (CDE and CHR) in the CDK1 promoter, indicating that silencing occurs at the transcriptional level. These elements have previously been implicated in the repression of transcription during G(1) that is normally lifted as cells progress into S and G(2). Interestingly, we find that other genes, including those for CDC25C, cyclin A2, cyclin B1, CENP-A, and topoisomerase IIalpha, that are normally expressed preferentially in G(2) and whose promoter regions include putative CDE and CHR elements are also downregulated in response to DNA damage. These data, together with those of other groups, support the existence of a p53-dependent, DNA damage-activated pathway leading to CHR- and CDE-mediated transcriptional repression of various G(2)-specific genes. This pathway may be required for sustained periods of G(2) arrest following DNA damage.
CDC2 Protein Kinase↗
Systemic cytokine response to hepatic resections under total vascular exclusion.
OBJECTIVE: To investigate the systemic cytokine response to major liver surgery as the basis for assessing potential new treatments. DESIGN: Open prospective study. SETTING: University hospital, UK. SUBJECTS: Thirteen patients undergoing elective hepatic resections that involved total vascular exclusion of the liver. INTERVENTIONS: Blood samples were taken preoperatively, during the operation, and during the first four postoperative days. Concentrations of endotoxin, interferon gamma (IFN-gamma), tumour necrosis factor alpha (TNFalpha), interleukin-1 (IL-1), and interleukin-6 (IL-6) were measured. RESULTS: Endotoxin concentrations were raised in 3/13 patients before operation and in 6 patients during the postoperative period. TNFalpha concentrations were undetectable. IFN-gamma and IL-1 responses followed a low and inconclusive pattern. IL-6 was significantly increased from 6 hours after operation to the third postoperative day, peaking at 699 (+/-277) pg/ml at 24 hours (p < 0.01). The two patients who died had the highest postoperative concentrations of IL-6. CONCLUSIONS: There is a pronounced systemic response to hepatic resection under total vascular exclusion that is reflected by the increase in IL-6 concentration and correlates with the operative blood loss and postoperative outcome. This might be used as an indicator of the response to specific treatments in this type of surgery. Treatments that minimise the IL-6 response to major hepatic resection may be of value.
APACHE↗
Acute suppurative epididymal orchitis.
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Acute Disease↗
An improved vasoactive drug combination for a pharmacological erection program.
Papaverine hydrochloride (smooth muscle relaxant), phentolamine mesylate (alpha-adrenergic blocking agent) and prostaglandin E1 (vasodilator and smooth muscle relaxant) were combined to produce a potent vasoactive drug therapy for use in a pharmacological erection program. Doses of 2.5 cc papaverine (30 mg./cc), 0.5 cc phentolamine (5 mg./cc), 0.05 cc prostaglandin E1 (500 micrograms./cc) and 1.2 cc 0.9% normal saline were combined to produce a vial of 4.25 cc for patient convenience. Twenty unit vials were made from the 1 cc vial of prostaglandin E1, the most expensive ingredient. The solution is physiologically active for at least 6 months and can be stored at room temperature although refrigeration is recommended. The pH of the solution is 4. This vasoactive drug combination has been used in 116 patients for diagnostic testing and subsequent treatment. A dose of 0.25 cc has been effective for diagnosis and treatment in the majority of patients with mild to moderate arteriogenic and/or venogenic and diabetic impotence. For patients with neurogenic dysfunction 0.1 to 0.125 cc was the usual dose. Two patients had a prolonged erection requiring irrigation, 1 on the day of initial testing and 1 on home therapy. Pain at the site of injection or during intercourse was noted in only 2 patients and to date no fibrosis or plaques have been found.
Adult↗
Changes in plasma volume during bed rest: effects of menstrual cycle and estrogen administration.
Bed rest (BR) is associated with a decrease in plasma volume (PV), which may contribute to the impaired orthostatic and exercise tolerances seen immediately after BR. The purpose of this study was to determine whether increases in blood estrogen concentration, either during normal menstrual cycles or during exogenous estrogen administration, would attenuate this loss of PV. Nineteen healthy women (21-39 yr of age) completed the study. Twelve women underwent duplicate 11-day BR without estrogen supplementation. PV decreased significantly (P less than or equal to 0.01) during both BR's, from 2,531 +/- 113 to 2,027 +/- 102 ml during BR1 and from 2,445 +/- 115 to 2,244 +/- 96 ml during BR2. The women who began BR in the periovulatory stage of the menstrual cycle (n = 3), a time of elevated endogenous estrogens, had a transient delay in loss of PV during the first 5 days of BR. Women who began BR during other stages of the menstrual cycle (n = 17) showed the established trend to decrease PV primarily during the first few days of BR. Seven additional women underwent a single 12-day BR while taking estrogen supplementation (1.25 mg/day premarin). PV decreased during the first 4-5 days of BR, then returned toward the pre-BR level during the remainder of the BR (pre-BR PV, 2,525 +/- 149 ml; post-BR PV, 2,519 +/- 162 ml). Thus menstrual fluctuations in endogenous estrogens appear to have only small transient effects on the loss of PV during BR, whereas exogenous estrogen supplementation significantly attenuates PV loss.
Adult↗
Endogenous hormones subtly alter women's response to heat stress.
The thermoregulatory responses of menstruant women to exercise in dry heat (dry-bulb temperature/wet-bulb temperature = 48/25 degrees C) were evaluated at three times during the menstrual cycle: menstrual flow (MF), 3-5 days during midcycle including ovulation (OV), and in the middle of the luteal phase (LU). Serum concentrations of estradiol-17 beta (E2), progesterone (Pg), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) were measured by radioimmunoassay, and these values were used to determine the dates of OV (peak LH and FSH) and LU (peak postovulatory Pg). After heat acclimation, subjects received heat stress tests (HST) consisting of a 2-h cycle-ergometer exercise at 30% of maximal O2 consumption in the heat. Rectal (Tre) and mean skin (Tsk) temperatures, heart rate (HR), and sweat rate on the chest and thigh were recorded continuously. Total sweat loss (Msw), as indicated by weight loss, was recorded every 20 min, and equivalent water replacement was given. Steady-state exercise metabolic rate (M) was measured at 45 and 110 min. Seven of eight subjects had ovulatory cycles during experimental months. At rest, Tre was lowest at OV and significantly higher at LU. During steady-state exercise both Tre and Tsk were lowest at OV and significantly higher at LU. There were no differences between phases in Msw, sweat rate on the chest and thigh or M. Despite higher Tre and Tsk at LU, all subjects were able to complete the 2-h of exercise.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Readdressing personal cooling with ice.
An ice-based system of personal, non-restrictive cooling of workers exposed to high temperature work environments in nuclear power plants was evaluated. The garments were designed to be worn under the protective clothing donned for penetration into radiation areas. The cooling system consisted of direct body contact with small packets of frozen water enclosed in the pockets of a shirt in high ambient temperatures (55 degrees C) and moderate metabolic heat production (200-300 kcal/hr). Mean exposure time without cooling (control) was 52 min for workloads demanding 200 kcal/hr energy expenditure. A long garment with 7.2 kg of frozen water (LFWG) increased mean exposure time over the control by 242% (163% for the same garment with 6.2 kg of frozen water). A short version garment with 3.8 kg of frozen water (SFWG) increased the stay time by 115%. In field observations, the LFWG with 6.2 kg of frozen water improved stay time by 125%. The leveling off of the body temperatures and heart rates during the work both in the laboratory and in the field confirmed a reduction of heat strain associated with the use of these garments. Calculated heat balance equations of heat uptake by the ice predicted these results very closely. It was concluded that direct body contact with frozen water provided predictable adequate body cooling for the work and ambient conditions investigated in this study.
Adult↗
Automated pharmacy department in an academic medical center.
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Academic Medical Centers↗
The dynamics of a geriatric day hospital.
This report describes a prospective study of a geriatric day hospital. All 334 patients who attended during a six-month period were included with follow-up for a minimum of six months for each patient. One third were patients who had been discharged from the acute geriatric ward and most of the remainder were direct referrals from general practitioners. Transport was provided in 92% of cases by the Ambulance Service using a single-person crew in two-thirds and a driver plus attendant in the remainder. Only 8% came by private transport (family car). Patients were classified as 'once-only' attenders (22%), other new patients (37%), re-referrals (11%), current attenders (19%) and 11.1% were patients for whom a positive decision had been made to continue their day hospital attendance until death or admission to an institution (so-called 'chronic attenders'). This day hospital is an integral part of a comprehensive geriatric service which relies upon early referral and immediate response to avoid waiting lists both for in-patient and day hospital care. The services used by day patients are given with the proportion of patients receiving each service. The ecology of the day hospital was demonstrated to be more or less in balance. It is especially notable that the largest proportion of patients were discharged (from 41% to 63% of different patient categories) and there was no accumulation of chronic attenders. Of the 260 patients (excluding only the 74 once-only patients), only 25 were in geriatric accommodation and 12 in residential homes after a minimum of six months' follow-up. Forty-four patients had died.(ABSTRACT TRUNCATED AT 250 WORDS)
Aged↗
Simultaneous antegrade and retrograde reperfusion after cardioplegic arrest for coronary artery bypass.
Retrograde coronary sinus reperfusion with warm blood during proximal anastomoses permits completion of myocardial revascularization under a single cross-clamp application. Reperfusion with both antegrade (via arterial and vein grafts) and retrograde (via coronary sinus catheter) warm blood has raised concerns about maldistribution of perfusate or overpressurization of capillary beds. This prospective, randomized design compares postcardioplegic myocardial recovery among patients receiving retrograde reperfusion only and patients receiving simultaneous antegrade/retrograde reperfusion. Twenty-four patients were selected among all presenting as outpatients for elective coronary artery bypass (CAB). Each patient underwent CAB with cardioplegic arrest and single cross-clamp technique. During proximal anastomoses the heart was reperfused with warm blood from the cardiopulmonary bypass (CPB) circuit. Twelve received retrograde reperfusion only, and 12 received simultaneous antegrade/retrograde reperfusion via an internal mammary artery (IMA) graft, all vein grafts, and the coronary sinus catheter. Vein graft perfusion was interrupted in each vein as the proximal anastomosis was performed. Myocardial recovery time (interval from initiating reperfusion until electrical and mechanical activity), cardioversion incidence, requirement for inotropic support, and Swan-Ganz hemodynamic parameters measured immediately 6 and 24 hours postoperatively were compared between groups. There were no differences between groups in age, ventricular function, number of grafts, or CPB time. Also, there were no differences in cardioversion, inotropic need, or postoperative hemodynamic performance. Myocardial recovery time was reduced in patients receiving simultaneous antegrade/retrograde reperfusion (13.9+/-7.0 vs 2.6+/-2.1 minutes). Simultaneous reperfusion of warm blood antegrade and retrograde is not deleterious to the myocardium. More rapid recovery of myocardial function may represent a shorter period of warm ischemia but does not appear to translate to improved postoperative myocardial performance.
Aged↗