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Biomedical subjects

M C White

Publications and source records attributed to M C White.

At least 19 recordsLinked to original sources

Infections and infection risks in home care settings.

OBJECTIVES: To describe the characteristics of home healthcare clients with respect to infection risks and the presence of infections. DESIGN: Descriptive survey of client charts using a point prevalence design. SETTING: A private San Francisco, California, Bay area home care agency. PARTICIPANTS: A random sample of 175 clients (28%) was taken from the active client list for a single day; demographic data and clinical data from the last visit prior to the selection day were collected from each chart. RESULTS: The clients were predominantly elderly (mean = 68.6) with an average of 3.6 co-morbid conditions; 12% had an invasive device. Over 20% had an infection on the day surveyed. Five percent had an infection that occurred during home care delivery. CONCLUSIONS: A substantial proportion of home health clients have infections, and they represent persons with a number of the risks associated with infections. Guidelines for defining and monitoring infections in home care need to be developed. Hospital-based surveillance methods are not altogether appropriate in this setting; redesigning methods such as targeted surveillance, monitoring rehospitalization, or immunization practices are discussed as potential ways to measure quality of care in the home setting.

Aged

Alterations in the microbial flora and in the incidence of bacteremia at a university hospital after adoption of amikacin as the sole formulary aminoglycoside.

Because of the rapid emergence of resistance to gentamicin and tobramycin among isolates of aerobic and facultative gram-negative bacteria at our university hospital, we designed a prospective study to track aminoglycoside resistance, bacteremic episodes, and bacteremia-associated deaths before and after the institution of amikacin as the sole formulary aminoglycoside. From June 1984 through June 1987 (immediately before this policy change), amikacin accounted for only 20% of patient-days of aminoglycoside therapy, and rates of resistance to gentamicin, tobramycin, and amikacin among aerobic and facultative gram-negative bacterial isolates were 12.8%, 10.8%, and 5.9%, respectively. During the next 30 months (immediately after the change in policy), amikacin accounted for 98% of patient-days of aminoglycoside therapy, and rates of resistance to gentamicin, tobramycin, and amikacin were 6.3%, 5.0%, and 3.3%, respectively. Furthermore, during the latter 30 months, the incidence of both bacteremia and bacteremia-associated death decreased significantly. Hospitals at which resistance to gentamicin or tobramycin is increasing among the gram-negative flora may benefit from the use of amikacin as the principal aminoglycoside.

Amikacin

Investigation of adrenal function in women with oligomenorrhoea and hirsutism (clinical PCOS) from the north-east of England using an adrenal stimulation test.

OBJECTIVE: To determine the prevalence of adrenal enzyme dysfunction in women presenting with oligomenorrhoea and hirsutism, two clinical features of polycystic ovary syndrome (PCOS). DESIGN: A prospective study of women attending outpatient clinics with these complaints. Androstenedione, dehydroepiandrosterone (DHEA), 17-hydroxyprogesterone (17-OHP), 11-deoxycortisol and cortisol were measured before and after overnight dexamethasone suppression and at 60 minutes after adrenal stimulation by ACTH injection. SUBJECTS: Fifty women with clinical features of PCOS and 37 control women with regular cycles and normal hair distribution from the catchment area of the Royal Victoria Infirmary which includes Newcastle upon Tyne, Co. Durham, Cleveland, Cumbria and Northumberland. MEASUREMENTS: Number of women with steroid responses to ACTH beyond the normal range, as defined by the responses of the control group and in previous studies. RESULTS: Nineteen women (38%) were found to have some abnormality. One woman (2%) was identified with 21-hydroxylase (21-OHase) deficiency and a second (2%) had an increase in 17-OHP compatible with the heterozygote state for 21-OHase deficiency. Four women (8%) had isolated elevations in the DHEA response consistent with minimal 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD) deficiency. Thirteen women (26%) showed increases in both androstenedione and DHEA, or androstenedione alone, compatible with enhanced 17-20 lyase activity. CONCLUSIONS: Twelve per cent of the group showed evidence consistent with an adrenal enzyme deficiency; 26% had results in keeping with increased adrenal androgen production without an enzyme deficiency. These findings may be of relevance both in the pathogenesis of the features of PCOS and in determining appropriate treatment for individual patients.

3-Hydroxysteroid Dehydrogenases

Gonadotrophin secretion in vitro by cells of a pituitary tumour from a patient with multiple endocrine neoplasia type I.

OBJECTIVE: The aim was to investigate the hormone secretory products of a pituitary tumour from a patient with multiple endocrine neoplasia type I (MEN I) utilizing cell culture and immunoassay techniques. DESIGN: Adenoma tissue was enzymically dispersed and established in cell culture. Medium was collected for hormone measurement after 2 days, and also after 24-hour periods during long-term culture. In addition, tissue fixed at surgery was analysed by immunocytochemistry and electron microscopy. PATIENT: The subject was a 59-year-old male with a clinical history characteristic of familial MEN I syndrome. MEASUREMENTS: Pituitary hormones in serum and culture medium were measured by fully characterized radioimmunoassays. RESULTS: Preoperative serum LH and FSH levels were normal, or slightly elevated, and there was a progressively blunted gonadotrophin response to GnRH throughout the 8 years prior to adenomectomy. TRH induced a small, paradoxical increase in serum gonadotrophin levels 2 weeks preoperatively. Post-operative pituitary hormone responses to standard stimulation tests showed an active normal pituitary. In vitro, the pituitary tumour cells secreted only gonadotrophins and glycoprotein hormone alpha-subunit. The fixed tumour tissue immunostained for alpha-subunit alone, and electron microscopy confirmed the presence of secretory granules with diameters of 100-280 nm. Gonadotrophin secretion continued throughout 77 days in long-term culture, but whilst LH was released at a steady rate, that of FSH transiently increased between days 29 and 48 in vitro. CONCLUSIONS: These data demonstrate that a pituitary tumour associated with the MEN I syndrome secreted gonadotrophins in vitro.

Adenoma, Chromophobe

A comparison of octreotide delivered by continuous subcutaneous infusion with intermittent injection in the treatment of acromegaly.

This study was undertaken to evaluate GH, IGF1 and drug levels during incremental continuous subcutaneous infusion of octreotide and compare these parameters following long-term treatment of 300 micrograms 24 h-1 by intermittent injection in a group of acromegalic patients. Ten patients were treated by continuous subcutaneous infusion in increasing dose from 200 micrograms 24 h-1 to 1600 micrograms 24 h-1; this resulted in consistent 24-h growth hormone suppression (less than 5.0 mU l-1), and normalisation of IGF1; the optimum dose was 400 micrograms 24 h-1, the maximum dose was tolerated without any untoward effects. There was no deterioration in carbohydrate tolerance despite a marked decrease in fasting and stimulated insulin levels. After 1 year of maintenance treatment, 300 micrograms 24 h-1 by intermittent injection, patients were re-evaluated; GH levels were not so consistently suppressed over the 24-h period and carbohydrate tolerance had deteriorated. A sub-group of patients with sub-optimal GH suppression on this regimen were identified and reassessed after 6 weeks treatment with an increased dose, 600 micrograms 24 h-1 by intermittent injection; both mean GH suppression and carbohydrate tolerance improved. The dose of drug and method of administration is best adjusted for each patient to achieve optimum GH suppression, thereby minimise compensatory hyperinsuliaemia and hopefully reduce morbidity and mortality. Alterations in pituitary tumour size and acquisition of gallstones during treatment have been observed which substantiate the need to re-evaluate these parameters on routine follow-up of acromegalic patients on long-term octreotide.

Acromegaly

Autocrine control of human meningioma proliferation: secretion of platelet-derived growth-factor-like molecules.

We have used cell-culture techniques to investigate growth-factor production by human meningioma cells. Meningioma tissue was dispersed with collagenase and the cells grown to high density in tissue-culture flasks. The cultures were used to generate conditioned medium (MEN-CM), which was used to cultivate IMR32 cells (a human neuroblastoma line) and freshly dispersed primary meningioma cells. MEN-CM profoundly stimulated the in vitro growth of both IMR32 and meningioma cells. In addition, H3-thymidine uptake by cultured meningioma cells was increased in a dose-dependent manner by varying concentrations of MEN-CM. A neutralizing anti-body against platelet-derived growth factor (PDGF) completely abolished the stimulatory effects of MEN-CM, whereas an antibody against TGF-alpha was without effect. The mitogenic activity of MEN-CM, as assayed by promotion of H3-thymidine uptake by cultured meningioma cells, eluted from a Sephadex G-100 column in 3 peaks corresponding to molecular weights of greater than or equal to 150, 56 and 28 kDa. Our results show that proliferation of human meningiomas may be under autocrine control via secretion of PDGF-like molecules.

Cell Division

Human insulin and awareness of acute hypoglycaemic symptoms in insulin-dependent diabetes.

Some insulin-dependent diabetic patients who have clear symptoms of hypoglycaemia during animal insulin treatment have reported loss of these symptoms when human insulin preparations are introduced. A survey of Mersey Region, UK, identified eleven patients whose awareness of hypoglycaemia was lost after introduction of human insulin but returned with animal insulin treatment; seven took part in the study. Acute hypoglycaemia was induced in these patients on two occasions by intravenous infusion of porcine or human soluble insulin (2.5 mU.kg-1, min-1) in random order. There was no significant difference between porcine and soluble insulin in the plasma glucose profile; mean (SEM) plasma glucose fell from 7.1 (0.4) mmol/l to a nadir of 1.5 (0.1) mmol/l with porcine insulin and from 7.1 (0.5) mmol/l to 1.6 (0.2) mmol/l with human insulin. An acute autonomic reaction occurred in all seven patients, at a similar plasma glucose concentration (1.9 [0.1] mmol/l with porcine insulin; 2.0 [0.2] mmol/l with human insulin). There were no significant differences in the frequency of symptoms or signs of hypoglycaemia between the two insulin species, nor any consistent differences in plasma glucagon, cortisol, growth hormone, adrenaline, or noradrenaline responses to hypoglycaemia. Symptomatic and hormonal responses to acute hypoglycaemia induced by porcine and human soluble insulins therefore seem to be almost indistinguishable, even in patients carefully selected for their apparent loss of hypoglycaemia awareness with human insulin.

Acute Disease

Interleukin 6 is secreted by breast fibroblasts and stimulates 17 beta-oestradiol oxidoreductase activity of MCF-7 cells: possible paracrine regulation of breast 17 beta-oestradiol levels.

Previous studies have demonstrated that cultured human breast fibroblasts secrete a high-molecular-weight polypeptide which stimulates the ability of human breast-cancer MCF-7 cells to convert oestrone (E1) to the biologically more active 17 beta-oestradiol (E2). This effect is mediated by an increase in reductive E2 oxidoreductase (EOR) activity. We have identified the fibroblast-derived stimulatory factor as interleukin 6 (IL6) or an immunologically related peptide. Human breast fibroblasts in culture secreted up to 10 ng IL6/ml medium during 24 hr of incubation. The effects of IL6 and breast fibroblast conditioned medium (CM) on reductive EOR activity of MCF-7 cells were similar; both CM and IL6 potently stimulated enzyme activity in a dose-dependent manner, and both exerted synergistic stimulatory effects in combination with E2. A polyclonal neutralizing antibody to IL6 completely abolished the reductive EOR-stimulating activity of CM. These results indicate that breast stromal fibroblasts may have a paracrine role in regulation of breast-cancer-tissue levels of E2, and that this effect is mediated by IL6 or a closely related peptide.

Breast

LH and FSH secretion and responses to GnRH and TRH in patients with clinically functionless pituitary adenomas.

Serum concentrations of LH and FSH and their response to the separate administration of GnRH (100 micrograms i.v.) and TRH (200 micrograms i.v.) have been studied preoperatively in 12 patients with a clinically functionless pituitary adenoma, of whom nine (3F: 6M) were found to secrete gonadotrophins in vitro. In three patients with a gonadotrophin-secreting adenoma (GSA) the pulsatile release of LH and FSH was also assessed preoperatively. An elevated serum FSH was recorded in six of nine patients with a GSA, and was subnormal in one, whilst an elevated LH was recorded in only two and was subnormal in six. A doubling of LH occurred in only four of the nine patients after GnRH and in three of six after TRH. None of the three patients with a non-GSA was shown to have an aberrant response to GnRH or TRH. In patients with a GSA, pulsatile release of LH and FSH was usually asynchronous and neither hormone demonstrated any regular harmonic pattern. These data show that in patients with a GSA the serum FSH level is usually elevated but this is not invariable, and the LH may well be low. Pathological responses of LH are frequently found following the administration of either GnRH or TRH and these stimulation tests should be performed separately in patients presenting with a clinically 'non-functioning' pituitary tumour to assist in the preoperative diagnosis. The absence of normal LH and FSH pulsing also appears to be a feature of GS adenomas, and suggests that tumorous gonadotrophin secretion is not under physiological control by hypothalamic GnRH.

Adenoma

Rapid pulses of luteinizing hormone during the ovarian cycle.

Luteinizing hormone has been shown to be secreted in a complex pattern of low-amplitude, high-frequency pulses superimposed on high-amplitude, low-frequency pulses. To test the hypothesis that the rapid, small pulses vary during the ovarian cycle, 16 normal women were studied on two occasions each, in the early and late follicular phases of one cycle or the luteal and following early follicular phase. Blood samples were taken every 1 min for 1 h. Statistical methods of time series analysis were applied to the data. There were significant amplitude differences between subjects at all stages of the cycle. We found no evidence to support the hypothesis that the frequency of the small rapid pulses varied during folliculogenesis. The results for the luteal phase, while less uniform, showed no consistent change. It is suggested that the rapid pulses may be related to function of the hypothalamic-pituitary axis rather than direct ovarian control.

Adolescent

Analysis of regulation of the ilvGMEDA operon by using leader-attenuator-galK gene fusions.

Five of the genes for the biosynthesis of isoleucine and valine form the ilvGMEDA operon of Escherichia coli K-12. Expression of the operon responds to changes in the availability of isoleucine, leucine, and valine (ILV). Addition of an excess of all three amino acids results in reduced expression of the operon, whereas limitation for one of the three amino acids causes an increase in expression. The operon is preceded by a leader-attenuator which clearly regulates the increased expression that occurs due to reduced aminoacylation of tRNA. To assess the factors that result in the reduced expression of this operon upon the addition of ILV, a series of plasmids were constructed in which the ilv regulatory region was fused to galK. In response to addition of the amino acids, expression of the galK gene fused to the leader-attenuator decreased five- to sevenfold, instead of the twofold observed for the chromosomal operon. A deletion analysis with these plasmids indicated that the ILV-specific decrease in expression required an intact leader-attenuator but not ilvGp2 or the DNA that precedes this promoter. This conclusion was supported by both S1 nuclease analysis of transcription initiation and determination of galK mRNA levels by RNA-RNA hybridization.

Cloning, Molecular

Administration of high-dose octreotide (Sandostatin) by continuous subcutaneous infusion for the treatment of acromegaly.

Patients with active acromegaly were treated with octreotide (SMS 201-995, Sandostatin; Sandoz Pharmaceuticals) given in high dosage by continuous subcutaneous administration (CSI). Serum growth hormone (GH) and insulin-like growth factor 1 (IGF-1) concentrations were rapidly and consistently reduced to the normal range and maintained for up to 14 weeks of study. Maximal inhibition of GH and IGF-1 secretion was obtained at a dose of 600 micrograms/24 h; all except 1 of the 7 patients were able to tolerate a higher dose of 1,600 micrograms/24 h. A single patient failed to show GH suppression at any dosage of octreotide. Computed tomographic evidence of tumour shrinkage was not demonstrated in these 7 patients, although in 2 patients subsequently studied by us definite tumour shrinkage was observed. These data show that the administration of octreotide by CSI is a highly satisfactory method for persistently lowering GH and IGF-1 concentrations in acromegalic patients sensitive to this drug.

Acromegaly

Continuous infusion of octreotide in acromegaly.

15 patients with acromegaly were treated with continuous subcutaneous infusion of octreotide in increasing dose from 200 to 1600 micrograms per 24 h by 200 micrograms increments each week. Patients were studied during the initial 7 h of infusion, weekly at each dose level, then after 1 and 2 months at maximum dosage. 13 patients responded well, as judged by growth hormone (GH) suppression and return of insulin-like growth factor 1 to normal, although 1 patient withdrew due to adverse effects; 2 patients showed no significant reduction in GH. In the 12 responders GH level fell within the first 3 h of infusion at a mean plasma octreotide level of 0.76 (SE 0.26) micrograms/l, corresponding to 25 micrograms of infused drug. Optimum suppression of GH occurred at a dosage of 600 micrograms per 24 h, a plasma drug level of 3.5 (0.5) micrograms/l. A definite reduction in tumour size was seen on computerised tomographic scan in 2 patients. All responders noted subjective improvement in acromegalic symptoms. Adverse effects comprised gastrointestinal disturbances, which were transient and mild in 14 patients but severe in 1; biliary sludging occurred in 1 patient. No significant deterioration in carbohydrate tolerance was seen in the responders.

Acromegaly

Octreotide.

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Acromegaly