A simple measure of insulin resistance.
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Blood Glucose↗
Biomedical subjects
G Carter
Publications and source records attributed to G Carter.
Raised serum 11-deoxycortisol in men with persistent acne vulgaris.
OBJECTIVE: Acne vulgaris is androgen dependent but the hormonal mechanisms are unclear. Although there have been many studies of serum hormones in women with acne there are few studies in men and the results are conflicting. We have therefore carried out a further study in men. DESIGN AND PATIENTS: Fifty men with acne vulgaris were age-matched against 50 normal men. MEASUREMENTS: Serum levels of dehydroepiandrosterone sulphate (DHEAS), 17 alpha-hydroxyprogesterone, 11-deoxycortisol, androstenedione and testosterone were measured by radioimmunoassay, sex hormone binding globulin (SHBG) by immunoradiometric assay and LH, FSH and oestradiol by automated ELISA. RESULTS: The acne patients had higher levels of androstenedione, median 7.35 nmol/l, (interquartile range 2-7) vs 6.05 (2.3), P = 0.004; testosterone, 21.7 nmol/l (7.5) vs 17.55 (7.7), P = 0.04; and free androgen index (FAI) 78.26 (40) vs 65.06 (20), P = 0.007, but also had higher levels of 11-deoxycortisol, 13.65 nmol/l (4.3) vs 12.0 (4.3), P = 0.022. The LH, FSH, 17 alpha-hydroxyprogesterone, DHEAS, oestradiol and SHBG levels were not significantly different. Examination of the Spearman rank correlation coefficient matrices for the serum levels of 17 alpha-hydroxyprogesterone, androstenedione and 11-deoxycortisol showed that the strongest correlation was between androstenedione and 11-deoxycortisol. CONCLUSION: Although there was overlap between the results of the acne patients and controls the acne patients tended to have higher levels of androstenedione, testosterone, free androgen index and 11-deoxycortisol. The higher levels of 11-deoxycortisol are suggestive of 11 beta-hydroyxlase dysfunction which could be due to a primary adrenal defect or a consequence of raised androgens. Also, a pathway between androstenedione and 11-deoxycortisol has been described in sheep and, although unsubstantiated in man, requires consideration.
17-alpha-Hydroxyprogesterone↗
In vivo pharmacological evaluation of two novel type II (inducible) nitric oxide synthase inhibitors.
Selective type II (inducible) nitric oxide synthase (NOS) inhibitors have several potential therapeutic applications, including treatment of sepsis, diabetes, and autoimmune diseases. The ability of two novel, selective inhibitors of type II NOS, S-ethylisothiourea (EIT) and 2-amino-5,6-dihydro-6-methyl-4H-1,3-thiazine (AMT), to inhibit type II NOS function in vivo was studied in lipopolysaccharide (LPS) treated rats. Type II NOS activity was assessed by measuring changes in plasma nitrite and nitrate concentrations ([NOx]). Both EIT and AMT elicited a dose-dependent and > 95% inhibition of the LPS-induced increase in plasma [NOx]. The ED50 values for EIT and AMT were 0.4 and 0.2 mg/kg, respectively. In addition, the administration of LPS and either NOS inhibitor resulted in a dose-dependent increase in animal mortality; neither compound was lethal when administered alone. Pretreatment with L-arginine (but not D-arginine) prevented the mortality, while not affecting the type II NOS-dependent NO production, suggesting the toxicity may be due to inhibition of one of the other NOS isoforms (endothelial or neuronal). Thus, although EIT and AMT are potent inhibitors of type II NOS function in vivo, type II NOS inhibitors of even greater selectivity may need to be developed for therapeutic applications.
Animals↗
Antidepressants and side effects.
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Antidepressive Agents↗
Lipopolysaccharide-induced changes in plasma nitrite and nitrate concentrations in rats and mice: pharmacological evaluation of nitric oxide synthase inhibitors.
The benefits of nitric oxide synthase (NOS) inhibitors in the treatment of endotoxemia or sepsis presumably arise from inhibition of the type II (inducible) NOS. However, inasmuch as the effect of these inhibitors on NOS function in vivo is rarely assessed, NOS activity was evaluated in rats and mice by measuring changes in plasma nitrite and nitrate concentrations ([NOx]) after administration of lipopolysaccharide (LPS). In both species, [NOx] peaked at 20 hr, returning to base line by 48 to 72 hr. The ED50 values (dose that elicited a 50% inhibition of the LPS-dependent increase in [NOx] 6 hr after LPS administration) for L-NG-monomethylarginine acetate, L-NG-nitroarginine methyl ester and aminoguanidine (administered 3 hr after LPS) were 34, 21 and 19 mg/kg in the rat and 32, 5 and 4 mg/kg in the mouse. These compounds also decreased the survival of LPS-challenged animals, which in the case of L-NG-nitroarginine methyl ester was reversed by L-arginine. Dexamethasone (which prevents the induction of type II NOS) also inhibited the LPS-dependent increase in [NOx] with ED50 values of 0.05 mg/kg (rat) and 1 mg/kg (mouse), but did not lead to decreased survival. Thus, inhibition of the type I (neuronal) or type III (endothelial) NOS, rather than the type II isoform, may be a possible mechanism for the animal mortality. These models provide a simple and reproducible means for assessing the in vivo inhibition of type II NOS by various compounds.
Amino Acid Oxidoreductases↗
The nitric oxide synthase inhibitor, L-NG-monomethylarginine, reduces carrageenan-induced pleurisy in the rat.
Nitric oxide (NO) is a biological mediator that, when produced by the type II (inducible) nitric oxide synthase (NOS), has been implicated in the pathophysiology of inflammatory diseases. To examine this putative role of NO, pleural inflammation was elicited in rats by the intrapleural injection of carrageenan (1 mg). A pleural exudate and cellular influx developed, which peaked at 24 h and generally resolved by 72 h. The cellular influx was primarily composed of polymorphonuclear cells during the first 24 h, followed by macrophages during the subsequent 24 h. Inflammatory cell-associated NOS activity and pleural exudate nitrite (NO2-) + nitrate (NO3-) (NOx) also increased, peaking at 6 h and 24 h, respectively. Cell-associated NOS activity was calcium-independent, indicating the presence of the type II NOS isoform; NOS activity in the pleural cavity and polymorphonuclear cells influx were temporally correlated. Administration of L-NG-monomethylarginine (L-NMA) (200 mg/kg/day) attenuated the pleural exudation, cellular influx, pleural exudate NOx, and cell-associated NOS activity. The relative composition of the pleural cavity cellular infiltrate was not changed by L-NMA, indicating the influx of individual cell types were affected equally. L-Arginine (500 mg/kg/day) completely prevented the effects of L-NMA on pleural exudation and cellular influx and partially prevented the inhibition of pleural exudate NOx accumulation by L-NMA. These data implicate NO as a modulator of the pleural inflammatory response and support a future clinical role for NOS inhibitors in the treatment of inflammatory disease.
Amino Acid Oxidoreductases↗
Thrombolysis and coronary occlusion: effects upon the non-infarct zone.
Regional wall motion was examined by angiography after 3 weeks in 154 patients taking part in the Thrombolysis in Coronary Occlusion (TICO) Trial. Coronary patency rate was greater after administration of recombinant tissue plasminogen activator, (rt-PA 62/77pts 81%) than after a placebo (P 49/77pts 64% P = 0.02), particularly for the left anterior descending artery compared with the right coronary artery (LAD 27/28 96% vs RCA 28/40 70% P = 0.006). Left ventricular ejection fraction (LVEF) was preserved after rt-PA (rt-PA 59 +/- 14% vs P 53 +/- 15% P = 0.01), predominantly because of more effective non-infarct zone contraction (rt-PA 0.52 +/- 1.16 SD/cord vs P 1.01 +/- 1.07 SD/cord P = 0.008). Infarct zone scores differed little (rt-PA 2.88 +/- 0.95 SD/cord vs P 3.16 +/- 1.11 SD/cord P = 0.09). Left ventricular ejection fraction and non-infarct zone function were best preserved after rt-PA compared with the placebo, particularly in patients with single vessel disease and in patients in whom the infarct-related artery was the left anterior descending vessel.
Adult↗
Genetic lesions in preleukemia.
Preleukemia is thought to be a clonal disorder of hemopoietic stem cells. The conversion of a normal cell into a preleukemic and ultimately leukemic state is a multistep process requiring the accumulation of a number of genetic lesions. The myelodysplastic syndromes have become a paradigm for human preleukemia, where nonrandom chromosomal abnormalities, including complete or partial deletions of chromosomes five and seven, trisomy eight and Y chromosome loss suggest specific changes. Of particular significance are 5q deletions, as many genes important in hemopoiesis are located in this region, including the proto-oncogene FMS, which encodes the receptor for the macrophage colony-stimulating factor, CSF-1. Genetic damage such as point mutations in the RAS and FMS genes has been detected in preleukemia patients. The RAS gene family (N, K and H) encodes membrane-bound G proteins, which, like other proto-oncogenes, are components of the intracellular signal transduction pathways controlling mitogenesis and differentiation. The characterization of such lesions may ultimately identify those patients at greatest risk of leukemic transformation.
Chromosome Aberrations↗
Clavicular fractures in neonates.
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Birth Injuries↗
The relationship between serum cholesterol and serum thyrotropin in women with peripheral arterial disease.
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Aged↗
Pharmacokinetics, safety, and ability to diminish leukotriene synthesis by zileuton, an inhibitor of 5-lipoxygenase.
Zileuton is a potent and specific inhibitor of 5-lipoxygenase, the first dedicated enzyme in the metabolism of arachidonic acid to the leukotrienes. The leukotrienes have been implicated in numerous pathological conditions. Zileuton was given to normal human volunteers in single doses of 200 mg to 800 mg. Results of these studies indicated that zileuton was well absorbed orally with an elimination half-life of approximately 2.5 hours. Leukotriene B4 production by ex vivo calcium ionophone stimulated whole blood was inhibited by up to 80% of baseline and correlated with plasma concentrations. Zileuton did not significantly inhibit cyclooxygenase as demonstrated by thromboxane B2 levels. There were no safety concerns that would preclude development.
Adolescent↗
Postural vasoconstriction in women during the normal menstrual cycle.
1. Postural vasoconstriction in the foot was examined in 15 women during the menstrual, follicular and luteal phases of the menstrual cycle, and in 13 age-matched men on two separate occasions, in a constant-temperature environment (22 degrees C). 2. Skin blood flow was measured using laser Doppler flowmetry with the subject lying down, first with the foot maintained at heart level, then with the foot lowered passively 50 cm below the heart. In six of the women, at the time of experiment, serum oestradiol and progesterone were determined by radioimmunoassay. In four women and three men, foot swelling rate was also measured in the dependent foot using a strain gauge plethysmograph in addition to the postural changes in flow. At each visit, in all subjects, arterial blood pressure, heart rate, body temperature, foot skin temperature and body weight were also recorded. 3. The men showed no significant changes in all the variables assessed. In contrast, in women during the luteal phase diastolic and mean arterial pressures were significantly reduced, whereas heart rate, body temperature, foot skin temperature and body weight were significantly increased, as compared with the follicular and menstrual phases of the cycle. 4. During the follicular phase, when oestradiol concentration was high, there were significant reductions in dependent flow and foot swelling rate associated with a significantly augmented postural fall in flow, whereas during the luteal phase, when both oestradiol and progesterone levels were high, there were significant increases in dependent flow and foot swelling rate associated with a significantly impaired postural fall in flow.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Sulphinpyrazone reduces endocardial injury and mural thrombosis.
STUDY OBJECTIVE: The aim of the study was to investigate the effectiveness of sulphinpyrazone, a drug which stabilises endothelial cell membranes, in reducing endocardial injury and mural thrombosis produced by lactic acid in the left ventricle. DESIGN: The left ventricular endocardium of isolated beating rat hearts, perfused via the aorta with oxygenated Krebs-Henseleit buffer, was exposed for up to 4 h to additional lactic acid (pH 6.4), with and without sulphinpyrazone (100 ng x ml-1). After flushing with buffer, passage of 10 ml blood, and further flushing, the hearts were fixed by coronary perfusion and the endocardium examined by scanning electron microscopy. EXPERIMENTAL MATERIAL: Hearts from 48 male albino Wistar rats, weight 270-380 g, were used. MAIN RESULTS: Morphometric analysis of the surface of the papillary muscles showed that lactic acid caused membrane injury in endothelial cells, up to 30% of which exfoliated. However when sulphinpyrazone was present, endothelial cell damage was reduced and there was up to 75% reduction in the area of exposed basal lamina or connective tissue. This was associated with a corresponding reduction in the extent of platelet adhesion (79%) and thrombus formation (94%). CONCLUSIONS: The results show that sulphinpyrazone has the potential to reduce the risk of mural thrombosis following endocardial injury.
Animals↗
Is the mdr 1 gene relevant in chronic lymphocytic leukemia?
Chronic lymphocytic leukemia (CLL) is a progressive disease in which chemotherapy may result in temporary suppression of the peripheral blood lymphocyte count, but cure is not usually possible. Drug resistance mechanisms and the multidrug resistant (MDR) phenotype may be relevant to the therapeutic response. We have studied 34 patients with CLL (seven untreated, 27 treated), screening both DNA and RNA with the mdr 1 gene probe. In pure lymphocyte populations from 10 normal subjects, low levels of mdr 1 RNA expression were found. Eighteen CLL patients (four untreated, 14 treated) had levels of mdr 1 RNA expression above the normal range. No evidence of mdr 1 gene amplification could be found in these patients. Sequential estimations of RNA levels in three patients suggest that malignant lymphocytes in CLL can increase mdr 1 expression in response to chemotherapy and return to basal levels on withdrawal of the treatment. Such data raise important questions about the type of timing of cytotoxic therapy in CLL.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
RAS mutations in patients following cytotoxic therapy for lymphoma.
The occurrence of Myelodysplastic Syndrome (MDS) and Acute Myeloblastic Leukaemia (AML) following cytotoxic therapy for neoplastic disease is well recognised. RAS mutations are common in patients with MDS and AML. To determine whether these lesions are found as early markers of secondary disease, we have studied the incidence of RAS mutations in the peripheral blood of 70 patients in complete remission from lymphoma. Patients were treated by standard chemotherapy regimes and/or localised radiotherapy. Treatment had been given 6 months to 14 1/2 years previously and no patient showed any sign of residual disease. Genomic DNA from peripheral blood leukocytes was amplified in vitro at target codons of N, K and H RAS genes, and mutations detected by hybridisation with oligonucleotide probes. RAS mutations were detected in 9 subjects. One patient with an N12 valine (Val) substitution had been in complete remission from Hodgkin's disease (HD) for 9 years. DNA from this patient registered in a nude mouse tumorigenicity assay (NMT). The N12 Val mutation was not detected in the original tumour tissue from the same patient. A second patient in remission from HD showed evidence of co-existent N12 cysteine (Cys) and N13 valine (Val) substitutions which were not detected in presentation material or unaffected tissues. All patients are currently haematologically normal, indicating that clones of mutant RAS bearing cells may be detected prior to any overt sign of disease.
Animals↗
Can thyroxine halt the progression of peripheral arterial disease?
Fifteen women with claudication and increased serum thyrotrophin (TSH) were treated with L-thyroxine (25-75 micrograms). These women were selected from a group of 80 consecutive women presenting with claudication, rest pain or gangrene. One year after their TSH was normal, their progress, serum lipids and lipoproteins were compared with the 58 women with normal levels of serum TSH; the remainder were already receiving thyroxine. Non-invasive assessment showed that three of the 15 (20%) women treated with thyroxine had progression of arterial disease, two in the legs and one in the legs and coronary arteries; two women showed improvement of ankle/brachial pressure indices. There was no accelerated angina, myocardial infarction, stroke or death in this group. Fifty-six of the 58 patients with normal levels of TSH were alive at follow-up and there was progression of distal disease in 24 (43%), coronary artery disease in 6 (11%), increasing carotid stenosis in four and two complained of transient ischaemic attacks. In this group, disease progression affected 32/56 (57%) of the women and this is significantly greater than in the thyroxine treated group chi 2 (P less than 0.05). Treatment with L-thyroxine caused a significant increase in HDL-cholesterol from 1.29 +/- 0.34 to 1.45 +/- 0.49 mmol/L (P less than 0.05) and a significant decrease in cholesterol from 8.0 +/- 1.3 to 7.2 +/- 1.1 mmol/L (P less than 0.01) and apolipoprotein B from 1.23 +/- 0.20 to 1.04 +/- 0.16 g/l (P less than 0.001). Significant changes in apolipoprotein B were observed after 3 months of treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
Aged↗
Endocardial injury and the pathogenesis of mural thrombosis in the left ventricle.
To define the interactions between blood and endocardium damaged by lactic acid, the left ventricles of 48 isolated continuously perfused and beating hearts were exposed for 0-4 hours to Krebs Henseleit buffer (KHB) with or without 33 mumol.ml-1 of lactic acid (pH 6.4). After excising its apex, the left ventricle was flushed with KHB, followed by 10 ml of lightly heparinised blood, and then by a further 10 ml of KHB. Lactic acid caused endothelial cell membrane rupture, intercellular separation, and exfoliation with exposure of the basal lamina and underlying connective tissue. Whereas multilayered platelet aggregations formed on exposed basal lamina, fibrin deposition and incorporation of blood cells were only observed in the larger thrombi which formed on exposed collagen. These findings indicate that a metabolite which accumulates in ischaemic myocardium can cause endocardial injury which would predispose to the mural thrombosis which can complicate myocardial infarction.
Animals↗