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Biomedical subjects

A Middleton

Publications and source records attributed to A Middleton.

At least 37 records · Page 2Linked to original sources
PubMed1992

Cyclic AMP stimulates the synthesis and function of the low-density lipoprotein receptor in human vascular smooth-muscle cells and fibroblasts.

1. Cyclic AMP-elevating agents stimulate low-density lipoprotein (LDL) receptor activity in human vascular smooth-muscle cells by increasing the rate of receptor protein synthesis. The stimulation is not secondary to the decrease in the regulatory pool of free cholesterol, since it is unaffected, or even enhanced, by inhibition of cholesterol synthesis and esterification, or inhibition of the conversion of cholesterol into its repressor metabolites. The cyclic AMP-mediated up-regulation of the receptor is maintained at low concentrations of inhibitory sterols, but is eventually over-ridden at high concentrations of these sterols. 2. Cyclic AMP-elevating agents also stimulate the hydrolysis of lysosomal cholesterol esters, thus increasing the cellular cholesterol pool and repressing the expression of the LDL receptor. This cholesterol-mediated repressive effect of cyclic AMP can be prevented by chloroquine, which inhibits lysosomal actions, or by ketoconazole, which inhibits conversion of free cholesterol into its repressor metabolite. Thus the cyclic AMP stimulation of the LDL receptor can be masked by the rapid mobilization of free cholesterol from existing cholesterol esters within cultured cells. 3. We have observed that elevated cyclic AMP concentrations will up-regulate the LDL receptor in cholesterol-depleted human vascular smooth-muscle cells, skin fibroblasts and foetal-lung fibroblasts. We propose that our results are evidence for a cyclic AMP-stimulated, sterol-independent, control of LDL-receptor synthesis which is of widespread occurrence in human cells.

Cells, Cultured↗
PubMed1990

Agents which increase cyclic AMP have diverse effects on low-density-lipoprotein-receptor function in human vascular smooth-muscle cells and skin fibroblasts.

Receptor-mediated binding and metabolism of low-density lipoproteins (LDL) in cultured human vascular smooth-muscle cells and skin fibroblasts are altered by increased cellular cyclic AMP concentrations. However, the LDL receptor does not respond to changes in cyclic AMP concentration in a simple manner. The activation of adenylate cyclase with forskolin, or the addition of membrane-permeant cyclic AMP analogues, initially decreases the expression of the LDL receptor, but is followed by a substantial increase in receptor expression after 24 h. This increase does not occur in the presence of inhibitors of RNA or protein synthesis, and is due to doubling of the Bmax. of the LDL receptor, without alteration of its affinity for LDL. By contrast, elevation of cyclic AMP concentration by inhibition of phosphodiesterases results in decreased receptor expression throughout the 24 h period. These two response patterns are reproducible phenomena, consistently observed in low-passaged cells derived from seven unrelated individuals.

1-Methyl-3-isobutylxanthine↗
PubMed1988

Forensic dental training in Australia.

To facilitate in the identification of victims of a major disaster a trained dental manpower reserve is required. In the state of New South Wales, Australia, an annual three-day training course has been designed to familiarize dentists from both the public and private sectors with identification techniques. The course is aimed to preserve the flexibility of personnel so that they can be utilized in a variety of roles rather than rigidly structuring the make up of a team. It is envisaged though, that in a mass disaster situation teams would be specialized into dental autopsy, antemortem or comparison roles.

Disaster Planning↗
PubMed1985

Altered erythrocyte cation transport related to hypertension or oral contraception.

Intracellular cation concentrations (Nai, Ki), and the influx of Rb86 and of Na22 were measured in the erythrocytes of 22 normal women with no family history of hypertension, 16 women with untreated essential hypertension, and 14 normotensive women treated with hormonal contraceptives. Values for total Rb influx, and for its components denoting sodium pump activity (ouabain-sensitive) and Na, K co-transport (ouabain-resistant, frusemide-sensitive), were significantly greater in the hypertensive and contraceptive-treated groups than in the normal group. Na, K cotransport measured by Na influx (frusemide-sensitive) was found to be significantly increased in the contraceptive-treated but not the hypertensive group. Passive sodium diffusion (frusemide-resistant Na influx) and Ki did not differ significantly between groups. Nai was lower in the hypertensive group than in the other two groups. These findings support the hypothesis that hypertension or hormonal contraception are associated with increased leakage of K ions from erythrocytes, without a corresponding increase in passive Na influx: the change in cell membrane permeability is compensated for by increases in Na, K co-transport and sodium pump activity, adjusted to allow for altered differential permeability to K and Na ions.

Adult↗
PubMed1983

In vivo inhibition of hepatic lipogenesis in the rat by cyclandelate (3,3',5-trimethylcyclohexanylmandelate).

Rates of hepatic lipogenesis were measured in vivo in rats by incorporation into lipids of [3H] from injected [3H]H2O 17 hr after a single oral dose of cyclandelate (3,3',5-trimethylcyclohexanylmandelate, a vasoactive substance). Cyclandelate administration resulted in a significant inhibition (40-60%) of both sterol and fatty acid synthesis in the livers which was independent of the 3.2-fold diurnal variation in the rates of hepatic sterol and fatty acid synthesis. The inhibition of accumulation of newly synthesized fatty acid in intestine also reached statistical significance. The accumulation of newly synthesized sterol was significantly depressed in serum but did not result in any change in the concentration of serum total cholesterol. These results are interpreted in terms of the inhibitory effect of cyclandelate on hepatic 3-hydroxy-3-methylglutaryl-CoA reductase previously reported by us (Biochem. Pharmac. 32, 649, 1983).

Animals↗
PubMed1983

The inhibition of hepatic S-3-hydroxy-3-methylglutaryl-CoA reductase by 3,3,5-trimethylcyclohexanol and its mandelic acid ester, cyclandelate.

Rat hepatic HMGCoA reductase was found to be at least 50% inhibited 17 hr after administration of a single oral dose of 3,3,5-trimethylcyclohexanyl mandelate (cyclandelate), a vasoactive substance. This inhibition was also found in rats given the 3,3,5-trimethylcyclohexanol component but only slight inhibition was seen after an equimolar dose of mandelate. The inhibition of HMGCoA was observed both around the high point and near the low point of the diurnal activity cycle. The effect did not persist to 41 hr after treatment. There was no direct inhibition of HMGCoA reductase by trimethylcyclohexanol when added to the assay system in vitro. The in vivo effect of these inhibitors was specific for HMGCoA reductase. There was no change, neither elevation nor depression, of the amount of microsomal membrane components cytochromes b5 and P-450, not was the activity of another microsomal enzyme, arylesterase, affected by dosing with cyclandelate or trimethylcyclohexanol.

Administration, Oral↗
PubMed1983

Persistent pharyngeal pouch derivatives in the neonate.

Internal branchial sinuses are rare compared to other branchial anomalies. A case is described in which such a sinus presented as an air-containing inflammatory lateral neck mass in a neonate and evidence is presented to support the theory that this originated from the fourth pharyngeal pouch. Review of six similar cases from the literature shows this to be a well-defined clinical entity.

Branchial Region↗
PubMed1983

Philadelphia chromosome and terminal transferase-positive acute leukemia: similarity of terminal phase of chronic myelogenous leukemia and de novo acute presentation.

Twenty-eight patients with Philadelphia chromosome (Ph1)--positive and terminal transferase (TdT)--positive acute leukemia (AL) were treated with intensive chemotherapy used for adult acute lymphoblastic leukemia (L-10 and L-10M protocols). Fifteen patients had a documented chronic phase of Ph1-positive chronic myelogenous leukemia preceding the acute transformation (TdT + BLCML) while the remaining 13 patients did not (TdT + Ph1 + AL). An overall complete remission (CR) rate of 71% was obtained with a median survival of 13 months in the responders. Clinical presentation, laboratory data, cytogenetics, response to treatment, and survivals of the two groups of patients are compared. These results appear to be similar, suggesting a common or closely related origin. Since the overall survival of those receiving chemotherapy maintenance is poor, three patients underwent allogeneic bone marrow transplantation (BMT) from histocompatibility leukocyte antigen--matched siblings after they achieved CR. One of them is a long-term survivor (35 + months) with a Ph1-negative bone marrow. New techniques such as BMT should be considered in young patients with a histocompatibility leukocyte antigen--compatible sibling once a CR has been achieved.

Acute Disease↗
PubMed1980

Elevation of serum high density lipoprotein cholesterol by rowachol, a proprietary mixture of six pure monoterpenes.

Rowachol, a proprietary choleretic containing 6 pure monoterpenes markedly elevates serum HDL cholesterol (SHDL-C) concentrations in man. The concentration of SHDL-C showed a progressive increase in 16 patients treated with 6-9 capsules of Rowachol daily for periods of 2-28 weeks. There was no accompanying significant change in the concentrations of serum total cholesterol or triglyceride. In view of the significant inverse relationship between SHDL-C concentration and the risk of developing ischaemic heart disease, it is suggested that Rowachol and possibly other terpenes merit further investigation as possible therapeutic agents in the prevention and treatment of atheroma.

Adolescent↗