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Biomedical subjects

S J Hurel

Publications and source records attributed to S J Hurel.

11 recordsLinked to original sources
PubMed1997

Avascular necrosis secondary to postoperative steroid therapy.

Hypothalamic and pituitary tumours may present with vague symptoms owing to excess or lack of hormone production, including diabetes insipidus. Corticosteroids are commonly employed to limit cerebral oedema and at much lower doses to treat secondary hypocorticalism. Continuation of steroids at inappropriately high doses predisposes to the development of avascular necrosis as in the case we describe in a young woman of 34 years. This is a potentially preventable crippling disorder. When prescribing steroids the lowest effective dose should be used.

Adult↗
PubMed1997

Metastatic prolactinoma: effect of octreotide, cabergoline, carboplatin and etoposide; immunocytochemical analysis of proto-oncogene expression.

A 49-yr-old woman presented with an extensive prolactinoma (serum PRL > 10,000 mU/L, normal range < 450 mU/L). Over a 5-yr period following transsphenoidal surgery and pituitary irradiation, she became increasingly resistant to high doses of bromocriptine and underwent transfrontal surgery followed by stereotactic radiotherapy. In spite of these treatments, serum prolactin estimations rose progressively to > 100,000 mU/L. Magnetic resonance imaging scanning demonstrated a massive cystic tumor invading the temporal lobes, extending into the cervical and thoracic spine, with metastases to cervical lymph nodes. High-dose cabergoline administration resulted in a 30% decrease in serum PRL. Octreotide was administered as a continuous sc infusion with a profound analgesic effect on facial pain but with no effect on tumor progression. She was treated with a course of chemotherapy consisting of carboplatin and etoposide without any noticeable effect. The patient died 6 months following chemotherapy. Immunocytochemical analysis demonstrated positive nuclear staining for WAF-1, Rb protein, c-myc, and p53 both in the original and metastatic tumors. The metastases but not the primary tumor stained for c-jun. Metastatic prolactinoma remains a therapeutic challenge. It is associated with a variable proto-oncogene expression, which may be coincidental or causal. Cabergoline had no advantage over bromocriptine. Octreotide relieved facial pain but did not alter tumor progression. An effective therapy for metastatic prolactinoma remains to be identified.

Antineoplastic Agents, Hormonal↗
PubMed1996

Insulin action in cultured human myoblasts: contribution of different signalling pathways to regulation of glycogen synthesis.

A key metabolic action of insulin is the stimulation of non-oxidative glucose utilization in skeletal muscle, by increasing both glucose uptake and glycogen synthesis. The molecular mechanism underlying this process has been investigated using a variety of experimental systems. We report here the use of cultured human myoblasts to study insulin control of glycogen synthesis in humans. In these cells insulin stimulates glycogen synthesis approx. 2.2-fold, associated with a similar activation of glycogen synthase (GS) which occurs within 5-10 min of the addition of insulin. Insulin also causes inactivation of glycogen synthase kinase-3 (GSK-3) and activation of protein kinase B, both processes being sufficiently rapid to account for the effects of insulin on GS. Activation by insulin of the protein kinases p70s6K, p90s6K and extracellular signal-regulated kinase 2 (ERK2) is observed, but is significantly slower than the activation of GS. Selective inhibitors of the p70s6K pathway (rapamycin), the ERK2/p90s6K pathway (PD98059) and phosphatidylinositol 3-kinase (wortmannin) have been used to probe the contribution of these components to insulin signalling in human muscle. Wortmannin blocks activation of both glycogen synthesis and GS and inactivation of GSK-3. PD98059 is without effect on these events, while rapamycin is without effect on inactivation of GSK-3 but partially blocks activation of glycogen synthesis and GS. Taken together, these findings suggest that protein kinase B is responsible for the inactivation of GSK-3, but that an additional rapamycin-sensitive mechanism may contribute to the activation of GS and stimulation of glycogen synthesis.

Androstadienes↗
PubMed1996

The short Synacthen and insulin stress tests in the assessment of the hypothalamic-pituitary-adrenal axis.

OBJECTIVE: The best dynamic test for the assessment of the hypothalamic-pituitary-adrenal axis and the interpretation of the cortisol levels, remain a matter of controversy. We aimed to establish normal ranges with current assays, for both the short Synacthen (SST) and insulin stress tests (IST) and then to use these data to examine whether the SST can satisfactorily substitute for the IST in assessment of the hypothalamic-pituitary-adrenal axis. DESIGN: Thirty SSTs and 27 ISTs were performed on different healthy volunteers. The results of all paired tests performed on patients in the last three years are reviewed. SETTING: Programmed Investigation Unit. SUBJECTS: Fifty-seven healthy volunteers and 166 patients. MAIN OUTCOME MEASURES: Basal serum cortisol concentration and cortisol values obtained at 30 and 60 minutes during the SST compared to the maximum obtained with adequate hypoglycemia (plasma glucose < 2 mmol/l) during an IST. RESULTS: From normal data the mean-2SD 30-minute value during the SST was 392 nmol/l and 60-minute value was 497 nmol/l. The maximal cortisol response (mean - 2SD) during the IST was 519 nmol/l. Sixty patients failed the IST, none of whom had a basal cortisol > 450 nmol/l and only six (10%) had a 30-minute cortisol value > 600 nmol/l. The 30-minute value provided a better index than the 60-minute value. The basal, 30 and 60-minute values during the SST all correlated positively and significantly with the maximal cortisol on IST. The correlations persisted for all microadenomas and macroadenomas secreting prolactin, gonadotrophins or growth hormone, patients undergoing either pre or post-adenomectomy evaluation, and in those patients who had received long-term steroids provided that the medication had been reduced and stopped two days prior to admission. CONCLUSIONS: Using a 30-minute cortisol value > 600 nmol/l as a cut-off, the short Synacthen test provides a suitable substitute for the insulin stress test. Adopting this policy will decrease the number of insulin stress tests performed by one-quarter and thus provide a substantial saving without detriment to patient care.

Adrenal Cortex Function Tests↗
PubMed1995

Inhibition of glycogen synthase kinase-3 by insulin in cultured human skeletal muscle myoblasts.

The acute effects of insulin on the activity of glycogen synthase kinase 3 (GSK-3) have been investigated both in the rat L6 muscle cell line and in cultured human myoblasts. The alpha and beta isoforms of GSK-3 are present in both cell types, with the beta isoform being predominant in the human cells. Insulin causes a rapid inactivation of both isoforms in both cell lines, with 50% inactivation being observed in the human myoblasts.

Amino Acid Sequence↗
PubMed1995

The effect of acute (60 minute) insulin stimulation upon human skeletal muscle glycogen synthase and protein phosphatase-1 in non-insulin-dependent diabetic patients and control subjects.

Previous studies have established that activation of muscle glycogen synthase (GS) is abnormal in non-insulin-dependent diabetes mellitus (NIDDM). Insulin-mediated activation of GS depends upon protein phosphatase-1 (PP1), which dephosphorylates the relevant sites of GS. In order to determine whether defects in PP1 activation cause subnormal activation of GS or whether PP1 activation itself is normal, we administered a short insulin infusion to 8 NIDDM subjects and 8 healthy controls matched for gender, age, and body mass index (BMI). GS fractional activity and PP1 activity were determined in biopsies taken from the gastrocnemius muscle before and after 60 min insulin infusion (0.1 U kg h-1). In the NIDDM group, muscle GS fractional activity was 6.8 +/- 1.6 and 10.0 +/- 1.5% (mean +/- SEM) (p = 0.11) before and after insulin infusion. In the control group, muscle GS fractional activity increased from 7.3 +/- 2.0 to 13.3 +/- 2.7% (p < 0.02). PP1 activity had returned towards basal levels after insulin infusion; NIDDM group 156 +/- 24.7 to 184.1 +/- 28.1 U mg-1; control group 220.8 +/- 30.1 to 233.8 +/- 29.8 U mg-1. In the NIDDM group there was a positive correlation between the increases in GS fractional activity and PP1 activity following insulin stimulation r = 0.77; p < 0.025). These data indicate that in vivo insulin-dependent activation of muscle PP1 is transient in normal subjects but is delayed in NIDDM. The defect in GS activation in NIDDM is likely to be proximal to PP1 in the pathway of transmission of the insulin signal.

Biopsy↗