Rapid changes in somatomedin activity during insulin-induced hypoglycemia: possible release of an inhibitory factor.

Somatomedin activity was determined by bioassay during insulin-induced hypoglycemia in 24 patients with a variety of pituitary disorders. Initial somatomedin levels appeared to depend primarily on the state of GH secretion and were unaffected by abnormal PRL secretion. During the test, somatomedin activity fell to a minimum after 45 to 60 min and subsequently returned to initial values in those patients whose GH levels rose in response to insulin hypoglycemia, but not in patients lacking a GH response. Heat treatment of the plasma abolished the change in somatomedin activity in the majority of patients, and it is likely that the apparent fall in somatomedin was due to the presence of a heat-labile inhibitor of somatomedin action on cartilage.

Efficacy of the new long-acting formulation of lanreotide (lanreotide Autogel) in the management of acromegaly.

Lanreotide Autogel is a new long-acting aqueous preparation of lanreotide for the treatment of acromegaly and is administered by deep sc injection from a small volume, prefilled syringe. The aim of this study was to evaluate the efficacy and safety of this new long-acting formulation in a large population of acromegalic patients previously responsive to lanreotide 30 mg, im (sustained release microparticle formulation). Lanreotide Autogel was administered by deep sc injection every 28 d to 107 patients (54 males and 53 females; mean age, 54 +/- 1.2 yr). All patients had been treated with lanreotide (30 mg) for at least 3 months before study entry and had a mean GH level less than 10 ng/ml after at least 4 subsequent im injections every 14 d (48%), 10 d (32%), or 7 d (20%). Treatment was switched from lanreotide 30 mg injected every 14, 10, or 7 d to 60, 90, or 120 mg lanreotide Autogel, respectively, every 28 d. After three fixed dose injections of lanreotide Autogel, mean lanreotide levels were similar to those obtained at steady state with lanreotide 30 mg. During lanreotide Autogel treatment, the control of acromegalic symptoms was comparable with that previously achieved during lanreotide 30 mg treatment. After 3 injections of lanreotide Autogel, mean GH (2.87 +/- 0.22 ng/ml) and IGF-I (317 +/- 15 ng/ml) values were comparable with those recorded at the end of lanreotide 30 mg treatment (GH, 2.82 +/- 0.19 ng/ml; IGF-I, 323 +/- 16 ng/ml). GH levels below 2.5 ng/ml and age-/sex-normalized IGF-I were achieved in 33% and 39% of patients during lanreotide 30 mg and lanreotide Autogel treatment, respectively. Diarrhea, abdominal pain, and nausea were reported by 38%, 22%, and 18% of patients during lanreotide 30 mg treatment and by 29%, 17%, and 9% of patients, respectively, during lanreotide Autogel treatment. In conclusion, this clinical study shows that lanreotide Autogel is at least as efficacious and well tolerated as lanreotide 30 mg. This new long-acting lanreotide formulation, lanreotide Autogel, which is administered from a small volume, prefilled syringe by deep sc injection, is therefore likely to improve the acceptability of medical treatment for patients requiring long-term somatostatin analog therapy.

Tissue kallikrein is associated with prolactin-secreting cells within human growth hormone-secreting adenomas.

Tissue kallikrein is a serine protease which may be involved in the intracellular processing of prolactin in the anterior pituitary gland. The expression of tissue kallikrein, in the rat, is promoted by oestrogen and inhibited by dopamine. Human and rat prolactinomas contain markedly increased amounts of tissue kallikrein; this is comparatively reduced if patients are pretreated with the dopamine agonist, bromocriptine, before surgery. Some GH-secreting adenomas are mixed and also contain prolactin-secreting cells. We therefore investigated 27 GH-immunostaining human pituitary adenomas for the presence of immunoreactive tissue kallikrein. Sixteen of the adenomas had positive immunostaining for prolactin; eight of these patients had associated clinical hyperprolactinaemia before the tumour was removed. Tissue kallikrein immunoreactivity was found in ten adenomas, all of which also had prolactin immunopositivity. There was a close relationship between the percentage of cells staining for prolactin and tissue kallikrein but not for GH. A further eight adenomas had patchy positivity, i.e. less than 1% of cells immunostained for tissue kallikrein and six of these also had some prolactin-staining cells. Nine out of eleven purely GH-staining adenomas had no tissue kallikrein immunopositivity, the remaining two showing patchy staining. A review of bromocriptine responsiveness, as assessed by mean GH hormone levels during oral glucose tolerance tests before and after therapy was commenced, indicated that patients with adenomas which stained for prolactin and tissue kallikrein were more likely to respond to bromocriptine than those which failed to do so.

Characterization of a tissue kallikrein in human prolactin-secreting adenomas.

Immunoreactive tissue kallikrein was co-localized with prolactin in all the eleven prolactin-secreting adenomas of the human anterior pituitary gland examined in this study. The intracellular distribution of immunoreactivity in the prolactin-secreting cells suggests that tissue kallikrein is located within the Golgi complex of these cells. Both the intracellular hormone-processing action and the kininogenase activity of tissue kallikrein may be of functional importance in human prolactinomas.

Pharmacokinetics and tolerability of a bioadhesive buccal testosterone tablet in hypogonadal men.

OBJECTIVE: A phase I single centre, open label study of the pharmacokinetics and tolerability of a buccal testosterone tablet (COL 1621) was carried out. DESIGN: Twelve testosterone-deficient males were treated with the buccal tablet twice daily for 7 consecutive days. Multiple blood samples were drawn for testosterone, dihydrotestosterone (DHT), bioavailable testosterone and sex hormone-binding globulin (SHBG). RESULTS: After COL 1621, means+/-S.D. serum testosterone level increased to a peak concentration of 26.6+/-5.8 nmol/l (7.7+/-1.7 ng/ml) at 4.8+/-5.8 h and stayed in the eugonadal range. Steady state was achieved within the first 24 h and was maintained in the normal range. The bioavailable testosterone, DHT and free testosterone index followed a pattern very similar to that of testosterone. The mean serum testosterone to DHT ratio was within the normal male range throughout treatment. There was only one treatment-related adverse event (headache). Two-thirds of patients indicated that treatment with COL 1621 was acceptable and that the tablet was convenient to use. Six patients (50.0%) preferred COL 1621 to their previous testosterone replacement therapy, two patients gave preference to their previous treatment and three patients found both treatments to be equally acceptable. Data for one patient was not available. CONCLUSION: We conclude that COL 1621 can efficiently elevate serum testosterone and DHT levels in hypogonadal men within the first day of application, achieve a steady state within 24 h and maintain serum testosterone in the normal range with a twice-daily treatment regimen. COL 1621 provides an effective alternative oral testosterone replacement therapy that gives physiological levels of testosterone and is well tolerated by the patients.

IL-8 mRNA expression by in situ hybridisation in human pituitary adenomas.

Several cytokines have been shown to be expressed in normal and adenomatous pituitary tissue. Recently, interleukin-8 (IL-8) mRNA was identified by reverse transcription (RT)-PCR in each of a series of 17 pituitary tumours examined. We have investigated further the presence of IL-8 mRNA, using in situ hybridisation in two normal human anterior pituitary specimens and 25 human pituitary adenomas. IL-8 mRNA was not identified in either of the two normal pituitary specimens. Only three of the 25 adenomas were positive for IL-8 mRNA. In these three tumours, which included two null cell adenomas and one gonadotrophinoma, the majority of tumour cells (>90%) were positive for IL-8 mRNA. The remaining 22 adenomas were completely negative. There was no difference in tumour size or type between the IL-8 positive and the IL-8 negative tumours, and immunocytochemistry for von Willebrandt factor showed that the two groups were also similar in their degree of vascularisation. In conclusion, IL-8 mRNA was found in 12% of pituitary adenomas studied and was histologically identified within the tumour cells. In situ hybridisation is a more appropriate technique for assessing cytokine mRNA production by human pituitary tumours because RT-PCR may be too sensitive, identifying very small, possibly pathologically insignificant, quantities of mRNA that could be produced by supporting cells such as fibroblasts, endothelial cells or macrophages.

The association between serum triglycerides and gamma glutamyl transpeptidase activity in diabetes mellitus.

A study conducted on 228 diabetic patients has shown a significant positive association between serum gamma-glutamyl transpeptidase (GGT) and triglyceride levels. Both fall with treatment, the most marked reduction occurring in patients on insulin. We suggest that the association between serum GGT and triglyceride levels and also the higher incidence of raised GGT and triglyceride levels in new diabetics may reflect hepatic microsomal enzyme induction of the rate-limiting enzymes of triglyceride synthesis. Serum GGT does not seem to correlate with hepatomegaly in diabetes mellitus.

Amino acid profiles in early diabetic and non-diabetic pregnancy.

Plasma amino acid concentrations were measured in six insulin-dependent diabetic women and seven non-diabetic women in early pregnancy while fasting and one hour after a standard meal. Fasting plasma levels of total amino acids and individual amino acids were similar in the two groups, excepting isoleucine, which was raised in the diabetics. One hour post-prandially total amino acid concentrations were similar in the two groups; however, mean concentrations of total branched chain amino acids and mean concentration of the individual amino acids, serine, valine, isoleucine, leucine and tyrosine were elevated in the diabetics. Amino acids are important in early islet development and in insulin secretion from fetal pancreas in vitro. The elevated post-prandial amino acid levels found in pregnant diabetics in early pregnancy may contribute to fetal islet hypertrophy and hyperinsulinaemia.

Diabetic ketoacidosis precipitated by genital herpes infection.

Diabetic ketoacidosis is frequently precipitated by infections. We report three cases in which ketoacidosis was induced by genital herpes infection. There is good evidence that early treatment with systemic Acyclovir is effective in patients with a first attack of genital herpes. Therefore genital examination should be considered in patients with diabetic ketoacidosis particularly when there are symptoms of genital herpes. During episodes of recurrence, diabetic patients need to monitor their blood sugars more frequently and adjust insulin requirements accordingly. We believe that this is the first description of ketoacidosis being associated with this increasingly common and recurrent infection.

Coxiella burnetii serology in granulomatous hepatitis.

Granulomatous hepatitis as the sole manifestation of acute Q fever has been reported only rarely, although minimal hepatic dysfunction may be common in the acute disease. In this paper we report two patients with acute Q fever who presented with hepatitis; one of whom had granulomatous hepatitis on liver biopsy. We discuss the serological diagnosis of acute and chronic Q fever particularly in relation to hepatitis.

Adrenal scintigraphy with 75Se selenonorcholestenol: a review.

We have reviewed 58 patients on whom adrenal scintigraphy has been performed using 75Se selenonorcholestenol. For 15 patients whose adrenal function was biochemically normal, the upper limit of normal of the 7 day adrenal uptake test was 0.45%, considerably higher than the generally accepted value of 0.3%. There is evidence from this group of patients that stress and obesity might account for uptakes in the range 0.3-0.45%. The sensitivity of the uptake test is poor, with 7 out of 23 patients with Cushing's syndrome having uptakes within the normal range. Scintigraphy of such patients may still be useful in differentiating between unilateral and bilateral adrenal involvement.

Tensile strength of elastomeric impression materials, adhesive and cohesive bonding.

Numerous factors are known to effect the accuracy of elastomeric impression materials. Factors often overlooked are the quality of the bond between low-viscosity and high-viscosity elastomers and the presumed cohesive bond between materials during an impression reline procedure. This study examined the bond strength of condensation polymerization polysiloxanes, addition polymerization polysiloxanes, polyethers, and a light-cured polyether urethane dimethacrylate. Of the tested materials, light-cured polyether urethane dimethacrylate exhibited the greatest bond strength. The reline technique, light-body cured to previously cured heavy-body putty, yielded results similar to the simultaneous-cure technique. In terms of bond strength there is no advantage of one technique over the other. The corrective reline technique yielded acceptable results in bond strength. In general, the tested materials exhibited greater tensile strength than bond strength.

Wettability of elastomeric impression materials and voids in gypsum casts.

Numerous factors are involved in making an accurate void-free dental artificial stone cast or die. The relationship of the wettability of an elastomeric impression material and its interaction with the gypsum slurry is an important factor. This study examined the relative "pourability" of several impression materials by counting the number of resultant voids in artificial stone casts containing 48 point angles. Those elastomers that exhibited the lowest contact angle with water produced artificial stone casts with the fewest voids. Surfactants applied to the impression material significantly reduced the number of voids in artificial stone casts, as did modified elastomers designated by the manufacturer as hydrophilic.

Peroxide bleaches: effect on tensile strength of composite resins.

Research concerning bleaching agents on the mechanical properties of composite resin restorative materials has produced conflicting reports. Representative brands of composite resin restorative materials were studied, including microfil, hybrid, and posterior types. The bleaching agents selected were 30% hydrogen peroxide and two commercial brands of 10% carbamide peroxide. Ten specimens of each material, prepared according to American National Standards Institute/American Dental Association specification No. 27 for diametral tensile testing, were stored in bleaching agents for 1 hour and 168 hours at 37 degrees C. An equal number of specimens stored in deionized water with identical conditions were designated controls. Qualitative examination of bleached specimens revealed a marked change in color, especially the microfilled composite resins. There was no significant difference in tensile strength between controls and exposed samples at either time except for the diminished strength of microfilled composite resins in 30% hydrogen peroxide for one week (p < 0.01).

Hepatic microsomal enzyme induction and adrenal crisis due to o,p'DDD therapy for metastatic adrenocortical carcinoma.

Two cases are described in which metastatic adrenocortical carcinoma associated with Cushing's syndrome was treated with mitotane (o,p'DDD). The first patient had initially been treated by bilateral adrenalectomy and, whilst responding to mitotane biochemically and by remission of metastases, experienced repeated episodes of adrenal crisis requiring a substantial increase in steroid therapy. The second patient failed to respond to the drug, but evidence of hepatic enzyme induction was noted during its administration. It is suggested that hepatic microsomal enzyme induction can occur in association with treatment with mitotane and that this can lead to an increased destruction of exogenous steroid with clinical consequences.

Subcutaneous continuous insulin infusion and control of blood glucose concentration in diabetics in third trimester of pregnancy.

The effect of subcutaneous continuous insulin infusion on the control of blood glucose concentrations was assessed in eight pregnant diabetics in the third trimester. Twenty-four-hour glucose profiles were obtained after strict inpatient control on conventional insulin regimens and after the start of the continuous infusion, which was maintained for 5-55 days. Mean 24-hour glucose concentrations (6.2 mmol/l on conventional regimen, 5.9 mmol/l on continuous infusion; 111.6 and 106.2 mg/100 ml respectively) and mean fasting concentrations (5.3 v 6.2 mmol/l; 95.4 v 111.6 mg/100 ml) were not significantly changed by continuous infusion. Diurnal variations in glucose concentration tended to be smaller on continuous infusion: standard deviation from mean 24-hour glucose concentration was reduced from 2.5 to 2.0 mmol/l (from 45 to 36 mg/100 ml), maximum excursion from 8.4 to 7.4 mmol/l (151.2 to 133.2 mg/100 ml), and M value from 16 to 14. Subcutaneous continuous insulin infusion may be useful in limiting diurnal variations of blood glucose concentrations and warrants further investigation since such an action may be beneficial in the management of pregnant diabetics, in whom the best possible control of blood glucose concentrations is sought for the good of the fetus.