Effect of naloxone on met-enkephalin-induced gastric acid secretion and serum gastrin in man.

It has previously been demonstrated that met-enkephalin, and endogenous opiate, stimulates gastric acid secretion in man, while naloxone inhibits meal-stimulated acid secretion. In seven healthy subjects the opiate receptor antagonist naloxone was infused in a dose of 10 microgram/kg/h during stimulation of gastric acid secretion with pentagastrin 100 ng/kg/h and met-enkephalin 0.1 microgram/kg/h. Naloxone had no effect on pentagastrin-induced acid secretion, whereas met-enkephalin-induced acid secretion was completely abolished in both studies without affecting serum gastrin levels, suggesting that the acid inhibitory effect of naloxone is specifically directed towards met-enkephalin-induced acid secretion. The results support the assumption that met-enkephalin participates in the physiological stimulation of gastric acid secretion.     

Diurnal plasma profiles of metabolite and hormone concentration in insulin-dependent diabetic patients during conventional insulin treatment and continuous subcutaneous insulin infusion. A controlled study

In addition to hyperglycaemia, derangement of metabolic and hormonal control may play an important role in the development of microvascular complications in diabetes. Little, however, is known about the impact of insulin pump treatment on metabolic and hormonal parameters. In a 6-month prospective randomized study in insulin-dependent diabetics we therefore investigated the effects of continuous subcutaneous insulin infusion by pump (10 patients) and conventional insulin treatment (10 patients) on the 24-h profiles of blood glucose, glycerol, lactate, 3-hydroxybutyrate, insulin, glucagon and growth hormone by measuring the respective concentrations every 2 h. We found that average blood glucose levels and HbA1c were significantly lower in the group treated by continuous subcutaneous insulin infusion as compared with the group on conventional insulin treatment. Furthermore, we observed an improvement in diurnal levels of lactate and 3-hydroxybutyrate in the pump-treated group which was not seen in the conventionally treated group. A slight increment in alanine was seen in the group treated with insulin pump. Serum growth hormone, glycerol, plasma free insulin as well as the daily insulin supply were unchanged and identical in the two groups. It is noteworthy that in the pump group, the decrease in blood glucose and 3-hydroxybutyrate takes place concomitantly with a significant suppression of glucagon.     

Are disease duration and degree of functional impairment determinants of bone loss in rheumatoid arthritis?

One hundred and five patients with rheumatoid arthritis treated with a variety of antirheumatic drugs, excepting glucocorticoids, were stratified according to the degree of functional impairment (functional classes I to IV) and duration of the disease (0-3 years; 4-8 years; and greater than 8 years). The variables investigated were distal forearm bone mineral content (BMC), biochemical markers of bone formation: serum alkaline phosphatase and serum bone gamma-carboxyglutamic acid containing protein (BGP) and biochemical markers of bone resorption: fasting urinary calcium and fasting urinary hydroxyproline. Significant relationships were found between BMC and functional impairment and duration of the disease. Indices of bone formation and bone resorption rose with increasing functional impairment, particularly those of bone resorption. It is concluded that disability induces osteopenia in rheumatoid arthritis by increasing the bone turnover with a more marked increased in resorption than in the formation processes. The effect of the disease duration is merely that of adding more years of functional impairment.     

Circulating levels of incretin hormones and amylin in the fasting state and after oral glucose in GH-deficient patients before and after GH replacement: a placebo-controlled study

OBJECTIVE: Hyperinsulinemia in association with GH excess is considered a compensatory response to insulin resistance, but the possibility of alternative insulinotropic mechanisms has not been investigated in vivo. It is also unknown how GH influences the secretion from pancreatic beta-cells of amylin, a peptide which regulates prandial glucose homeostasis and may be linked to development of beta-cell dysfunction. We therefore measured plasma concentrations of two gut insulinotropic hormones, glucagon-like peptide 1 (GLP-1) and glucose-dependent insulin-releasing peptide (GIP), and total as well as non-glycosylated amylin, in 24 GH-deficient adults before and after 4 months of GH replacement (daily evening injections of 2 IU GH/m). DESIGN: Double-blind, placebo-controlled, parallel study. METHODS: All participants underwent an oral glucose tolerance test (OGTT) at 0 and 4 months. RESULTS: A 33% suppression of fasting GLP-1 concentrations was measured in the GH group at 4 months (P=0.02), whereas a non-significant increase occurred in the placebo group (P=0.08). Fasting levels of GIP and amylin did not change significantly after 4 months in either group. The incremental response in GLP-1 during the OGTT was significantly lower after GH treatment as compared with both baseline (P=0.02) and the response in the placebo group (P=0. 03). The stimulation of GIP secretion following OGTT was similar on all occasions. The OGTT-induced incremental response in non-glycosylated amylin was moderately elevated after GH treatment as compared with placebo (P=0.05). Plasma concentrations of glucose and insulin, both in the fasting state and after the OGTT, were higher after GH treatment, but the ratio between amylin and insulin remained unchanged. CONCLUSIONS: GH-induced hyperinsulinemia is accompanied by proportionate elevations in amylin concentrations and a blunting of gut GLP-1 secretion. The mechanisms underlying the suppression of GLP-1 remain to be elucidated.     

Does a suitable animal model for research on partial left ventriculectomy exist? Animal models for PLV

Partial left ventriculectomy is a new surgical option quickly introduced into clinical use worldwide for treating end-stage heart failure in patients with dilated cardiomyopathy. Due to the overwhelming success of this new kind of surgical treatment for dilated cardiomyopathy, experimental research on the physiological and pathophysiological basis was initially not performed. Now, demands for an appropriate animal model have arisen more and more since the outcome of patients treated by partial left ventriculectomy has differed considerably. This review summarizes available experimental models for heart failure in large animals, and discusses their suitability for research on partial left ventriculectomy.     

Alpha2-antiplasmin: potential therapeutic roles in fibrin survival and removal

Alpha2-antiplasmin (alpha2AP) is the primary inhibitor of plasmin, a proteinase that digests fibrin, the main component of blood clots. Two forms of alpha2AP circulate in human plasma: a 464-residue protein with methionine as the amino-terminus (Met-alpha2AP) and an N-terminally-shortened 452-residue form with asparagine as the amino-terminus (Asn-alpha2AP). Human plasma alpha2AP concentration is 1 micro M and consists of approximately 30% Met-alpha2AP and approximately 70% Asn-alpha2AP. The major form (Asn-alpha2AP) is rapidly crosslinked to fibrin during blood clotting by activated coagulation factor XIII and as a consequence, fibrin becomes more resistant to fibrinolysis. It is apparent that alpha2AP is important in modulating the effectiveness and persistence of fibrin with respect to its susceptibility to digestion and removal by plasmin. Hence, the physiologic role of alpha2AP suggests that it may be a useful target for developing more effective treatment of thrombotic diseases. Research on alpha2AP appears to be moving in two main directions: (1) efforts to use variant forms of alpha2AP to reduce bleeding secondary to thrombolytic therapy while not slowing thrombolysis; and (2) efforts to use variant forms to diminish the activity of alpha2AP as a plasmin inhibitor so that fibrinolysis becomes enhanced. Methods to accomplish these two goals mostly involve manipulation of defined functional domains within the molecular structure of alpha2AP, or inhibition of a newly described novel plasma proteinase, termed antiplasmin-cleaving enzyme, that generates the more favorable form of alpha2AP, Asn-alpha2AP, for crosslinking to fibrin. The antiplasmin-cleaving enzyme has similarity in primary structure and catalytic properties to fibroblast activation protein/seprase. This review summarizes recent studies that may hold promise for modulating alpha2AP activity and its interactions with certain proteins as new therapeutic strategies for preventing and treating thrombotic disorders.     

The effect of strict short-term metabolic control on retinal nervous system abnormalities in newly diagnosed Type 1 (insulin-dependent) diabetic patients

Summary The oscillatory potential of the electroretinogram and the initial 2-min phase of dark-adaptation were studied in seven newly diagnosed Type 1 (insulin-dependent) diabetic patients before and during initial insulin treatment. Strict metabolic control was achieved in all seven patients using multiple subcutaneous injections of insulin. Seven to 11 days of strict metabolic control improved the added amplitude value of the oscillatory potential from 236±8 to 268±8 V (mean±SEM; p < 0.01) and the dark-adaptation from 90 ±5 to 67±5 s (p < 0.01). Our study has demonstrated reversible neurophysiological abnormalities in the diabetic retina which are related to metabolic control.     

Discontinuous calcitonin treatment of established osteoporosis--effects of withdrawal of treatment

PURPOSE: The purpose of this study was to examine the effects of discontinuous treatments with intranasal salmon calcitonin on bone and calcium metabolism in postmenopausal women and to establish the effects of withdrawing treatment. PATIENTS AND METHODS: This report presents data from 26 postmenopausal women with established osteoporosis (forearm fracture) 12 months after withdrawal of a 1-year double-blind, placebo-controlled therapy with intranasal calcitonin. The women then resumed treatment with calcitonin 200 IU plus calcium 500 mg daily in an open design for an additional 1-year period. A control group of 19 age-matched women (no forearm fracture) did not receive any treatment. RESULTS: At the end of the 3 years, the control group had lost significantly more bone in the forearm (single photon absorptiometry) and spine (dual photon absorptiometry) than had the group treated with intranasal calcitonin for 2 years, whereas the group receiving calcitonin for 1 year had intermediate values. During the year of withdrawal, the rate of bone loss was similar in the women who had received calcitonin and those who had received placebo. Calcitonin was especially effective in women with initially high bone turnover and low bone mass. The bone response in the spine could, furthermore, be estimated by the changes in bone turnover. CONCLUSION: Discontinuous treatment with intranasal calcitonin affects bone and calcium metabolism in established osteoporosis. In women with high-turnover osteoporosis, therapy results in a net gain of bone in both the peripheral and axial skeleton. Response to treatment may be monitored by changes in bone turnover.     

Increased fracture rates in Turner's syndrome: a nationwide questionnaire survey

BACKGROUND AND OBJECTIVES: Reduced bone mineral content (BMC) and bone mineral density (BMD) have previously been reported in Turner's syndrome, although appropriate GH treatment and early induction of puberty seem to permit normal bone mass accumulation. Furthermore, an increased risk of fractures and osteoporosis have been reported in a registry study. The aim of the present study was to further characterize the risk of fractures in TS and to explore risk factors, in a historical follow-up survey based on a self-administered questionnaire. STUDY GROUPS: The questionnaire was issued to all females with TS (n = 632) in Denmark and to 1888 randomly selected controls (C) matched for age and geographical region. A total of 322 patients (51%) and 1169 controls (62%) returned the questionnaire. RESULTS: TS women were younger than C (30 years, range: 1-73 years vs. 34 years, range 2-82 years, P < 0.0005), smoked less often (17%vs. 27%, P < 0.0005), and had less frequent spontaneous menstruation (18%vs. 86%, P < 0.0005). In contrast, they used hormonal replacement therapy (HRT) more often (71%vs. 7%, P < 0.0005). The median age at start of HRT was 16 years (range 8-59 years) in TS vs. 42 years (range 12-53 years) in C (P < 0.0005). Above the age of 15 years, 83% of TS and 8% of C used HRT. GH had been used by 37% of TS but only 0.2% of C. Both type 1 and 2 diabetes were increased sevenfold among TS. Altogether, 77 individuals with TS had 109 fractures. The fracture risk was increased in TS [hazard ratio (HR, status) 1.35, confidence interval (CI) 1.04-1.75, P = 0.025]. Time to first fracture was reduced in TS (53 +/- 2 vs. 63 +/- 1; log-rank P = 0.03). Spontaneous menstruation was protective in females above 13 years of age (HR: 0.70, CI 0.54-0.93, P = 0.012). A history of parental fractures increased the risk (HR 1.92, CI 1.62-2.27, P < 0.001). Fractures of the forearm was more frequent among TS (P = 0.02). CONCLUSION: The present nationwide survey, based on questionnaires, confirms an increased risk of early fractures in TS, especially in those without ovarian function and with a positive family history of fracture and osteoporosis. It thereby emphasizes the need for being vigilant with respect to BMD measurements in these patients.     

Physiological profiles of episodic progesterone release during the midluteal phase of the human menstrual cycle: analysis of circadian and ultradian rhythms, discrete pulse properties, and correlations with simultaneous luteinizing hormone release

To define the physiological relationships between episodic progesterone and LH release, we measured serum progesterone and LH concentrations in blood sampled at 10-min intervals for 24 h in seven young women in the midluteal phase of the menstrual cycle. The resultant time series were assessed further by Fourier transformation, Cluster analysis, and cross-correlation analysis with autoregressive modeling. These techniques permitted an examination of circadian rhythms, discrete (ultradian) pulse properties, and simultaneous or lagged correlations between progesterone and LH release. We found the following. 1) Both serum LH and progesterone concentrations had significant circadian periodicities, with similar acrophases (times of maximal nyctohemeral values). LH and progesterone also manifested multiple ultradian rhythms of similar periodicities (range, 48-241 min). 2) Discrete serum progesterone peaks occurred at a mean interpulse interval of 118 +/- 12 (+/- SE) min, had durations of 92 +/- 12 min, and had incremental amplitudes of 4.3 +/- 0.9 ng/mL (14 +/- 3 nmol/L). The frequency and duration characteristics of the progesterone and LH peaks were not significantly different, but progesterone fractional peak amplitudes were one quarter those of LH pulses. 3) Fractional progesterone peak amplitudes in the seven women correlated inversely (r = -0.811) with 24-h mean LH concentrations, suggesting a negative feedback relationship between progesterone and LH release. 4) LH and progesterone interpulse intervals both exhibited significant nyctohemeral variations, with diurnal amplitudes of 73 +/- 12 min for LH and 43 +/- 8.9 min for progesterone (P less than 0.01). 5) Significant positive cross-correlations existed in all seven women between serum LH and progesterone concentrations considered simultaneously and at progesterone time lags of 10-50 min. By autoregressive modeling, the later (20-50 min) cross-correlations could be accounted for by sustained autocorrelations in the individual progesterone and LH time series and significant cross-correlations between LH and simultaneous progesterone concentrations and between LH and 10-min lagged progesterone concentrations. We conclude that progesterone release occurs in a periodic (circadian and ultradian) fashion as well as in a discrete (episodic or pulsatile) mode. Moreover, both positive and negative feedback relationships operate to coordinate LH and progesterone secretion in the midluteal phase of the human menstrual cycle.