The comparison of four weight reduction strategies aimed at overweight patients with diabetes mellitus: four-year follow-up.

Weight change and glycaemic control in 132 diabetic patients previously treated for 1 year by four different methods aimed at weight loss were reanalysed 4 years after the outset. The four treatment groups comprised clinic visits, home visits, behavioural group therapy, and dexfenfluramine given for the initial 3 months followed by clinic visits. When analysed on an intention to treat basis only the dexfenfluramine group maintained a significant weight loss at year 4 (mean -2.46 kg) with 43% of patients losing 3 kg or more; HBA1c was not decreased. The other treatment groups showed overall weight regain from year 1 to year 4. Within the home visit group however, the number of patients losing at least 3 kg doubled between years 1 (21%) and 4 (38%). When analysed on a completion basis, weight loss in the dexfenfluramine group was significant in females but not in males at year 4. During the 4 years of observation a cohort of 54 patients reflecting our routine clinic practice gained on average 0.35 kg. Although now withdrawn, the use of an appetite suppressant dexfenfluramine for just 3 months would appear to have a long-term advantage on weight loss in this diabetic population, although the weight lost was not associated with improvement in glycaemic control.

Overview of the Mars Pathfinder mission and assessment of landing site predictions.

Chemical analyses returned by Mars Pathfinder indicate that some rocks may be high in silica, implying differentiated parent materials. Rounded pebbles and cobbles and a possible conglomerate suggest fluvial processes that imply liquid water in equilibrium with the atmosphere and thus a warmer and wetter past. The moment of inertia indicates a central metallic core of 1300 to 2000 kilometers in radius. Composite airborne dust particles appear magnetized by freeze-dried maghemite stain or cement that may have been leached from crustal materials by an active hydrologic cycle. Remote-sensing data at a scale of generally greater than approximately 1 kilometer and an Earth analog correctly predicted a rocky plain safe for landing and roving with a variety of rocks deposited by catastrophic floods that are relatively dust-free.

The comparison of four weight reduction strategies aimed at overweight diabetic patients.

Four weight reduction strategies were investigated in a diabetic population who previously had shown little motivation to lose weight. Some 409 patients, body mass index 28-45 were invited to participate. Only 51% replied, although 22 patients (5.4%) lost > 3 kg by invitation alone. The study comprised 159 patients, randomly allotted to either regular clinic visits, behavioural group therapy, dexfenfluramine (30 mg d-1 for initial 3 months) or combined home and clinic visits. A further 58 patients were monitored as controls. At 3 months the best weight loss (intention to treat) was achieved using dexfenfluramine with mean weight losses of 1.6, 1.2, 3.4, and 1.7 kg, respectively, in each group. At 1 year weight losses were similar (1.2, 1.8, 2.8, 1.2 kg, respectively) but contrasted with a mean 1.2 kg weight gain in the controls. Some 38% lost > 3 kg on dexfenfluramine compared to 19-23% for the others. In those who completed the study, weight loss was similar with behavioural therapy (3 kg) or dexfenfluramine (3.2 kg). We conclude that intensive dietetic efforts can reverse the weight increase in the diabetic population although weight loss is minimal. Dexfenfluramine was most effective in the short term, behavioural therapy useful long term but only in those who remained within the group; home visits offered no advantage.

Cytochemical bioassay of parathyroid hormone in maternal and cord blood.

Parathyroid hormone and calcium were measured in plasma taken from pregnant women at term and from the umbilical veins of their infants at birth. Three assays were used to measure parathyroid hormone, a cytochemical bioassay of bioactivity and two immunoradiometric assays, one specific for the amino terminus, the other specific for the carboxy terminus of the parathyroid hormone molecule. Plasma calcium was significantly higher in the infants than in the mothers. Maternal parathyroid hormone bioactivity and the amino terminus were both slightly raised, but the carboxy terminus value was normal; these findings supported the view that late pregnancy is a time of mild physiological hyperparathyroidism. In the infants, the amino terminus was undetectable and the carboxy terminus was either undetectable or towards the lower end of the normal range: bioactivity of parathyroid hormone was considerably raised and was related to the gradient of calcium across the placenta. This suggests that the parathyroid glands are not suppressed during fetal life and that they may play an important part in the maintenance of high fetal plasma calcium concentrations.

Suppression of secondary hyperparathyroidism in uraemia: acute and chronic studies.

A study was conducted evaluating the response of serum parathyroid hormone to acute hypercalcaemia and long term administration of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) in patients receiving maintenance haemodialysis. During infusion of elemental calcium 4 mg/kg/h over four hours in 12 patients not receiving vitamin D the concentration of serum amino terminal parathyroid hormone fell by 31-96% (mean 74.8 (SD 17.6)%) while that of carboxy terminal parathyroid hormone changed little. There was a strong inverse correlation between baseline serum calcium concentration and percentage fall in amino terminal parathyroid hormone during infusion (r = 0.88; p less than 0.001). In seven patients who received prolonged treatment with 1,25(OH)2D3 after calcium infusion there was a positive correlation between maximum percentage fall in amino terminal parathyroid hormone during infusion and the percentage fall in amino terminal parathyroid hormone after 1,25(OH)2D3 treatment (r = 0.79; p less than 0.05). The responsiveness of the parathyroid glands to changes in calcium in acute studies may be used to predict the efficacy of long term treatment with 1,25(OH)2D3. Patients in whom calcium infusion does not suppress parathyroid hormone may have true parathyroid autonomy and require early parathyroidectomy.

Calcium homeostasis in the fetal pig.

Acute studies have been carried out with pregnant sows and their fetuses during the last 2 weeks of gestation. In blood samples obtained simultaneously it was shown that the concentrations of ionized calcium, calcitonin and parathyroid hormone (PTH) in fetal plasma were all greater than the corresponding values in maternal plasma. In contrast, the fetal concentrations of 24,25-dihydroxy vitamin D3 were lower than maternal and those of 1,25-dihydroxy vitamin D3 were not significantly different. In one experiment the circulatory level of fetal PTH was shown to be higher than in the sow by both an immunoradiometric assay and a very sensitive cytochemical assay. The latter showed the fetal: maternal ratio to be approximately three. This inappropriately high level of fetal PTH was unaffected by short term hypocalcaemic and hypercalcaemic changes in the fetal circulation. Although part of this fetal PTH may have been secreted in response to the action of beta-catecholamines released as a result of the experimental conditions, the transplacental gradient of PTH was also demonstrated in the chronically catheterized fetus. A short term period of either hypercalcaemia or hypocalcaemia induced in the mother was without consistent effect upon plasma calcium concentration in the fetus. However, an increase in ionized calcium concentration in the fetal plasma was found to follow the cessation of a period of maternal hypocalcaemia. It can be seen that the porcine fetus possesses the important elements of a calcium homeostatic mechanism, namely parathyroid hormone, calcitonin and the biologically active metabolites of vitamin D. Although the degree of independence from the mother is somewhat less than in the sheep, it is concluded that the porcine fetus is largely autonomous with respect to calcium homeostasis.

Long-term experience of alfacalcidol in renal osteodystrophy.

Thirteen patients receiving regular haemodialysis, with biochemical or radiological evidence of renal osteodystrophy, were treated with alfacalcidol (1 alpha hydroxy vitamin D3) for four years. During the first eighteen months of treatment plasma alkaline phosphatase and serum parathyroid hormone concentrations fell and subperiosteal phalangeal erosions improved. Thereafter plasma alkaline phosphatase and serum parathyroid hormone concentrations rose and after four years' treatment only four patients had a normal plasma alkaline phosphatase, only five a normal serum parathyroid hormone level and in only six had the erosions healed completely. Hypercalcaemia occurred in twelve patients, plasma calcium exceeding 3.0 mmol/l in ten. Plasma calcium rose abruptly close to the time when plasma alkaline phosphatase became normal and often remained raised despite reduction in dosage of alfacalcidol. We have reservations about the ultimate value of long-term treatment with alfacalcidol in haemodialysed patients with renal osteodystrophy and urge caution in its use.

Studies of circulating parathyroid hormone in man using a homologous amino-terminal specific immunoradiometric assay.

Circulating immunoreactive parathyroid hormone (PTH) was measured by a homologous, amino-terminal, specific, immunoradiometric assay in man. In forty-two healthy subjects the concentrations ranged between < 40 pg/ml and 120 pg/ml. No hormone could be detected in the sera of eleven patients with hypoparathyroidism, but the concentrations were clearly elevated in six patients with pseudohypoparathyroidism (range 190-1120 pg/ml). In thirty-five patients with primary hyperparathyroidism the mean (+/- SEM) concentration was 283.4 +/- 42.4 pg/ml (range 100-1350 pg/ml). A significant positive correlation was demonstrated between immunoassayable hormone and serum calcium concentrations in these patients. In nine patients PTH concentrations were measured before and after parathyroidectomy. In all of them they were elevated pre-operatively but fell to the normal range after parathyroidectomy. The disappearance of exogenously administered synthetic human PTH (1-34) from the circulation of two normal subjects was rapid with an apparent plasma half-disappearance time (t1/2) between 2 and 3 min; the metabolic clearance rate was 12.9 and 9.0 ml. kg-1 . min-1 respectively. Similarly, the disappearance of endogenous, amino-terminal, immunoreactive PTH from the circulation of two patients with primary hyperparathyroidism after parathyroidectomy was rapid; the apparent t1/2 was approximately 3 min. Homologous amino-terminal specific immunoassays for PTH can thus be useful for the study of both the acute, and chronic, changes of circulating hormone in man and represent an improvement over heterologous unselected assay systems.

Development of homologous immunological assays for human parathyroid hormone.

Antisera to a trichloroacetic-acid precipitate of human parathyroid hormone (PTH) were produced in goats. Two of these antisera (G36 and G31) were of high affinity, and the bovine and porcine hormones were less reactive. Synthetic peptides containing the amino-terminal region of human PTH reacted with both antisera; the 1--34 peptide (PTH-(1--34)), with the sequence proposed by Niall, Sauer, Jacobs, Keutmann, Segre, O'Riordan, Aurbach & Potts in 1974, was more reactive than that having the sequence proposed by Brewer, Fairwell, Ronan, Sizemore & Arnaud in 1972. The antisera were further characterized with a number of other native and synthetic fragments of human PTH and reacted poorly with fragments from the carboxy-terminal region of the molecule. Since the amino-terminal fragments did not account for all the immunoreactivity, it is assumed that the antisera had some recognition sites for the central part of the molecule. Highly purified human PTH-(1==84) was labelled with 125I and radioimmunoassays were developed using this tracer and antiserum G36. To avoid the problems associated with labelling human PTH with 125I, a labelled antibody assay was developed with G36 and an immunoadsorbent consisting of human PTH-(1--34) (sequence of Niall et al.) coupled to cellulose. A sensitive homologous amino-terminal specific assay was developed in this way.

Immunological properties of synthetic human parathyroid hormone 53--84 fragment.

The immunological properties of a synthetic peptide comprising the carboxyl-terminal 53--84 region of human parathyroid hormone (PTH) have been studied. The immunoreactivity of the synthetic human PTH-(53--84) peptide paralleled that of a 53--84 fragment of the native human hormone prepared by enzymic digestion, in both a standard radioimmunoassay, which was not region-specific, and also a radioimmunoassay specific for the carboxyl-terminal region of PTH. However, in both types of radioimmunoassay the synthetic human PTH-(53--84) peptide was four to five times more reactive than the native human PTH-(53--84) fragment.