End-organ resistance to PTH infusion in hypercalcaemic and normocalcaemic patients with solid tumours

Ten hypercalcaemic patients with solid tumours were studied to evaluate the renal response on PTH infusion as assessed by nephrogenous cAMP excretion and maximum tubular re-absorption of phosphate. In addition, 20 normocalcaemic patients, 11 with an adenocarcinoma and 9 with a squamous cell carcinoma, were studied. All cancer patients had moderately extensive disease. Results were compared with those of 9 patients with primary hyperparathyroidism and with 10 elderly controls. All groups studied had comparable renal function, magnesium and 25-hydroxy-vitamin D levels. Comparable results were obtained in patients with an adenocarcinoma and in controls. cAMP response (delta nephrogenous cAMP) was significantly lower in the hypercalcaemic patients with a solid tumour compared with the controls (8.13 +/- 4.68 nmol/100 ml glomerular filtrate vs 29.52 +/- 25.62 nmol/100 ml glomerular filtrate; P less than 0.005). In the group of patients with primary hyperparathyroidism delta nephrogenous cAMP was 13.41 +/- 7.54 nmol/100 ml glomerular filtrate (P less than 0.06 vs controls). The group of patients with a squamous cell cancer showed an intermediate value of 14.83 +/- 10.74 nmol/100 ml glomerular filtrate (P less than 0.025 vs the normocalcaemic adenocarcinoma patients, but NS vs controls). In two hypercalcaemic patients with a solid tumour in whom PTH infusion was repeated after normalization of serum calcium no influence on renal responsiveness was observed. Responses of maximum tubular re-absorption of phosphate were lowest in the group of hypercalcaemic patients with a solid tumour and in the patients with primary hyperparathyroidism compared with controls (0.11 +/- 0.10 vs 0.22 +/- 0.09 mmol/l and 0.09 +/- vs 0.22 +/- 0.09 mmol/l; P less than 0.025 and P less than 0.005, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)     

Directed HIV-1 evolution of protease inhibitor resistance by second-generation short hairpin RNAs

Despite the success of antiretroviral drugs in decreasing AIDS-related mortality, a substantial fraction of HIV-infected patients experience therapy failure due to the emergence of drug-resistant virus variants. For durable inhibition of HIV-1 replication, the emergence of such escape viruses must be controlled. In addition to antiretroviral drugs, RNA interference (RNAi)-based gene therapy can be used to inhibit HIV-1 replication by targeting the viral RNA genome. RNAi is an evolutionary conserved gene silencing mechanism that mediates the sequence-specific breakdown of the targeted mRNA. Here we investigated an alternative strategy combining the activity of a protease inhibitor (PI) with second-generation short hairpin RNAs (shRNAs) designed to specifically block the emergence of PI-resistant HIV-1 variants. We demonstrate that dominant viral escape routes can be effectively blocked by second-generation shRNAs and that virus evolution can be redirected toward less-fit variants. These results are of importance for a deeper understanding of HIV-1 evolution under combined drug and RNAi pressure and may be used to design future therapeutic approaches.     

Primary somatomedin deficiency: Case report*

A child presenting with the clinical features of hyposomatotropism but with high immunoreactive plasma growth hormone is described. During short-term administration of human growth hormone (HGH) his response with regard to fasting blood-glucose and free fatty acids, plasma-somatomedin, urinary excretion of calcium, nitrogen, and hydroxyproline was minimal or absent. 6 months of treatment with HGH did not reduce the endogenous HGH secretion. Insulin secretion had not increased and plasma somatomedin levels remained extremely low. Over a period of 2 years of treatment, growth response and loss of subcutaneous fat were minimal. On serial dilution in radioimmunoassay, his growth hormone (GH) molecule yielded a parallel line with the HGH standard. In electrofocusing experiments the GH molecule was in the same pH range as growth hormone in acromegalic plasma and the major peak of clinical grade HGH (5·03 against 5·01 and 4·98).It is concluded that an overall and specific diminished responsiveness to HGH is present in this patient. This includes a lack of generation of somatomedin, which is thought to be the cause of his short stature. There was no evidence of abnormality of the GH molecule.     

Thyroid function in healthy normal,low birthweight and preterm infants

To delineate more precisely the role of gestational age, weight at birth and thyroid status at birth on the postnatal changes in thyroid hormone levels, serum T₄, T₃, TSH and in some cases FT3I were measured at birth and at 3–4 h, 24–30 h, 6–9 days and 13–20 days.Subjects studied were healthy appropriate-for-date (AFD) and small-for-date (SFD) term neonates and healthy AFD and SFD preterm children. At birth T₄ and T₃ are related to both gestational age and weight with T₄ and T₃ showing lower values in preterm and SFD term neonates than in AFD term children. After birth T₄ and T₃ concentrations show a better correlation with gestational age than with weight at birth.For TSH no correlation was found at birth, a positive correlation at 24–30 h, no correlation at 6–9 days and a negative correlation at 13–20 days both with gestational age and weight at birth. In term and close-to-term infants (36 weeks) individual T₄ levels at 6–7 days show a colse relationship with those at birth; in the younger children (34 and 35 weeks) lower T₄ values are found, despite equal cord blood values. The individual cord blood FT3I/TSH values correlate well with those at 6–7 days of age.It is concluded that after birth all children have changing T₄ and T₃ values, but the pattern and level are influenced by the maturity of the child and its thyroid status at birth measured by T₄ and by the FT3I/TSH ratio. Weight at birth influences T₄ at birth, but during the 1st week the weight of the child influences the T₄ and T₃ levels in only a minor way.Abbreviations AFD appropriate for date - SFD small for date - CHT congenital hypothyroidism     

Dissociation between changes in immunoreactive parathormone and its biological indices induced by cimetidine in primary hyperparathyroidism

In three out of four patients with primary hyperparathyroidism, 2 000 mg of cimetidine daily caused a reduction of immunoreactive parathormone (iPTH) when measured at 8.30 and 11.30 on days 16 and 17 on treatment. Serum Ca, PO4 and maximal tubular reabsorption of PO4 remained unchanged. Excretion of cAMP/100 ml GFR remained elevated to at least the same extent as before treatment. Two patients, in whom cimetidine treatment was continued for an additional 4 weeks, did not show further hormonal or biochemical changes compared with the evaluation on days 16 and 17. We conclude that reduction of iPTH is not accompanied by any change in biological activity of this hormone. The reason for this discrepancy remains unclear.     

The effect of age on the renal response to PTH infusion

Summary The renal responses to PTH infusion were compared in two age groups of healthy subjects. Basal nephrogenous cyclic AMP (NcAMP) was higher (1.68±0.74 vs. 0.97±0.50 nmol/dl GF;P<0.05) and TmPO₄/GFR was lower (0.93±0.21 vs. 1.16±0.14 mmol/liter;P<0.025) in 10 elderly subjects compared with 12 young adults. Creatinine clearance was decreased in the elderly (84.8±25.7 vs. 144.7±43.2 ml/min;P<0.005) and serum iPTH tended to be increased (0.15±0.11 vs. 0.11±0.03 pmol/liter). Following the infusion of 3 IU bPTH/kg bodyweight, no significant differences in ΔNcAMP and ΔTmPO₄/GFR were seen between the groups. When responses were expressed as percentual change of basal level, elderly subjects showed a % NcAMP of 1831±1200 which was comparable with 2038±1503% in young adults. However, the percentual change in TmPO₄/GFR was significantly higher in elderly persons (24.2±11.9 vs. 11.9±8.0%;P<0.01). In young subjects, virtually absent TmPO₄/GFR responses were found in 3 cases with a relatively low basal TmPO₄/GFR (between 0.92 and 0.98 mmol/liter), but these cases showed normal increases in NcAMP. Elderly subjects retained a considerable ΔTmPO₄/GFR notwithstanding a basal TmPO₄/GFR below 0.92 in seven out of 10 cases. These results confirm the existence of a slight increase in parathyroid activity in the elderly. In addition, they suggest an augmented sensitivity of the renal tubule concerning PO₄ reabsorption in elderly subjects. It is speculated that this phenomenon is related to the fall in bone mineral retention in senescence and might reflect a defense mechanism against phosphate overload.     

Extrapancreatic insulin effect of glibenclamide

Summary In eight patients with uncomplicated non insulin dependent diabetes mellitus, serum insulin levels, serum C-peptide levels and blood glucose levels were measured before and after oral administration of glibenclamide 0.1 mg/kg body weight and a test meal, or after a test meal alone.The rise in serum insulin levels persisted longer after glibenclamide. The initial rise in serum insulin was of the same magnitude in both situations, as was the rise in serum C-peptide levels during the entire 5 h study.It is concluded that glibenclamide is able to maintain a more protonged increase in serum insulin levels by inhibiting the degradation of insulin in the vascular endothelial cells of the liver. The inhibition contributes to the blood glucose lowering effect of glibenclamide.