Hormonal alterations in experimental diabetes: Role of a primary disturbance in calcium homeostasis

Summary Chronic diabetes mellitus in the rat is attended by a reduced bone turnover and growth arrest, decreased circulating immunoreactive parathyroid hormone (iPTH), and hypercorticosteronism. Since chronic insulin deficiency in the rat is associated with intestinal hyperabsorption of calcium and a positive calcium balance that may account for the decreased iPTH, as well as other hormonal alterations observed in these animals, we studied the effect of long-term (5 week) dietary calcium restriction (0.1% Ca, 0.8% P) in control and streptozotocin-induced diabetic rats. Chronic diabetic rats reared on a normal calcium (1.2% Ca) diet had increased serum calcium and phosphate (Pi) concentrations and were markedly hypercalciuric and phosphaturic compared with controls. Serum corticosterone was increased and iPTH markedly decreased in the diabetic animals. Dietary Ca restriction (0.1% Ca) decreased urinary calcium excretion and resulted in a comparable phosphaturic response in both control and diabetic rats. Moreover, although Ca restriction in diabetic animals had no appreciable effect on serum insulin, serum glucose, or urinary glucose excretion, it was associated with a marked increase in circulating iPTH; this resulted in serum concentrations comparable with that observed in control animals reared on the low Ca diet. These results support the hypothesis that the decreased circulating iPTH observed in chronic diabetic rats results predominantly from their intestinal hyperabsorption of Ca. In contrast to control animals, diabetic rats reared on a low Ca diet failed to maintain their serum Ca despite the marked increase in serum iPTH and striking decrease in calciuria, thus underscoring the reliance of these animals on intestinal hyperabsorption of Ca to maintain Ca balance under conditions of adequate Ca intake. Serum corticosterone was insignificantly altered by dietary Ca restriction in control rats; hypercorticosteronism, characteristically observed in diabetic rats, was normalized by Ca restriction. We conclude that a primary disturbance in Ca homeostasis may contribute, in part, to hormonal alterations observed in chronic experimental diabetes.     

Granulocyte Fc-IgG and C3b receptor expression in the primary myelodysplastic syndromes (MDS): relationship with dysgranulopoiesis and evidence for heterogeneity of morphological subgroups.

The expression of Fc-IgG and C3b membrane receptors by granulocytes and their precursors was examined in 78 patients with primary myeloid dysplasia (MDS). The marrows were categorized into five morphological groups, broadly corresponding to those described by the FAB group, and further graded into mild and severe according to the severity of dysgranulopoiesis. Fractionated bone marrow and peripheral blood granulocyte receptors were assessed by rosette formation with optimally sensitized ox erythrocytes and the results compared with those found in 17 normal marrows and with those previously reported in megaloblastic anaemia. Fc-IgG and C3b receptor expression was generally increased in maturing granulocytes in all MDS diagnostic groups but premature expression was particularly marked in chronic myelomonocytic leukaemia and refractory cytopenia. Receptor patterns showed a better correlation with the severity of dysgranulopoiesis than with the morphological types. It is suggested that, as in megaloblastic anaemia, changes in membrane receptor expression reflect nuclear-cytoplasmic asynchrony. The results further indicate considerable immunological heterogeneity of granulocytes within individual MDS categories.     

Effects of 5,6-dimethylxanthenone-4-acetic acid on human tumor microcirculation assessed by dynamic contrast-enhanced magnetic resonance imaging.

PURPOSE: 5,6-Dimethylxanthenone-4-acetic acid (DMXAA) causes vascular shutdown in preclinical models. Dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) studies were performed in the phase I trials to examine changes related to blood flow and permeability in tumor and muscle. PATIENTS AND METHODS: Sixteen patients treated with DMXAA from 500 to 4,900 mg/m(2) had DCE-MRI examinations before and after treatment. The maximum gradient, the maximum enhancement, and the area under the signal-intensity-time curve (AUC) over the first 90 seconds were calculated for each pixel in regions of interest (ROIs) in muscle and tumor, and the median value for each ROI was obtained. Changes after treatment were compared with 95% limits of agreement for an individual and for groups using data from our reproducibility study. RESULTS: Nine of 16 patients had significant reductions in AUC 24 hours after the first dose of DMXAA, and eight of 11 patients had reductions of up to 66% in AUC 24 hours after the last dose. Mean reductions in gradient, enhancement, and AUC were 25%, 18%, and 31%, respectively, 24 hours after the last dose, significantly greater than the 95% limits of change for a group of 11 patients. Enhancement and AUC in muscle 24 hours after the first dose were significantly reduced, but no significant changes were seen 24 hours after the last dose. CONCLUSION: DMXAA significantly reduces DCE-MRI parameters related to tumor blood flow, over a wide dose range, consistent with the reported tumor vascular targeting activity. Further clinical evaluation of DMXAA is warranted.     

Chronic Lymphatic Leukaemia: Correlation of Immunofluorescent Characteristics and Clinical Features

60 patients with chronic lymphatic leukaemia (CLL) were classified according to the immunofluorescent characteristics of their lymphocytes. A group expressing surface membrane (Sm) IgM had a significantly less aggressive disease than those expressing a mixture of SmIgM and SmIgD or those without surface immunoglobulin. The patients were older than in most comparable series and had a 2:I preponderance of women. It is suggested that especially among old ladies there is a benign variety of CLL which expresses SmIgMK, and that determination of the SmIg class in CLL has prognostic value.     

Immunoglobulin expression and synthesis by human haemic cell lines

Twenty-six human cell lines derived from a variety of lymphoid and non-lymphoid malignancies, were investigated for their immunological markers, with special reference to the class of immunoglobulin expressed. Twenty-five of the lines stained positively for surface immunoglobulin and IgD together with IgM proved to be the major immunoglobulin classes on these cells. Six of the lines were chosen for a study of their immunoglobulin synthesis patterns over an 18-h period and the immunoglobulin produced was analysed on SDS-polyacrylamide gel electrophoresis. Patterns obtained from the cell lines were similar to that from normal lymph node lymphocytes and differed markedly to plasma cells. Two of the cell lines had abnormal immunoglobulin synthesis patterns characterized as free light chains in one case. The cell lines are evaluated for their usefulness as models of immunoglobulin synthesis and analogues of normal and neoplastic states.     

Selectivity of 4-methylhistamine at H1- and H2-receptors in the guinea-pig isolated ileum

The selectivity of 4-methylhistamine (4-MH) as an agonist at histamine H1- and H2-receptors has been evaluated in the guinea-pig isolated ileum. The EC50 values of 4-MH on H1- and H2-receptors that mediate contractile responses were determined. The EC50 at H1-receptors was estimated after selective blockade of H2-receptors by tiotidine and the EC50 at H2-receptors estimated after selective blockade of H1-receptors by mepyramine. The -log EC50 values at H1- and at H2-receptors were 4.57 and 5.23, respectively. The dissociation constants for the interaction of 4-MH with H1- and H2-receptors were determined. The -log KD values at H1- and H2-receptors were 3.55 and 4.27, respectively. These results suggest that 4-MH is only about 5 times as potent at H2- as it is at H1-receptors in the guinea-pig ileum and that 4-MH should be used with caution to discriminate between H1- and H2-receptors.