IMPROVEMENT OF ADULT HEIGHT PROGNOSIS IN PRECOCIOUS PUBERTY BY CYPROTERONE ACETATE

Three girls and one boy with idiopathic precocious puberty and one boy with operated suprasellar hamartoma and progressing precocious puberty were treated with Cyproterone acetate for periods ranging from 15 months to 4 years and 6 months. In all children, the signs of puberty were reduced. Height velocity, as related to bone age, was increased, as was the ratio of height age increment to bone age increment. An improvement of adult height prognosis in precocious puberty has been achieved by Cyproterone acetate.     

Relationship between depressed baroreflex function and exaggerated sympathetic response to exercise in patients with heart failure

The relationship between impaired baroreflex sensitivity (BS) and the degree of sympathetic activation during exercise in patients with heart failure (HF) has not been studied in detail. For this purpose, we studied BS and measured plasma norepinephrine (NE) at rest, and during and after treadmill exercise in 15 patients and 10 controls. HF patients showed lower BS in comparison to controls (3. 51 +/- 3.62 vs. 9.74 +/- 4.56 ms/mm Hg; p < 0.001), and higher levels of plasma NE at rest (449.3 +/- 147.1 vs. 261.1 +/- 82.48 pg/ml; p < 0.001) and during exercise (1,542 +/- 361.2 vs. 524.6 +/- 92.61 pg/ml; p < 0.001). BS was directly related to pVO2 (r = 0.62; p = 0.0008) and inversely related to NE at peak exercise and to the increase in NE during exercise (r = 0.59, p = 0.005, and r = 0.53; p = 0.0058). Thus, during exercise, a marked sympathetic activation exists in patients with moderate HF. The relationship between increased plasma NE during exercise and decreased BS suggests that impaired baroreceptor function may be present in sympathetic activation in HF patients.     

Impaired angiotensin II-extracellular signal-regulated kinase signaling in failing human ventricular myocytes

Angiotensin II was reported to induce insulin-like growth factor-I and endothelin-1 gene expression and peptide release by ventricular cardiomyocytes. However, the progression from cardiac hypertrophy to failure in humans is characterized by a reduced myocyte expression of insulin-like growth factor-I and endothelin-1, notwithstanding the enhanced cardiac generation of angiotensin II. In the present study we investigated the functional status of the signaling pathways responsible for angiotensin II-induced endothelin-1 and insulin-like growth factor-I formation in human ventricular myocytes isolated from patients with dilated (n = 19) or ischemic (n = 14) cardiomyopathy and nonfailing donor hearts (n = 6).In human nonfailing ventricular myocytes, angiotensin II (100 nmol/l) induced insulin-like growth factor-I and endothelin-1 gene expression, and peptide release was mediated by extracellular signal-regulated kinase activation and inhibited by extracellular signal-regulated kinase antagonism (PD98059, 30 micromol/l), endothelin-1 formation being partially reduced also by c-Jun N-terminal kinase inhibition (SP600125, 10 micromol/l); insulin-like growth factor-I and endothelin-1 formations were unaffected by the inhibition of p38 mitogen-activated protein kinase (SB203580, 10 micromol/l) and Janus tyrosine kinase 2 (AG490, 10 micromol/l). In failing myocytes, angiotensin II failed to induce insulin-like growth factor-I and endothelin-1 formation; angiotensin II-induced extracellular signal-regulated kinase activation was significantly impaired (-88% vs. controls) although c-Jun NH2-terminal kinase activation was preserved. The impaired extracellular signal-regulated kinase phosphorylation in failing myocytes was associated with increased myocyte levels of mitogen-activated protein kinase phosphatases.Therefore, the altered growth factor production in failing myocytes is associated with a significant derangement in intracellular signaling.     

Pentoxifylline treatment in patients with occlusive peripheral arterial disease. Circulatory changes and effects on prostaglandin synthesis

Pentoxifylline has recently been reported to stimulate in vitro the synthesis of prostacyclin. However it is not known so far whether the drug is able to stimulate prostacyclin synthesis in man also in vivo. In the present study the effects of pentoxifylline on prostaglandin synthesis and several circulatory parameters were studied in 10 controls and 10 patients with occlusive arterial disease after acute i.v. and medium term oral treatment. Prostacyclin (as 6-keto-PGF1 alpha) and PGE2 plasma concentrations have been measured together with arterial blood flow, peripheral vascular resistance, platelet aggregation and red blood cell deformability. Pentoxifylline was found both in healthy subjects and patients to significantly increase prostacyclin plasma concentration after i.v. treatment. In medium term oral treatment prostacyclin concentration was found to increase only two hours after administration and not 8 hours after. No significant variations in PGE2 plasma concentration were found at any time in both groups. Pentoxifylline significantly enhanced resting and post-ischemic blood flow of the lower limbs and simultaneously decreased peripheral vascular resistance both in healthy subjects and patients. Different grades of delayed platelet aggregation and increased red blood cell deformability were also observed. In conclusion results of the present placebo controlled study show that pentoxifylline increases arterial blood flow in patients with occlusive arterial disease. Moreover pentoxifylline induces a temporary stimulation of prostacyclin synthesis which can be suggested to contribute to the clinical activity of the drug as far as an antithrombotic effect in terms of inhibition of platelet aggregation is concerned.     

Clinical evaluation of the QuietTrak blood pressure recorder according to the protocol of the British Hypertension Society

METHODS: The QuietTrak ambulatory blood pressure recorder (Tycos-Welch-Allyn, Arden, North Carolina, USA) was evaluated according to the protocol of the British Hypertension Society (BHS). QuietTrak, a lightweight (355 g), automatic, programmable device, uses an auscultatory measuring system. The protocol of the BHS was composed of subsequent phases with QuietTrak and two observers taking simultaneous measurements on the same arm. RESULTS: No interdevice differences were observed at analysis of variance test either before or after a 1-month period of routine clinical use. The average difference between mercury sphygmomanometer and QuietTrak for systolic and diastolic blood pressures was -0.6+/-3.6 and -0.4+/- 3.6 mmHg before and -0.7+/- 3.3 mmHg and 0.6+/- 3.8 mmHg after the 1-month use. At the main static device validation procedure, performed in 85 subjects, the average difference between observers and QuietTrak was -0.3+/- 3.4 and 0.1+/- 3.5 mmHg for systolic and diastolic blood pressures. Eighty-nine per cent and 99% of systolic and 88% and 98% of diastolic QuietTrak readings were within 5 and 10 mmHg of obsevers, determinations (Class A). In children (n = 33) 87% of systolic and 90% of diastolic QuietTrak readings differed by less than 5 mmHg from the observers' readings (average difference -1.1+/-3.9 and 0.1+/- 3.6 mmHg, respectively). In the elderly (n = 30), 95% and 92% of systolic and diastolic readings were within 5 mmHg of mercury column determinations (average difference -0.8+/-3.2 and -0.2+/-4.5 mmHg). In pregnancy (n = 30), 93% of systolic and 100% of diastolic readings were within 5 mmHg of mercury column determination (average difference -0.3+/-3.4 and 0.1+/- 2.9 mmHg). Device reliability was not affected by posture. Ninety-six per cent and 89% of systolic and diastolic readings differed by less than 5 mmHg from the mercury column determinations in the supine position, 90% and 90% in the standing position, and 88% and 90% in the sitting position. During the treadmill exercise (Bruce protocol), 69% and 88% of systolic and 56% and 83% of diastolic QuietTrak readings differed by less than 5 and 10 mmHg from the observers' measurements. CONCLUSION: The QuietTrak achieved A rating for systolic blood pressure and A rating for diastolic blood pressure according to the criteria of the BHS protocol. The device was acceptable to patients because of its small size, light weight and noiseless performance.     

Erythroid burst-promoting activity of purified recombinant human GM-CSF and interleukin-3: studies with anti-GM-CSF and anti-IL-3 sera and studies in serum-free cultures

We studied the erythroid burst-promoting activity (BPA) of recombinant human granulocyte/macrophage colony-stimulating factor (GM-CSF) and Interleukin-3 (IL-3) with two experimental approaches. First we studied the effects of polyclonal antisera prepared against human GM-CSF and gibbon IL-3 on colony formation from 1,000 bone marrow null cells/dish in serum-containing culture. Both GM-CSF and IL-3 independently enhanced erythroid burst formation; however, IL-3 showed more BPA activity than GM-CSF. These data are in agreement with an emerging view that the primary targets of IL-3 are primitive progenitors and that the targets of GM-CSF are intermediate progenitors, including erythroid burst-forming units (BFU-E). The proliferation of one population of BFU- E was independent of GM-CSF or IL-3. To characterize this population of BFU-E further, we developed a serum-free culture assay for the purified progenitors by incorporating insulin-like growth factor-1 (IGF-1) to the serum-free medium. The development of erythroid bursts was supported by IL-3, IGF-1, and erythropoietin (Ep) in a serum-free culture system and to a lesser extent by the combination of GM-CSF, IGF- 1, and Ep. Although the burst-promoting ability of GM-CSF and IL-3 was again demonstrated in this system, unlike serum-containing culture Ep alone did not support burst formation. These results indicate that when fetal calf serum (FCS) is present, the culture system contains BPA that is not GM-CSF or IL-3.     

Synergistic factors for stem cell proliferation: further studies of the target stem cells and the mechanism of stimulation by interleukin-1, interleukin-6, and granulocyte colony-stimulating factor

Serial observations of blast cell colony development from spleen cells of mice treated with 5-fluorouracil (5-FU) four days earlier revealed that either form of human interleukin-1 (IL-1 alpha or IL-1 beta) hastens the emergence of interleukin-3 (IL-3)-dependent blast cell colonies. This activity was essentially indistinguishable from the effect of interleukin-6 (IL-6) or granulocyte colony-stimulating factor (G-CSF) in the same system, an effect that we have ascribed previously to a shortening of the G0 period of the dormant stem cells. We also analyzed the time courses of colony formation from cultures of day-2 post-5-FU marrow cells supported by IL-1 alpha, IL-6, or G-CSF alone or in combination with IL-3. In the presence of IL-3, G-CSF and IL-6 but not IL-1 alpha hastened the development of colonies and increased the numbers of multilineage colonies relative to cultures of IL-3 alone. This observation, together with our previous data from the human system, suggests that the synergistic effect of IL-1 is likely due to induction of secondary growth factors, including IL-6 and G-CSF, by accessory cells in culture. The effect of IL-6 on G0 was confirmed by analysis of the cycling status of progenitor cells in short-term culture. While neither IL-3 nor IL-6 alone had any effect on the cycling status, the combination of factors resulted in a rapid recruitment of quiescent cells into cell cycle (within 48 hours) as represented by a twofold increase in the numbers of multipotential progenitors and a significant increase in the sensitivity of these cells to 3H-thymidine with high specific activity. Combinational testing of all of these synergistic factors revealed that the target cell populations for the IL-1, IL-6, and G-CSF overlap considerably, suggesting that they all may act through a common mechanism. This is further supported by our finding that cells from blast cell colonies grown in the presence of a combination of any one of the synergistic factors with IL-3 replate with higher efficiency and yield more multilineage secondary colonies than those from colonies grown in IL-3 alone. These findings provide further evidence that IL-1, IL-6, and G- CSF serve to integrate the immediate host responses to infection through augmentation of effector cells and antibody production as well as the longer term host responses by recruitment of dormant hemopoietic stem cells into active cell cycling.     

Biologic properties in vitro of a recombinant human granulocyte- macrophage colony-stimulating factor

Recombinant human granulocyte-macrophage colony-stimulating factor (rH GM-CSF) was purified to homogeneity from medium conditioned by COS cells transfected with a cloned human GM-CSF cDNA and shown to be an effective proliferative stimulus in human marrow cultures for GM and eosinophil colony formation. The specific activity of purified rH GM- CSF in human marrow cultures was calculated to be at least 4 X 10(7) U/mg protein. Clone transfer experiments showed that this proliferation was due to direct stimulation of responding clonogenic cells. Acting alone, rH GM-CSF did not stimulate erythroid colony formation, but in combination with erythropoietin, increased erythroid and multipotential colony formation in cultures of peripheral blood cells. rH GM-CSF had no proliferative effects on adult or fetal murine hematopoietic cells, did not induce differentiation in murine myelomonocytic WEHI-3B cells, and was unable to stimulate the survival or proliferation of murine hematopoietic cell lines dependent on murine multi-CSF (IL 3). rH GM- CSF stimulated antibody-dependent cytolysis of tumor cells by both mature human neutrophils and eosinophils and increased eosinophil autofluorescence and phagocytosis by neutrophils. From a comparison of these effects with those of semipurified preparations of human CSF alpha and -beta, it was concluded that rH GM-CSF exhibited all the biologic activities previously noted for CSF alpha.