The course of a case of Maffucci's syndrome

The syndrome of Maffucci is characterized by angioma association of the enchondromatose. It is a relatively rare syndrome. The lesions are evolutived. The treatment is surgical. His pronostic is marqued by high percentage of malign degenerescence.     

Pharmacological evidence for stimulation of growth hormone secretion by a central noradrenergic system in dogs

The role of brain catecholamines in the regulation of growth hormone secretion was investigated in pentobarbital-anesthetized dogs by using drugs which modify the function of adrenergic neurons and receptors. Intravenous administration of L-dopa produced a prompt, statistically significant increase in plasma growth hormone concentration. This response was not significantly reduced by blockade of peripheral dopa decarboxylase activity with carbidopa. Clonidine, an alpha-agonist which penetrates the brain, increased plasma growth hormone secretion. Norepinephrine, epinephrine, dopamine and isoproterenol, catecholamines which do not penetrate the blood-brain barrier, failed to affect plasma growth hormone concentration when administered intravenously. Apomorphine did not produce a statistically significant increase in plasma growth hormone concentration when administered directly into the the third ventricle, and pimozide failed to abolish the increase in plasma growth hormone produced by L-dopa. The increase in plasma growth hormone concentration produced by intravenous L-dopa and clonidine was prevented by administration of phentolamine or phenoxybenzamine directly into the third ventricle. The response to L-dopa was also abolished by intraventricular procaine. In dogs in which central beta-adrenergic blockade was produced by intraventricular L-propranolol, the growth hormone response to L-dopa was greater than it was in control dogs treated with intraventricular D-propranolol. The data indicate that in pentobarbital anesthetized dogs, the increase in growth hormone secretion produced by L-dopa is mediated by norepinephrine, rather than dopamine, that the site of action of the norepinephrine is central, above the median eminence and inside the 'blood-brain barrier', and that the norepinephrine acts via alpha-adrenergic receptors.     

Differences in resource use and costs of primary care in a large HMO according to physician specialty.

OBJECTIVE: To determine if primary care physician specialty is associated with differences in use of health services. DATA SOURCES: Automated outpatient diagnostic, utilization, and cost data on 15,223 members (35-85 years of age) of a large group model HMO. STUDY DESIGN: One-year prospective comparison of primary care provided by 245 general internists (GIMs), 60 family physicians (FPs), and 55 subspecialty internists (SIMs) with case-mix assessed during a nine-month baseline period using Ambulatory Diagnostic Groups. PRINCIPAL FINDINGS: Adjusting for demographics and case mix, patients of GIMs and FPs had similar hospitalization and ambulatory visit rates, and similar laboratory and radiology costs. Patients of FPs made fewer visits to dermatology, psychiatry, and gynecology (combined visit rate ratio: 0.86, 95% CI: 0.74-0.96). However, they made more urgent care visits (rate ratio 1.19, 95% CI: 1.07-1.23). Patients of SIMs had higher hospitalization rates than those of GIMs (rate ratio 1.33, 95% CI: 1.06-1.68), greater use of urgent care (rate ratio: 1.14, 95% CI: 1.04-1.25), and higher costs for pharmacy (cost ratio: 1.17, 95% CI: 0.93-1.18) and radiologic services (cost ratio: 1.14, 95% CI: 1.01-1.30). The hospitalization difference was due partly to the inclusion of patients with specialty-related diagnoses in panels of SIMs. Radiology and pharmacy differences persisted after excluding these patients. CONCLUSIONS: In this uniform practice environment, specialty differences in primary care practice were small. Subspecialists used slightly more resources than generalists. The broader practice style of FPs may have created access problems for their patients.     

Hormone ontogeny in the ovine fetus. XXIII. Pulsatile administration of follicle-stimulating hormone stimulates inhibin production and decreases testosterone synthesis in the ovine fetal gonad

Inhibin, a gonadal glycoprotein with selective FSH-suppressing activity, is synthesized by the Sertoli cell of the testis and the granulosa cell of the ovary mediated by the action of FSH. It is not known whether inhibin is produced by the fetal testes and ovaries or if FSH has the capacity to stimulate inhibin production by the fetal gonad. To explore these questions, we examined the bioactive inhibin content of the gonads of 16 chronically catheterized sheep fetuses between 111 and 143 days gestational age (0.7-0.95 gestation) in an ovine pituitary bioassay. Both the fetal testes and ovary contained inhibin activity (testes, 53.5-1,240 U inhibin/g tissue; ovaries, 58.5-2,250 U/g). After pulsatile administration of oFSH (5 micrograms every 3 h) to the fetus for 5 days in 1 fetus and 10 days in 2 fetuses, 10-day gonadal inhibin content of fetal testes increased to 5,080 +/- 3,180 U/testes (n = 3) vs. 165 +/- 50 U/testes in controls (n = 8; P less than 0.02); the concentration of testicular inhibin in these features rose to a mean of 9,100 +/- 6,620 vs. 415 +/- 126 U/g tissue in controls (P less than 0.01). Ovarian inhibin content in female fetuses given ovine FSH for 10 days was 5,220 +/- 4,920 U/ovary (n = 4) compared to 40 +/- 16 U/ovary in controls (n = 4); the inhibin concentration was 41,000 +/- 30,000 U/g in ovaries of FSH-treated fetuses vs. 1,190 +/- 960 U/g in controls. The ovary of 1 female fetus contained several large follicles and the highest inhibin concentration. Unexpectedly, FSH administration was associated with a decrease in testosterone content in the fetal testes and ovaries. The testosterone content was 0.54 +/- 0.42 ng/ovary after FSH treatment (n = 4) vs. 2.11 +/- 0.68 ng/ovary in controls (n = 4; P less than 0.02). The testosterone concentration fell to 5.8 +/- 2.0 ng/g in treated female fetuses vs. 60.3 +/- 14.6 ng/g in controls (P less than 0.0005). The testosterone content in fetal testes decreased to 21.7 +/- 6.9 ng/testes in FSH-treated fetuses (n = 3) vs. 75.1 +/- 24.0 ng/testes in controls (n = 5; P less than 0.04); the testosterone concentration fell to 38.6 +/- 16.1 ng/g tissue compared to 223.0 +/- 88.7 ng/g in untreated controls (P less than 0.03). In male fetuses the concentration of plasma testosterone decreased to 15.5 +/- 2.3 ng/dl after FSH treatment, significantly lower than 39.6 +/- 4.5 ng/dl in controls (P less than 0.02).(ABSTRACT TRUNCATED AT 400 WORDS)     

Engagement of the CrkL adaptor in interferon alpha signalling in BCR-ABL-expressing cells

Interferon alpha (IFNalpha) has significant clinical activity in the treatment of patients with chronic myelogenous leukaemia (CML), but the mechanisms of its selective efficacy in the treatment of the disease are unknown. The CrkL adaptor protein interacts directly with the BCR-ABL fusion protein that causes the malignant transformation and is constitutively phosphorylated in BCR-ABL-expressing cells. In the present study, we provide evidence that CrkL was engaged in IFNalpha-signalling in the CML-derived KT-1 cell line, which expresses BCR-ABL and is sensitive to the growth inhibitory effects of IFNalpha. CrkL is constitutively associated with BCR-ABL in these cells and treatment with IFNalpha had no effect on the BCR-ABL/CrkL interaction. After IFNalpha stimulation, CrkL associated with Stat5, which also underwent phosphorylation in an IFNalpha-dependent manner. The interaction of CrkL with Stat5 was facilitated by the function of both the SH2 and the N-terminus SH3 domains of CrkL. The resulting CrkL-Stat5 complex translocated to the nucleus and could be detected in gel shift assays using elements derived from either the beta-casein promoter or the promoter of the PML gene, an IFNalpha-inducible gene that mediates growth inhibitory responses. In addition to its interaction with Stat5, CrkL interacts with C3G in KT-1 cells and such an interaction regulates the downstream activation of the small GTPase Rap1, which also mediates inhibition of cell proliferation. Thus, despite its engagement by BCR-ABL in CML-derived cells, CrkL mediates activation of downstream signalling pathways in response to the activated type I IFN receptor and such signals may contribute to the generation of the anti-proliferative effects of IFNalpha in CML.     

Synthetic human pancreas growth hormone-releasing factor (hpGRF1-44-NH2) stimulates growth hormone secretion in normal men

A synthetic replicate of human pancreas growth hormone-releasing factor, hpGRF1-44-NH2, (hpGRF44), a 44-amino acid amidated peptide, was administered to seven normal men. In addition to placebo, 4 subjects received 3 doses of hpGRF44 (0.5 microgram/kg, 5 micrograms/kg, 10 micrograms/kg), while one subject received 2 doses (5 micrograms/kg, 10 micrograms/kg) and 2 subjects received one dose (0.5 microgram/kg or 5 micrograms/kg), each as a rapid intravenous injection. A significant increase in circulating growth hormone (GH) was observed at each dose (0.5 microgram/kg, p = 0.05; 5 micrograms/kg, p less than 0.005; 10 micrograms/kg, p = 0.01) when compared to placebo, with equivalent maximal responses. At all doses studied a rise in plasma GH occurred within 5 min, with a peak response in most patients at 30-45 min. There were no associated changes in any of the other anterior pituitary hormones or insulin. Other than transient flushing and minimal changes in vital signs, no side effects were noted. The results of these studies support the potential usefulness of hpGRF44 for the assessment of GH secretion and reserve, and of this peptide or an analog as a therapeutic agent to stimulate GH release.     

Spatiotemporal restriction of endothelial cell calcium signaling is required during leukocyte transmigration

Endothelial cell calcium flux is critical for leukocyte transendothelial migration (TEM), which in turn is essential for the inflammatory response. Intravital microscopy of endothelial cell calcium dynamics reveals that calcium increases locally and transiently around the transmigration pore during TEM. Endothelial calmodulin (CaM), a key calcium signaling protein, interacts with the IQ domain of IQGAP1, which is localized to endothelial junctions and is required for TEM. In the presence of calcium, CaM binds endothelial calcium/calmodulin kinase IIδ (CaMKIIδ). Disrupting the function of CaM or CaMKII with small-molecule inhibitors, expression of a CaMKII inhibitory peptide, or expression of dominant negative CaMKIIδ significantly reduces TEM by interfering with the delivery of the lateral border recycling compartment (LBRC) to the site of TEM. Endothelial CaMKII is also required for TEM in vivo as shown in two independent mouse models. These findings highlight novel roles for endothelial CaM and CaMKIIδ in transducing the spatiotemporally restricted calcium signaling required for TEM.