Bone-resorbing activity of thyroid hormones is related to prostaglandin production in cultured neonatal mouse calvaria

The bone-resorbing activity of thyroid hormones was evaluated in neonatal mouse calvaria maintained in organ culture for 96 h. Thyroxine (T4) between 10(-8) and 10(-5) mol/liter and triiodothyronine (T3) between 10(-8) and 10(-7) mol/liter caused a dose-dependent release of calcium from cultured bone. The thyroid hormone effect was delayed in onset for at least 24 h, and after 96 h of culture amounted to 50-90% of the bone-resorbing activity of 10(-8) mol/liter parathyroid hormone (PTH). The bone-resorbing action of T4 as well as of T3 was completely blocked by 100 U/ml interferon-gamma (IF-gamma) or 20 mU/ml salmon calcitonin (CT). "Escape" from CT inhibition, which is a well-known phenomenon in the action of PTH, was not observed with thyroid hormone-mediated bone resorption. Thyroid hormone treatment of cultured calvaria resulted in a gradual increase between 48 and 96 h of medium concentrations of prostaglandin (PG) E2 and particularly of 6-keto-PGF1 alpha, the inactive metabolite of prostacyclin (PGI2). The release of PGF2 alpha in general was not significantly affected. Although the effect of thyroid hormones on PG release from cultured calvaria was completely abolished by 5 x 10(-7) mol/liter indomethacin, in some experiments indomethacin reduced thyroid hormone-mediated bone resorption by only 50%. This indicates that thyroid hormone action on bone is also mediated by a PG-independent mechanism.     

Further characterization of the discriminative stimulus effects of buspirone using monoamine agonists and antagonists in the pigeon

White Carneau pigeons were trained to discriminate 1.0 mg/kg buspirone from saline when key pecking was maintained under a fixed-ratio 30 schedule of food presentation. Buspirone (0.3-10.0 mg/kg), the serotonin 1A (5-HT(1A)) agonist 8-OH-DPAT (0.1-1mg/kg), the buspirone analog BMY 7378 (3.0-5.6mg/kg), the mixed 5-HT(1A/1B) agonist RU 24969 (3.0-10.0mg/kg) and the 5-HT(1A) agonist spiroxatrine (0.1-1.0mg/kg) occasioned at least 80% buspirone-appropriate responding in all subjects tested. Administration of the 5-HT(1B) agonist (TFMPP 0.1-10.0mg/kg) or the 5-HT(3) antagonist (MDL 72222 (3.0-17.0mg/kg) resulted in primarily saline-key responding. The dopamine receptor antagonist chlorpromazine (1.0-17.0mg/kg), the specific D-2 receptor antagonist eticlopride (0.03-0.56mg/kg), the noradrenergic alpha-2 antagonist yohimbine (0.1-1.0mg/kg), the alpha-2 agonist clonidine (0.003-0.10mg/kg) and (+/-) and (-) propranolol (3.0-30.0mg/kg) all produced primarily saline-appropriate responding. Coadministration of the beta-adrenergic agonist isoproterenol (1.0-5.6mg/kg) or the 5-HT(1A) partial agonist BMY 7378 (0.01-10.0mg/kg) with 1.0mg/kg buspirone did not block the discriminative stimulus effects of buspirone. However, 3.0-10.0mg/kg BMY 7378, in combination with a lower dose of buspirone (0.3mg/kg) decreased drug-key responding to approximately 50%. Results from the present study suggest that (1) the discriminative stimulus effects of buspirone, 8-OH-DPAT, BMY 7378, RU 24969 and spiroxatrine are mediated through the 5-HT(1A) receptor; (2) buspirone's discriminative stimulus effects do not interact with the noradrenergic or dopaminergic system; and 3) under this procedure BMY 7378 was a partial agonist at 5-HT(1A) receptors.     

Socioeconomic position and cardiovascular and neuroendocrine responses following cognitive challenge in old age

Social disparities in health persist into old age, and differences in psychophysiological responsivity may contribute to this pattern. We assessed whether higher socioeconomic status (SES) is associated with attenuated cardiovascular and neuroendocrine responses elicited by cognitive tasks in old age. We tested 132 community-dwelling men and women aged 65-80 years, divided on the basis of educational attainment into higher and lower SES groups, and compared them with 26 higher educated participants aged 27-42 years. Blood pressure, hemodynamic variables and salivary cortisol were assessed in response to the performance of three cognitive tasks, and then during recovery. Older groups showed smaller heart rate and larger cortisol changes than younger participants. Post-task recovery in heart rate, stroke volume, pre-ejection period, and systolic blood pressure was greatest in the younger group, least in the older/lower education group, and intermediate in the older/higher education group. SES did not influence the increased cortisol responsivity of older participants. The results are consistent with the notion that higher SES protects against age-related changes in cardiovascular response profiles, particularly during recovery.     

Investigations on the biology,epidemiology, pathology and control of<Emphasis Type="Italic"> Tunga penetrans</Emphasis> in Brazil: I. Natural history of tungiasis in man

Tungiasis is an important health problem in poor communities in Brazil and is associated with severe morbidity, particularly in children. The causative agent, the female flea Tunga penetrans, burrows into the skin of its host, where it develops, produces eggs and eventually dies. From the beginning of the penetration to the elimination of the carcass of the ectoparasite by skin repair mechanisms, the whole process takes 4-6 weeks. The present study is based on specimens from 86 patients, for some of whom the exact time of penetration was known. Lesions were photographed, described in detail and biopsied. Biopsies were examined histologically and by means of scanning electron microscopy (SEM). Based on clinical, SEM and histological findings, the "Fortaleza classification" was elaborated. This allows the natural history of tungiasis to be divided into five stages: (1) the penetration phase, (2) the phase of beginning hypertrophy, (3) the white halo phase, (4) the involution phase and (5) residues in the host's skin. Based on morphological and functional criteria, stages 3 and 4 are divided into further substages. The proposed Fortaleza classification can be used for clinical and epidemiological purposes. It allows a more precise diagnosis, enables the assessment of chemotherapeutic approaches and helps to evaluate control measures at the community level.     

Gap-junctional coupling between neutrophils and endothelial cells: a novel modulator of transendothelial migration

Communication between leukocytes and endothelial cells is crucial for inflammatory reactions. Paracrine cross-talk and outside-in signaling (via adhesion molecules) have been characterized as communication pathways to date. As leukocytes and endothelial cells express connexins, we considered intercellular communication via gap junctions an intriguing additional concept. We found that gap-junctional coupling between neutrophils and endothelium occurred in a time-dependent, bidirectional manner and was facilitated by adhesion. After blockade of connexins, transmigration of neutrophils through the endothelial layer was enhanced, and the barrier function of cell monolayers was reduced during transmigration. Tumor necrosis factor alpha decreased coupling. In the presence of connexins, transmigration of neutrophils did not alter permeability. Thus, neutrophils couple to endothelium via gap junctions, functionally modulating transmigration and leakiness. Gap-junctional coupling may be a novel way of leukocyte-endothelial communication.     

Treatment of motoneuron degeneration by intracerebroventricular delivery of VEGF in a rat model of ALS

Neurotrophin treatment has so far failed to prolong the survival of individuals affected with amyotrophic lateral sclerosis (ALS), an incurable motoneuron degenerative disorder. Here we show that intracerebroventricular (i.c.v.) delivery of recombinant vascular endothelial growth factor (Vegf) in a SOD1(G93A) rat model of ALS delays onset of paralysis by 17 d, improves motor performance and prolongs survival by 22 d, representing the largest effects in animal models of ALS achieved by protein delivery. By protecting cervical motoneurons, i.c.v. delivery of Vegf is particularly effective in rats with the most severe form of ALS with forelimb onset. Vegf has direct neuroprotective effects on motoneurons in vivo, because neuronal expression of a transgene expressing the Vegf receptor prolongs the survival of SOD1(G93A) mice. On i.c.v. delivery, Vegf is anterogradely transported and preserves neuromuscular junctions in SOD1(G93A) rats. Our findings in preclinical rodent models of ALS may have implications for treatment of neurodegenerative disease in general.     

Non-heparan sulfate-binding interactions of endostatin/collagen XVIII in murine development.

Knobloch syndrome is characterized by a congenital generalized eye disease and cranial defect. Pathogenic mutations preferentially lead to a deletion or functional alteration of collagen XVIII's most C-terminal endostatin domain. Endostatin can be released from collagen XVIII and is a potent inhibitor of angiogenesis and tumor growth. We show differential expression of binding partners for endostatin, vascular endothelial growth factor (VEGF), and the collagen XV endostatin homologue in murine embryonal development using a set of alkaline phosphatase fusion proteins. Consistent with the human phenotype, vascular mesenchyme in the developing eye was identified as endostatin's primary target. While endostatin predominantly bound to blood vessels, the VEGF164 affinity probe labeled nonvascular tissues such as forebrain, hindbrain, the optic nerve, and the surface ectoderm of the future cornea. Strikingly increased staining specificity was observed with a non-heparin/heparan sulfate-binding endostatin probe. In contrast, elimination of the heparan sulfate binding site from VEGF led to complete loss of binding. The collagen XV endostatin homologue showed a highly restricted binding pattern. Oligomerization with endogenous endostatin was ruled out by use of collagen XVIII knockout mice. Our data provide strong evidence that collagen XVIII's C-terminal endostatin domain harbors a prominent tissue-binding site and that binding can occur in the absence of heparan sulfates in situ.     

Treatment of idiopathic inflammatory myositis associated interstitial lung disease: A systematic review and meta-analysis

Objective

Interstitial lung disease (ILD) is the most severe complication of idiopathic inflammatory myositis (IIM), resulting in significant increase in morbidity and mortality and for which the best treatment remains controversial. We conducted a meta-analysis to evaluate the efficacy of therapies used for the management of IIM-related ILD.