IL-6 negatively regulates IL-11 production in vitro and in vivo.

IL-6 and IL-11 are two cytokines that increase osteoclast formation and augment bone resorption. PTH stimulates the production of both cytokines by human osteoblast-like cells. Circulating levels of IL-6 are elevated in patients with states of PTH excess and correlate strongly to markers of bone resorption. In contrast, serum levels of IL-11 were significantly reduced in patients with primary hyperparathyroidism compared with values in euparathyroid controls. Further, after successful parathyroid adenomectomy, circulating levels of IL-6 fell, whereas IL-11 levels increased. Five-day infusions of human PTH-(1--84) in rodents resulted in a significant decline in mean circulating levels of IL-11, whereas IL-6 levels significantly increased. Pretreatment of cells and mice with neutralizing serum to IL-6 enhanced PTH-induced IL-11 production compared with the effect of pretreatment with nonimmune sera. These data indicate that IL-6 negatively regulates IL-11 production in vivo and in vitro. Analysis of steady state mRNA levels in SaOS-2 cells indicated that this effect is posttranscriptional. As both IL-6 and IL-11 stimulate osteoclast formation, down-regulation of IL-11 by IL-6 may help modulate the resorptive response to PTH.

Pulmonary hypertension caused by Graves' thyrotoxicosis: normal pulmonary hemodynamics restored by (131)I treatment.

We describe a case of pulmonary hypertension, initially thought to be idiopathic, which resolved after treatment of Graves' hyperthyroidism. Results of pulmonary artery catheterization before and after treatment are reported, and the effects of thyrotoxicosis on hemodynamics and pulmonary function are briefly reviewed. Possible mechanisms for development of pulmonary hypertension caused by hyperthyroidism include pulmonary vascular endothelial dysfunction or damage because of autoimmunity or the high cardiac output state, or increased metabolism of intrinsic pulmonary vasodilators.

Papillary thyroid carcinoma metastatic to the pituitary gland.

Many malignancies may present with metastases to the pituitary gland. The association of thyroid carcinoma with pituitary metastases is, however, very rare. This report describes two patients in whom metastases from a papillary thyroid carcinoma to the pituitary gland resulted in panhypopituitarism with blunted endogenous thyrotropin (TSH) production following withdrawal of levothyroxine. Both required the use of recombinant human TSH prior to radioiodine therapy. Symptoms of hypopituitarism may be difficult to distinguish clinically from those of hypothyroidism in the setting of levothyroxine withdrawal. Clinicians should be aware of the clinical and biochemical manifestations of this rare association.

Primary cardiac lymphoma: initial symptoms suggestive of gastrointestinal disease.

We report a case of primary cardiac lymphoma in a patient who was not infected with human immunodeficiency virus and had symptoms suggestive of upper gastrointestinal (GI) disease. Examination revealed no GI abnormalities. Echocardiography, prompted by sudden development of congestive heart failure, revealed a large right atrial mass. Cardiac biopsy followed by staging evaluation indicated primary cardiac non-Hodgkin's lymphoma. After chemotherapy was begun, the tumor shrunk and GI symptoms resolved, suggesting an etiologic relationship by a referred pain mechanism. Unusual features of our case include the initial predominance of GI symptoms and the circumstances that led to diagnosis antemortem. The case also underscores the importance of considering intrathoracic disease in patients with upper abdominal symptomatology.

Parathyroid hormone-related protein is required for tooth eruption.

Parathyroid hormone (PTH)-related protein (PTHrP)-knockout mice die at birth with a chondrodystrophic phenotype characterized by premature chondrocyte differentiation and accelerated bone formation, whereas overexpression of PTHrP in the chondrocytes of transgenic mice produces a delay in chondrocyte maturation and endochondral ossification. Replacement of PTHrP expression in the chondrocytes of PTHrP-knockout mice using a procollagen II-driven transgene results in the correction of the lethal skeletal abnormalities and generates animals that are effectively PTHrP-null in all sites other than cartilage. These rescued PTHrP-knockout mice survive to at least 6 months of age but are small in stature and display a number of developmental defects, including cranial chondrodystrophy and a failure of tooth eruption. Teeth appear to develop normally but become trapped by the surrounding bone and undergo progressive impaction. Localization of PTHrP mRNA during normal tooth development by in situ hybridization reveals increasing levels of expression in the enamel epithelium before the formation of the eruption pathway. The type I PTH/PTHrP receptor is expressed in both the adjacent dental mesenchyme and in the alveolar bone. The replacement of PTHrP expression in the enamel epithelium with a keratin 14-driven transgene corrects the defect in bone resorption and restores the normal program of tooth eruption. PTHrP therefore represents an essential signal in the formation of the eruption pathway.

Parathyroid hormone-related protein induces spontaneous osteoclast formation via a paracrine cascade.

Experiments in vivo have established that tooth eruption fails in the absence of parathyroid hormone (PTH)-related protein (PTHrP) action in the microenvironment of the tooth because of the failure of osteoclastic bone resorption on the coronal tooth surface to form an eruption pathway. To elucidate the effects of PTHrP on osteoclast regulation in this environment, we established primary cultures of epithelial stellate reticulum cells and mesenchymal dental follicle (DF) cells surrounding the teeth. When cocultured, these cells are fully capable of supporting the formation of functional osteoclasts in the absence of added splenic osteoclast precursors, osteoblasts, or vitamin D/PTH/PTHrP. Neutralizing the effects of PTHrP resulted in a decrease in the number of osteoclasts formed, suggesting that stellate reticulum-derived PTHrP drives osteoclast formation. DF cells were found to express functional PTH/PTHrP type I receptors, and conditioned media collected from PTHrP-treated DF cells were able to induce bone resorption in the fetal-rat long-bone assay. PTHrP treatment also induced an increase in osteoclast differentiation factor expression and a concomitant decrease in osteoclastogenesis inhibitory factor expression in DF cells. The addition of osteoclastogenesis inhibitory factor resulted in a decrease in the number of osteoclasts formed in the cocultures, suggesting that osteoclast formation is mediated by osteoclast differentiation factor. Thus, PTHrP seems to regulate osteoclast formation via mediation of the DF, in a manner analogous to the osteoblast-mediated process in the peripheral skeleton. The primary coculture system of dental crypt cells also offers a system for the study of osteoclast formation and regulation.

A decision analysis of mandatory compared with voluntary HIV testing in pregnant women.

BACKGROUND: The benefit of antiretroviral therapy in reducing maternal-fetal transmission of HIV during pregnancy has caused a public policy debate about the relative benefits of mandatory HIV screening and voluntary HIV screening in pregnant women. OBJECTIVE: To evaluate the benefits and risks of mandatory compared with voluntary HIV testing of pregnant women to help guide research and policy. DESIGN: A decision analysis that incorporated the following variables: acceptance and benefit of prenatal care, acceptance and benefit of zidovudine therapy in HIV-infected women, prevalence of HIV infection, and mandatory compared with voluntary HIV testing. MEASUREMENTS: The threshold deterrence rate (defined as the percentage of women who, if deterred from seeking prenatal care because of a mandatory HIV testing policy, would offset the benefit of zidovudine in reducing vertical HIV transmission) and the difference between a policy of mandatory testing and a policy of voluntary testing in the absolute number of HIV-infected infants or dead infants. RESULTS: Voluntary HIV testing was preferred over a broad range of values in the model. At baseline, the threshold deterrence rate was 0.4%. At a deterrence rate of 0.5%, the number of infants (n = 167) spared HIV infection annually in the United States under a mandatory HIV testing policy would be lower than the number of perinatal deaths (n = 189) caused by lack of prenatal care. CONCLUSIONS: The most important variables in the model were voluntary HIV testing, the deterrence rate associated with mandatory testing compared with voluntary testing, and the prevalence of HIV infection in women of child-bearing age. At high levels of acceptance of voluntary HIV testing, the benefits of a policy of mandatory testing are minimal and may create the potential harms of avoiding prenatal care to avoid mandatory testing.