Calcium indirectly regulates immunochemical reactivity and functional activities of the N-domain of thrombospondin-1.

Conformational changes induced in thrombospondin-1 by removal of calcium regulate interactions with some ligands of its N-modules. Because calcium binds primarily to elements of the C-terminal signature domain of thrombospondin-1, which are distant from the N-modules, such regulation was unexpected. To clarify the mechanism for this regulation, we compared ligand binding to the N-modules of thrombospondin-1 in the full-length protein and recombinant trimeric thrombospondin-1 truncated prior to the signature domain. Three monoclonal antibodies were identified that recognize the N-modules, two of which exhibit calcium-dependent binding to native thrombospondin-1 but not to the truncated trimeric protein. These antibodies or calcium selectively modulate interactions of fibronectin, heparin, sulfatide, alpha3beta1 integrin, tumor necrosis factor-alpha-stimulated gene-6 protein, and, to a lesser extent, alpha4beta1 integrin with native thrombospondin-1 but not with the truncated protein. These results indicate connectivity between calcium binding sites in the C-terminal signature domain and the N-modules of thrombospondin-1 that regulates ligand binding and functional activities of the N-modules.

Induction of a high affinity fibronectin receptor in Candida albicans by caspofungin: requirements for beta (1,6) glucans and the developmental regulator Hbr1p.

Candida albicans expresses at least two biochemically distinct fibronectin receptors. Hemoglobin induces expression of a low affinity receptor recognizing the fibronectin cell-binding domain, whereas growth in complex media induces a high affinity receptor recognizing the collagen-binding domain. We now show that sub-inhibitory concentrations of caspofungin and nikkomycin Z, but not fluconazole, induce the high affinity fibronectin receptor in a dose-dependent manner. Macromolecular complexes mechanically sheared from caspofungin-treated cells retained high affinity fibronectin binding that was sensitive to protease, disulfide reduction, and beta (1,3) glucanase digestion. The high affinity fibronectin receptor was not inducible in a Kre9 mutant strain of C. albicans deficient in beta (1,6) glucans. Conversely, a mutant strain lacking the fibronectin binding protein Als5p showed no defects in induction of high or low affinity fibronectin receptors. Heterozygous mutants of a regulator of white-opaque phenotypic switching, HBR1, lacked any detectable high affinity fibronectin receptor expression in response to caspofungin, and re-introduction of the gene restored activity. Therefore, sub-inhibitory dosages of caspofungin induce a high affinity fibronectin receptor that is distinct from the known receptor Als5p and is dependent on beta (1,6) glucans and HBR1.

Three successive generations of women with anhidrotic/hypohidrotic ectodermal dysplasia.

We describe the findings of anhidrotic/hypohidrotic ectodermal dysplasia in three successive generations of a family. All three women had variable alopecia, anhidrosis, hypodontia and malar hypoplasia. Chromosomal studies revealed a defect of the 2q12 region in all three patients. Previous studies have reported rare cases of autosomal dominant ectodermal dysplasia associated with defects in the 2q11-13 region1. These rare disorders are characterized by common anomalies of at least two elements of the ectoderm and its appendages--namely, the skin, teeth, hair, nails and sweat glands. These patients also frequently have chronic dental problems with early loss of teeth and recurrent lung, ear and nose infections secondary to a defect in mucous membrane function. The majority of reported cases of ectodermal dysplasias have historically been X-linked recessive, but our findings indicate that an autosomal version may be more prevalent than previously thought.

Steroids and antibiotics for treatment of acute asthma exacerbations in African-American children.

BACKGROUND: There has been great debate surrounding the appropriate treatment regimens in children who present with acute asthma exacerbations secondary to upper respiratory tract infections. OBJECTIVE: To determine whether treatment with corticosteroids alone or in combination with antibiotics will decrease respiratory symptoms in children who develop asthma exacerbations secondary to upper respiratory tract infections. METHODS: A retrospective cohort control study involving 86 African-American children, ages 5-16, with mild intermittent asthma. The patients were treated with an albuterol inhaler (control group), inhaler plus five days of Prednisone; or inhaler, Prednisone, and 10 days of Amoxicillin. All patients were assessed regarding peak flows, albuterol inhaler usage, and symptomatology. RESULTS: On follow up five- to seven days after presentation, the corticosteroids group demonstrated a marked improvement in peak flows (88% versus 77%) and a significantly lower albuterol inhaler usage rate (2.2 versus 3.7 times a day) relative to the control group. The corticosteroids plus antibiotics group demonstrated peak flows (86% versus 88%) and inhaler usage (2.4 versus 2.2) nearly identical to corticosteroids alone, but the severity of underlying respiratory symptoms was significantly less. CONCLUSION: A five-day course of oral corticosteroids will significantly improve lung function and lessen severity of asthma symptoms. The addition of antibiotics to the treatment regimen has no additive effect on the reactive airway symptoms.