Kiran K. Belani

Regulation of mature ADAM17 by redox agents for L-selectin shedding.

L-selectin is constitutively expressed by neutrophils and plays a key role in directing these cells to sites of inflammation. Upon neutrophil activation, L-selectin is rapidly and efficiently down-regulated from the cell surface by ectodomain shedding. We have directly shown that A disintegrin and metalloprotease 17 (ADAM17) is a primary and nonredundant sheddase of L-selection by activated neutrophils in vivo. Following cell activation, intracellular signals lead to the induction of ADAM17’s enzymatic activity; however, the target of this inducer mechanism remains unclear. Our study provides evidence of an activation mechanism that involves the extracellular region of the mature form of cell surface ADAM17 and not its intracellular region. We demonstrate that the catalytic activity of purified ADAM17 lacking a prodomain and its intracellular region is diminished under mild reducing conditions by DTT and enhanced by H2O2 oxidation. Moreover, H2O2 reversed ADAM17 inhibition by DTT. The treatment of neutrophils with H2O2 also induced L-selectin shedding in an ADAM17-dependent manner. These findings suggest that thiol-disulfide conversion occurring in the extracellular region of ADAM17 may be involved in its activation. An analysis of ADAM17 revealed that within its disintegrin/cysteine-rich region are two highly conserved, vicinal cysteine sulfhydryl motifs (cysteine-X-X-cysteine), which are well-characterized targets for thiol-disulfide exchange in various other proteins. Using a cell-based ADAM17 reconstitution assay, we demonstrate that the cysteine-X-X-cysteine motifs are critical for L-selectin cleavage. Taken together, our findings suggest that reduction-oxidation modifications of cysteinyl sulfhydryl groups in mature ADAM17 may serve as a mechanism for regulating the shedding of L-selectin following neutrophil stimulation.

ASSOCIATION OF EXOTOXIN-PRODUCING GROUP A STREPTOCOCCI AND SEVERE DISEASE IN CHILDREN

Clinical features and microbiologic data on all cases of serious (hospitalized) Group A streptococcal infections in children managed at our institution between 1985 and 1988 are presented. All 6 cases were caused by toxin-producing strains. Four of 6 were toxin A-producing strains whereas none of 58 community-acquired (Group A streptococcal) pharyngeal isolates in the same period was a toxin A producer. A review of the literature on the incidence of toxin A-producing strains provides information suggesting a resurgence of such strains in the late 1980s after a relative disappearance of toxin B production in isolates from these patients was also significantly greater than in the isolates acquired from the community in uncomplicated pharyngitis. These findings suggest a role for exotoxin in severe manifestations of Group A streptococcal disease in children.

Ganciclovir treatment of cytomegalovirus disease in immunocompromised children.

Twelve immunocompromised children were treated with 13 courses of intravenously administered ganciclovir for severe cytomegalovirus disease. All children were allograft recipients; 6 received organ transplants (5 liver, 1 kidney) and 6 received bone marrow. They presented with one or more of the following forms of cytomegalovirus disease: pneumonitis, 9; hepatitis, 3; colitis, 2; peritonitis, 1; and retinitis, 1. Clinical improvement was observed in 7 (58%) of 12 patients during ganciclovir therapy. Cessation of active viral replication during therapy accompanied 69% of the treatment courses. Mild and transient increases in creatinine and liver function tests and/or decreases in neutrophil count accompanied 77% of treatment courses but neutropenia (<1000 cells/mm3) did not occur. Transient decreases in platelet counts accompanied therapy in 3 bone marrow allograft recipients, but >50% decrease in lymphocyte count was not seen. We conclude that ganciclovir is safe and appears to have a beneficial effect on cytomegalovirus disease in some pediatric transplant recipients.

Rifampin for CSF shunt infections caused by coagulase-negative staphylococci

COAGULASE-NEGATIVE STAPHYLOCOCCAL INFECTIONS are a common complication of cerebrospinal fluid shunt surgery. It is reported that among 289 patients, shunt infections occurred in 27% and half of these infections were caused by coagulase-negative staphylococci? The use of r i fampin in conjunction with other antibiotics has been reported effective in the treatment of coagulase-negative staphylococcal infection of prosthetic valves and CSF shunts? We have observed two patients with coagulase-negative staphylococcal shunt infections who, after poor responses to other antibiotics, showed rapid improvement when rifampin was added to the antibiotic regimen. These patients illustrate the need for further investigation of this potentially valuable antibiotic for the treatment of coagulase-negative staphylococcal infections, especially when response to other therapy has been poor.

Surgery for pediatric invasive fungal sinonasal disease

To evaluate the management and outcomes of children with invasive fungal sinonasal disease treated with radical surgery.

A Case of Tuberculous Otitis Media

Chronic otorrhea is an uncommon but a frustrating condition to manage. Usually children with chronic otorrhea seek medical attention on multiple occasions and are treated with a variety of antibiotics. When a patient, particularly an immigrant, presents with otitis media that does not respond to the usual therapy, tuberculous (TB) otitis media should be considered in the differential diagnosis and appropriate investigations ordered. A delay in diagnosis and treatment of TB otitis media may result in serious complications. In this case report we present a toddler with chronic otorrhea, who was found to have TB otits media, and we also review the literature on TB otitis media.