Fire ant venom alkaloid, isosolenopsin A, a potent and selective inhibitor of neuronal nitric oxide synthase.

Massive, multiple fire ant, Solenopsis invicta, stings are often treated aggressively, particularly in the elderly, despite limited evidence of systemic toxicity due to the venom. Over 95% of the S. invicta venom is composed of piperidine alkaloid components, whose toxicity, if any, is unknown. To assess a possible pharmacological basis for systemic toxicity, an alkaloid-rich, protein-free methanol extract of the venom from whole ants was assayed for inhibitory activity on the following nitric oxide synthase (NOS) isoforms, rat cerebellar neuronal (nNOS), bovine recombinant endothelial (eNOS), and murine recombinant immunologic (iNOS). Cytosolic NOS activity was determined by measuring the conversion of [(3)H]arginine to [(3)H]citrulline in vitro. Rat nNOS activity was inhibited significantly and in a concentration-dependent manner by the alkaloid-rich venom extract. For nNOS, enzyme activity was inhibited by approximately 50% with 0.33 +/- 0.06 microg of this venom extract, and over 95% inhibition of the three isoforms, nNOS, eNOS, and iNOS, was found with doses of 60 microg in 60 microl reaction mixture. These results indicate that the alkaloid components of S. invicta venom can produce potent inhibition of all three major NOS isoforms. Isosolenopsin A (cis-2-methyl-6-undecylpiperidine), a naturally occurring fire ant piperidine alkaloid, was synthesized and tested for inhibitory activity against the three NOS isoforms. Enzyme activities for nNOS and eNOS were over 95% inhibited with 1000 microM of isosolenopsin A, whereas the activity of iNOS was inhibited by only about 20% at the same concentration. The IC(50) for each of three NOS isoforms was approximately 18 +/- 3.9 microM for nNOS, 156 +/- 10 microM for eNOS, and >1000 microM for iNOS, respectively. Kinetic studies showed isosolenopsin A inhibition to be noncompetitive with L-arginine (K(i) = 19 +/- 2 microM). The potency of isosolenopsin A as an inhibitor of nNOS compares favorably with the inhibitory potency of widely used nNOS inhibitors. Inhibition of NOS isoforms by isosolenopsin A and structurally similar compounds may have toxicological significance with respect to adverse reactions to fire ant stings.

Expanding habitat of the imported fire ant (Solenopsis invicta): a public health concern.

Residents in the southeastern United States would hardly describe life with the aggressive imported fire ant as peaceful coexistence. The continued spread of these insects has produced agricultural problems, changes in the ecosystem, and increasing numbers of subjects with sting sequelae, including hypersensitivity reactions, secondary infections, and rare neurologic sequelae. Evolutionary changes have facilitated their expansion northward into Virginia and westward into California, and increasing urbanization will likely permit further expansion. Recent reports of building invasion with sting attacks inside occupied dwellings, including health care facilities, heighten public health concerns. This article reviews the medically important entomology, clinical aspects of stings, and the current approaches to chemical control of fire ants. We also propose directions for future research and treatment.

Fire ant attacks on residents in health care facilities: a report of two cases.

BACKGROUND: Imported fire ants now infest more than 310 million acres in the United States and Puerto Rico. Colonies have been found in Arizona, California, New Mexico, and Virginia. Available reports suggest that each year, fire ants sting more than 50% of persons in endemic areas, resulting in a variety of medical consequences. OBJECTIVE: To describe fire ant attacks among patients in health care facilities. DESIGN: Case series and literature review. SETTING: Two nursing homes in Mississippi. PATIENTS: Two nursing home residents. MEASUREMENTS: Clinical records to describe clinical sequelae of multiple stings. RESULTS: With the 2 incidents reported here, the total number of reported indoor fire ant attacks on humans since 1989 is 10. Six of the persons attacked, including the 2 nursing home residents described here (who died after the stings), had preexisting neurologic impairment. Eight of the 10 attacks have been reported in the past 4 years. CONCLUSIONS: The presence of fire ants in occupied dwellings indicates the presence of active fire ant colonies in the immediate proximity. Efforts to eradicate these insects should be undertaken immediately, especially if immobile persons are present. These persons should be considered at risk for fire ant attacks as long as the ants are present.

Diagnostic criteria for sarcoidosis of the sinuses.

BACKGROUND: Although newer technologies facilitate its diagnosis and treatment, little is known about sarcoidosis of the paranasal sinuses. OBJECTIVES: We sought to better characterize sarcoidosis of the sinuses and establish criteria for diagnosis. METHODS: Case-finding criteria were established, and over 50 reports of sarcoidosis of the sinuses in the medical literature were reviewed. Nine case reports of patients fulfilling the case-finding criteria were identified, as were 6 additional patients from our clinics. RESULTS: Nasal obstruction and chronic sinusitis were the usual initial complaints from patients and were associated with mucosal crusting, studding, plaque-like changes, or polyps in the nose in 5 of 6 of our patients. The most consistent finding in nose and sinuses was an erythematous, edematous, friable, hypertrophied mucosa. Like 5 of 6 of our patients, most patients had extra-pulmonary sarcoidosis involving multiple organs, but some had isolated upper respiratory disease. Radiologic studies showed extensive and often complete opacification of the sinuses and nose similar to that seen in diffuse polyposis associated with chronic bacterial and fungal sinusitis. No specific histopathologic findings distinguished sinus disease from those reported with pulmonary involvement. Pharyngeal involvement was present in 2 case reports and caused the apparent asphyxiation of 1 of our patients. CONCLUSION: Sarcoidosis of the sinuses should be considered in the differential diagnosis of sinusitis, especially in association with nasal polyposis, even when the sarcoidosis has not been otherwise diagnosed. On the basis of this experience, we propose diagnostic criteria for sarcoidosis of the sinuses. These include (1) radiologic evidence of sinusitis, (2) histopathologic confirmation of noncaseating granuloma in the sinus tissue supported by negative stains for fungus and acid-fast bacilli, (3) negative serologic test results for syphilis and antineutrophil cytoplasmic antibodies, and (4) no clinical evidence of other disease processes associated with granulomatous nasal and sinus inflammation. These criteria will provide the basis for further studies to assess both the natural history and the effectiveness of treatment in sarcoidosis of the sinuses.

Fungal sinusitis.

Until several years ago, no criteria for diagnosis or consensus on the classification of fungal sinusitis existed. Many reports were grouped under the heading of "aspergillus sinusitis," regardless of invasiveness; thus, published information on the diagnosis, natural history, and treatment of fungal sinusitis was of limited value. Diagnostic criteria and clinical descriptions for allergic fungal sinusitis, sinus mycetoma, and invasive fungal sinusitis have now been published. These criteria, a new classification system, and the clinical approach to patients with fungal sinusitis are reviewed in this article. Although fungal sinusitis is not a rare disease, much remains to be learned about its optimal clinical management.

Allergic reactions to drugs and biologic agents.

Drug allergies are adverse reactions resulting from immunologic responses to drugs or their metabolites. These reactions result in predictable patterns of organ-specific or systemic hypersensitivity that usually recur on subsequent exposure to the same drug. Although diagnostic testing for drug allergy is available for only a few drugs, protocols have been developed to assist in management of allergic reactions to many drugs and biologic agents. Other protocols assist in the management of patients who develop drug reactions while undergoing multiple drug therapy or those with a history of adverse drug reactions who again require treatment for the same condition.

A new classification and diagnostic criteria for invasive fungal sinusitis.

OBJECTIVE: To develop criteria for the diagnosis of invasive fungal sinusitis. DESIGN: Review of the literature on invasive fungal sinusitis in the context of a population of 30 patients with fungal sinusitis and 24 patients with chronic bacterial sinusitis. SETTING: Tertiary care medical center. RESULTS: Our review revealed no consensus in the literature on the classification of the syndromes of invasive fungal sinusitis and no criteria for their diagnosis. Moreover, the existing syndromes of invasive fungal sinusitis lacked specificity and one of the more commonly cited syndromes, primary aspergillosis of the paranasal sinuses, is a granulomatous disease that occurs rarely outside Africa. Two of our 30 patients with fungal sinusitis had a previously unrecognized form of invasive disease. Both were middle-aged adults with well-controlled type 2 diabetes mellitus, apical orbital syndrome, and a similar course: proptosis resulting from fungal expansion out of an ethmoid sinus, a protracted illness of 6 months or longer, visual changes, late neurological symptoms reflecting cavernous sinus invasion, and death. The syndrome in these 2 patients is distinct from the syndrome of fulminant invasive fungal sinusitis, (eg, mucormycosis) with nasal eschar, intracerebral fungal dissemination by vascular invasion, and death in days, and the granulomatous form. CONCLUSIONS: We conclude that there are 3 forms of invasive fungal sinusitis and propose that they be termed (1) granulomatous, (2) acute fulminant, and (3) chronic invasive. The latter category reflects the syndrome seen in our 2 patients. Furthermore, the following 2 diagnostic criteria for invasive fungal sinusitis are proposed: (1) sinusitis confirmed by radiological imaging and (2) histopathological evidence of hyphal forms within sinus mucosa, submucosa, blood vessels, or bone. The specificity of hyphae within sinus mucosa for tissue invasion was supported by the absence of stainable hyphae in the mucosa of patients with chronic bacterial sinusitis or in the mucosa of our described patients with allergic fungal sinusitis and mycetoma.

Criteria for the diagnosis of sinus mycetoma.

Recent improvements in the treatment options for fungal disease of the sinuses make rapid distinction between the syndromes of invasive and noninvasive sinusitis necessary. On the basis of the extensive review of the literature detailed here, we developed case-finding criteria for the noninvasive syndrome of sinus mycetoma. Using these criteria, we identified 20 cases of sinus mycetoma in the medical literature and compared findings in these patients to those of five patients with mycetoma evaluated in our clinics. Like those in the literature, our patients appeared immunocompetent and were often first seen for evaluation of symptoms other than those usually associated with sinusitis. Two were first seen with a new-onset seizure disorder and one with nasal obstruction alone. Patients from both groups more commonly had mycetoma in their maxillary sinuses, and fungus failed to grow from the cheesy, grey-green, hyphae-rich material removed at the time of surgery. Clinical features in our five patients, which are not noted in published reports of sinus mycetoma, included frequent atopy, nasal polyps, calcification within the sinus on computed tomography, and an excellent response to surgical treatment. Serendipitously, one patient had both allergic fungal sinusitis and a mycetoma in the same sinus. On the basis of this experience, we have modified our case-finding criteria into proposed diagnostic criteria for sinus mycetoma. The elements of these criteria are designed to: (1) exclude patients with invasive fungal sinusitis and (2) differentiate sinus mycetoma from other forms of noninvasive fungal sinusitis on the basis of specific histopathologic findings. This study and the criteria presented reflect our view that sinus mycetoma represents a distinct but not necessarily isolated element in the spectrum of noninvasive fungal disease of the sinuses.

Multiple fire ant stings indoors.

The progressive spread and increasing colony density of imported fire ants throughout the southeastern United States will result in increasing numbers of individuals with untoward reactions to the stings of these insects. In order to alert physicians that imported fire ant colonies may exist within homes and other inhabited dwellings and result in multiple stings to the occupants and to provide information about the management of this problem, we report two cases where individuals were stung indoors by imported fire ants. One of these cases involved the attack of a bed-bound patient by a colony of ants. The other report documents the establishment of an intact fire ant colony within an inhabited dwelling. Physicians should become familiar with the biology of these insects to assist patients in dealing with this problem.

Diagnostic criteria for allergic fungal sinusitis.

Diagnostic criteria for allergic fungal sinusitis have not been established, and clinical information consists primarily of isolated case reports. We proposed five diagnostic criteria for allergic fungal sinusitis including: (1) the demonstration of the characteristic eosinophil-rich allergic mucin visually or histopathologically, (2) a positive fungal stain or culture from the sinus at surgery, and (3) the absence of immunodeficiency or diabetes. With these criteria, seven patients in our metropolitan area with allergic fungal sinusitis were identified in a short period. Initial symptoms in our seven patients reflected those in 99 case reports in that two children were first seen with proptosis, one child and three adults with nasal congestion, and one adult with symptoms of chronic sinusitis. All had pansinusitis as shown on x-ray films. Six patients were atopic, five had nasal polyposis, and five had Curvularia species cultured from the sinuses. Infections with Bipolaris species, asthma, and chronic sinusitis were less common in our patients than in those previously reported. Recurrent symptoms and additional surgery sometimes resulted when the diagnosis was delayed by failure to obtain silver stains for fungus on surgical material sent for histopathologic review. Sinus tomography showed that the fungal material in the sinuses was of high density, which distinguished it from polyps or bacterial exudate. Bony compression, erosion, and rupture of the sinus walls were common. Results of IgE levels, precipitin determinations, and eosinophil counts were variable in both our patients and those in the literature. On the basis of our review, we believe that the simple diagnostic criteria proposed are appropriate for both research and clinical purposes.