Discriminators between hantavirus-infected and -uninfected persons enrolled in a trial of intravenous ribavirin for presumptive hantavirus pulmonary syndrome.

To provide a potentially therapeutic intervention and to collect clinical and laboratory data during an outbreak of hantavirus pulmonary syndrome (HPS), 140 patients from the United States with suspected HPS were enrolled for investigational intravenous ribavirin treatment. HPS was subsequently laboratory confirmed in 30 persons and not confirmed in 105 persons with adequate specimens. Patients with HPS were significantly more likely than were hantavirus-negative patients to report myalgias from onset of symptoms through hospitalization, nausea at outpatient presentation, and diarrhea and nausea at the time of hospitalization; they were significantly less likely to report respiratory symptoms early in the illness. The groups did not differ with regard to time from the onset of illness to the point at which they sought care; time from onset, hospitalization, or enrollment to death was significantly shorter for patients with HPS. At the time of hospitalization, patients with HPS more commonly had myelocytes, metamyelocytes, or promyelocytes on a peripheral blood smear, and significantly more of them had thrombocytopenia, hemoconcentration, and hypocapnia. Patterns of clinical symptoms, the pace of clinical evolution, and specific clinical laboratory parameters discriminated between these 2 groups.

Intravenous ribavirin for hantavirus pulmonary syndrome: safety and tolerance during 1 year of open-label experience. Ribavirin Study Group.

Intravenous ribavirin was provided non-selectively for investigational open-label use among persons with suspected hantavirus pulmonary syndrome (HPS) in the United States between 4 June 1993 and 1 September 1994. Therapy was initiated prior to laboratory confirmation of hantavirus infection because most deaths from HPS occur within 48 h of hospitalization. Thirty patients with confirmed HPS, 105 patients without HPS and 5 patients without adequate diagnostic testing for HPS were enrolled. This observational study arguably provides the most complete information available on ribavirin-associated adverse effects. Although ribavirin was generally well tolerated, 71% of recipients became anaemic and 19% underwent transfusion. An apparent excess of hyperamylasaemia/pancreatitis was either therapy-associated or due to enrollment bias. The 30 enrolled HPS patients had a case-fatality rate of 47% (14/30). It is not possible to assess efficacy with this study design. However, comparison of survival curves for the 30 enrolled HPS patients and 34 patients who developed HPS during the same time period but were not enrolled did not suggest an appreciable drug effect. A randomized, placebo-controlled trial that enrolls patients during the prodrome phase would be necessary to assess the efficacy and further define the safety of intravenous ribavirin for HPS.

Sorivudine versus acyclovir for treatment of dermatomal herpes zoster in human immunodeficiency virus-infected patients: results from a randomized, controlled clinical trial. Collaborative Antiviral Study Group/AIDS Clinical Trials Group, Herpes Zoster Study Group.

The present randomized, double-blind, placebo-controlled, multicenter clinical trial was designed to compare the efficacy and tolerability of sorivudine [1-beta-D-arabinofuranosyl-E-(2-bromovinyl)uracil] and acyclovir for the treatment of dermatomal herpes zoster in human immunodeficiency virus (HIV)-seropositive patients. A total of 170 HIV-seropositive adults presenting with herpes zoster (confirmed by direct fluorescent-antigen testing and/or viral culture) were enrolled and randomized to receive a 10-day course of orally administered sorivudine (40 mg once daily plus acyclovir placebos) or acyclovir (800 mg five times daily plus sorivudine placebo). Patients were monitored daily to document the events of cutaneous healing, pain, zoster-related complications, and drug-related adverse events. Patients were reassessed on days 21 and 28 and then once monthly for 1 year. The primary efficacy endpoint was time to the cessation of new vesicle formation. Secondary efficacy endpoints included times to other events of cutaneous healing, resolution of pain, and frequency of dissemination and zoster recurrence. In a multivariate analysis, sorivudine was superior to acyclovir for reducing the times to the cessation of new vesicle formation (relative risk [RR] = 1.54, 95% confidence interval [CI] = 1.00 to 2.36; P = 0.049) and total lesion crusting (RR = 1.48, 95% CI = 1.07 to 2.04; P = 0.017). In a univariate analysis, there was a trend favoring sorivudine for the cessation of new vesicle formation (median of 3 versus 4 days; P = 0.07) and a significant advantage for time to total lesion crusting (median of 7 versus 8 days; P = 0.02). The time to the resolution of zoster-associated pain, the frequency of dissemination, and the frequency of zoster recurrence were not different between the two treatment groups. Both drugs were well tolerated. Sorivudine is an effective drug for the treatment of herpes zoster in HIV-infected patients and results in accelerated cutaneous healing when compared with acyclovir therapy.

Successful treatment of cutaneous leishmaniasis with allopurinol after failure of treatment with ketoconazole.

Treatment of persistent leishmaniasis with oral agents has received increasing attention, although the optimal agent for use in all settings has not been determined. This report describes a patient with persistent cutaneous infection due to Leishmania mexicana mexicana who apparently responded to therapy with allopurinol after treatment with a course of ketoconazole failed. In vitro testing of pre- and posttreatment isolates from the wound did not demonstrate the development of resistance to ketoconazole. To our knowledge, this is the first report that independently confirms the recently reported efficacy of allopurinol for treatment of leishmaniasis.

Purine nucleoside and nucleobase cell membrane transport in Giardia lamblia.

Giardia lamblia is dependent on the salvage of preformed purines and pyrimidines. This study investigated purine nucleoside and nucleobase transport utilizing rapid uptake determinations. Nucleoside substrate/velocity curves exhibited the hyperbolic kinetics of a saturable carrier-mediated system. Deoxynucleosides exhibited a much lower affinity for the transporter. Inhibition studies confirmed the relative carrier affinities of these ribonucleosides and deoxyribonucleosides. The nucleobase adenine did not exhibit saturation kinetics at a comparable substrate range, and did not inhibit nucleoside transport. Dipyridamole markedly inhibited nucleoside but not nucleobase transport, confirming the separate entry pathways. When cells were depleted of ATP, the velocity of nucleoside and nucleobase transport was unchanged, indicating that it is a non-energy-dependent process. Three nucleoside analogs, formycin A, adenine arabinoside and 7-deazaadenosine, were studied. Transport kinetics ranged widely among this group and could not completely account for their cytotoxic effect. When the apparent Km and Vmax of the nucleosides were compared, an approximately linear relationship (r2 = 0.95) was noted. This suggests that a high affinity of the nucleoside permease for the substrate retards disassociation of the substrate-carrier complex, slowing net influx.

Didanosine administration in a human immunodeficiency virus-positive renal transplant patient.

A human immunodeficiency virus-positive renal transplant patient taking no immunosuppressive medication for 40 months was treated with didanosine for the final 13 months of life. Over the latter period there were three acute episodes of creatinine elevation, but none could be attributed to didanosine-induced acute rejection. Based on this case, we cautiously suggest that didanosine may safely be administered in the setting of renal transplantation.

Purine deoxynucleoside salvage in Giardia lamblia.

Giardia lamblia is dependent on the salvage of preformed purines and pyrimidines, including deoxythymidine. Dependence on deoxynucleoside salvage is extremely unusual among eucaryotic cells (Moore, E. C., and Hurlbert, R. B. (1985) Pharmacol & Ther. 27, 167-196). The present study investigates the possibility that giardia lacks ribonucleotide reductase and depends entirely on deoxynucleoside salvage. A ribonucleotide reductase inhibitor, hydroxyurea, at concentrations up to 2 mM had no effect on the growth of giardia. This is 15-20 times the ED50 of hydroxyurea for the protozoans Trypanosoma cruzi, Trypanosoma gambiense, and Leishmania donovani. A lysate of giardia had no detectable ribonucleotide reductase. Although radiolabeled adenine, adenosine, guanine, and guanosine were readily incorporated into RNA by cultured cells, no adenine or adenosine and only trace amounts of guanine and guanosine were detectable in DNA. This is in contrast to deoxynucleosides, where 58% of deoxyadenosine and 10% of deoxyguanosine incorporated into nucleic acid were found in DNA. Phosphorylation of both deoxyadenosine and deoxyguanosine was catalyzed by a cell lysate of giardia when nucleoside kinase co-substrates were included in the assay but not when phosphotransferase co-substrates were present. The absence of detectable ribonucleotide reductase, the failure to incorporate purine nucleobases and nucleosides into DNA to any significant extent, the ready incorporation of deoxynucleosides into DNA, and the demonstration of a purine deoxynucleoside kinase suggest that giardia are dependent on the salvage of exogenous deoxynucleosides.

A new method for cloning Giardia lamblia, with a discussion of the statistical considerations of limiting dilution.

This report describes a method of cloning Giardia lamblia by limiting dilution which is simpler than the previously described semisolid agar technique and which may also be applied as an assay of cell viability. A discussion of the basic statistics of limiting dilution, which is applicable to any cell type, and a method of statistically comparing colony-forming efficiencies from different cell populations are included. The colony-forming efficiency (CFE) of this method, when applied to late log-phase cultures, is 72.1 +/- 10.05%. When only cells adherent to the sides of culture vials are cloned, the CFE is 87.1 +/- 9.85%.

The painful crisis of homozygous sickle cell disease. A study of the risk factors.

Some epidemiologic features of the painful crisis in homozygous sickle cell disease were examined in a retrospective study of 995 painful crises. Previously reported associations with cold weather and pregnancy were confirmed. There was a striking increase in painful crises in male patients between the ages of 15 and 25 years, whereas female patients showed little age-related change. The frequency of painful crises correlated positively with hemoglobin levels and reticulocyte counts in both sexes and negatively with mean corpuscular volume in female patients. There was a striking increase in painful crises in male patients with hemoglobin levels above 8.5 g/dL (greater than 85 g/L). High hemoglobin levels appear to be an important risk factor for painful crises.

Topical antibiotics in chronic sickle cell leg ulcers.

A randomized, controlled, trial of a topical antibiotic preparation (neomycin, bacitracin, and polymyxin B) was performed in 30 patients with homozygous sickle cell (SS) disease and chronic leg ulceration. Over a period of 8 weeks, the reduction in ulcer size was significantly (P less than 0.05) greater in the treatment group than in the control group. The results suggest that these topical antibiotics may contribute to the therapy of chronic leg ulceration associated with sickle cell disease.

Bacteriology of sickle cell leg ulcers.

The bacteria isolated on aerobic and anaerobic culture were compared in 80 unilateral ulcers in patients with homozygous sickle cell (SS) disease, 62 superficial skin lesions, and in 30 diabetic ulcers. In SS disease, the bacterial flora was predominantly aerobic and polymicrobial with Staphylococcus aureus, Pseudomonas aeruginosa and beta-haemolytic streptococci being the major isolates. Repeat sampling of 26 ulcers over a period of 23 weeks indicated the persistence of these three organisms, either singly or in combination in 21 ulcers. Although a variety of Enterobacteriaceae were recovered no single genus predominated and these organisms did not normally persist on follow-up. Simultaneous swabs from bilateral ulcers revealed similar if not identical flora in most cases, indicating good predictive value of a single swab in patients with multiple ulcers. Corynebacterium diphtheriae was recovered from eight ulcers and four of these strains were toxigenic. By contrast, the superficial skin lesions grew mainly S. aureus and beta 6-haemolytic streptococci, and the diabetic ulcers yielded a mixed growth of streptococci, Enterobacteriaceae and anaerobes. The recovery of known skin pathogens from most sickle cell leg ulcers, the persistence of these organisms, and the presence of associated lymphadenopathy, indicates that infection may be a significant factor in the pathology of these lesions.

Leukopheresis in the leukemic phase of hairy cell leukemia. A case report.

A 43-year-old male with hairy cell leukemia presented seven months after splenectomy with fatigue, adenopathy, dependence on erythrocyte transfusions, a leukocyte of 85 X 10(9)/L and a platelet count of 15 X 10(9)/L. Leukopheresis resulted in a transient resolution of adenopathy and an improvement in hematologic counts. Leukopheresis may be of value in stabilizing the patient in the leukemic phase of hairy cell leukemia.

Aspiration pneumonitis and pulmonary phospholipids.

Peptic aspiration pneumonitis (Mendelson's syndrome) results when gastric acid is aspirated into the lung, as may occur during anesthesia. In the present study, 0.1 N HCl was insufflated via the endotracheal tube into pentobarbital-anesthetized dogs in an amount sufficient to cause severe pulmonary damage. At death, the thorax was opened, the lungs grossly examined, and either weighed and desiccated for determination of wet/dry lung weight ratios, rinsed with saline for removal of alveolar surface phospholipids, or homogenized for whole lung phospholipid determination. Gross appearance and wet/dry lung weight ratios indicated severe pulmonary edema. The surface tension values of the lung wash were elevated over control values. Lysophophatidyl-choline (LPC) showed a striking increase over control values. Because LPC is a potent hemolytic agent which builds up in the lung following this pulmonary insult, and because increased hemorrhaging gradually develops following experimental acid insufflation, it is concluded that LPC is most probably causally related to the hemorrhagic pneumonia of Mendelson's syndrome.