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Biomedical subjects

H W Murray

Publications and source records attributed to H W Murray.

At least 73 records · Page 4Linked to original sources
PubMed1994

Colorado tick fever in a resident of New York City.

When a traveler returns from abroad with a febrile illness, clinicians appropriately concern themselves with a potentially vast array of diagnostic exotica. The patient we describe herein did not leave the United States but nevertheless posed the same clinical dilemma after returning home to New York City from the western United States. This case of Colorado tick fever, acquired on the Utah-Colorado border and first expressed in Manhattan, serves as a useful reminder of the importance of taking a careful travel history for national as well as international travelers.

Antibodies, Viral↗
PubMed1994

Interferon-gamma and host antimicrobial defense: current and future clinical applications.

In the 1980s, substantive experimental data and emerging clinical results suggested that interferon-gamma (IFN-gamma), a T-cell-derived lymphokine with broad macrophage-activating effects, had considerable potential in the treatment of nonviral infections as a host defense-enhancing antimicrobial agent. During the past 6 years, the breadth of the experimental activity with IFN-gamma against nonviral pathogens has been expanded still further, and pilot studies and formal clinical trials using IFN-gamma have been undertaken in the treatment of patients both at risk for and with active infections. Thus far, IFN-gamma has been approved for use as prophylaxis in patients with chronic granulomatous disease. However, IFN-gamma also appears effective as adjunctive therapy for at least one disseminated intracellular infection (visceral leishmaniasis), and in conjunction with conventional therapy, may benefit patients with certain forms of cutaneous leishmaniasis, disseminated Mycobacterium avium complex infection, and lepromatous leprosy. Despite a rationale for its use, IFN-gamma has not yet been tested in tuberculosis or fungal or common bacterial infections nor sufficiently examined in the prevention and/or treatment of the opportunistic infections related to acquired immunodeficiency syndrome. IFN-gamma remains a promising host defense-enhancing cytokine with still unexplored clinical potential.

Adjuvants, Immunologic↗
PubMed1994

Blood monocytes: differing effector role in experimental visceral versus cutaneous leishmaniasis.

Irrespective of the tissue infected or the strain involved, all Leishmania species selectively parasitize and replicate within the resident tissue macrophage. Henry Murray here discusses the role of a second mononuclear phagocyte, the blood monocyte, which is also attracted to leishmanial lesions, but which appears to play quite different roles in experimental visceral versus cutaneous infection: in visceral disease, the monocyte is a critical host defense effector cell, in cutaneous disease, it may, paradoxically, serve to perpetuate intracellular infection.

Journal Article↗
PubMed1994

Successful treatment of refractory visceral leishmaniasis in India using antimony plus interferon-gamma.

Fifteen Indian patients with relapsing or drug-refractory visceral leishmaniasis were retreated for 30 days with antimony plus interferon-gamma (IFN-gamma). All 15 had failure of an initial course of antimony and at least one additional course of antimony or pentamidine; 7 patients had failure of three or four prior courses of therapy. During the study, treatment was discontinued in 2 patients because of anemia and congestive heart failure in 1 and intractable vomiting in the other; both subsequently died. In the remaining 13 patients, IFN-gamma plus antimony treatment was associated with daily fever but no other adverse reactions. After 30 days of therapy, 9 (69%) of the 13 patients were apparently cured. Six months after treatment, all 9 were healthy, had parasite-free bone marrow aspirate smears, and were considered cured. None have relapsed during a mean follow-up of 15.9 +/- 1.7 months. These results support the use of antimony plus IFN-gamma as an immunochemotherapeutic alternative for kala-azar patients who have repeated failures of conventional treatment.

Adolescent↗
PubMed1994

Th1 and Th2 cell-associated cytokines in experimental visceral leishmaniasis.

In experimental Leishmania donovani infection in BALB/c mice, initial susceptibility gives way to T-cell-dependent acquired resistance and eventual control over visceral infection. Since various cytokines appear to underlie the host response to Leishmania infection, we examined infected liver tissue for gene expression of cytokines associated with Th1 (gamma interferon [IFN-gamma] and interleukin-2 [IL-2]) and Th2 cells (IL-4 and IL-10). By Northern (RNA) blot analysis, only IFN-gamma mRNA expression was detected in livers of infected euthymic mice. To determine whether activation of Th1 cells develops selectively in this model, qualitative PCR analysis was used. These results indicated that mRNAs for IFN-gamma, IL-2, IL-4, and IL-10 were all induced by L. donovani infection. The potentially negative Th2 cell-associated response did not appear to play a functional role, however, since resistance was acquired, anti-IL-4 monoclonal antibody treatment did not accelerate control over visceral infection, and serum immunoglobulin E levels remained low. As judged by PCR analysis, IL-4 and IL-10 mRNAs were also expressed under three other conditions without apparent effect: in naive euthymic mice treated with IL-2, which induces leishmanicidal activity; in rechallenged immune mice, which resist reinfection; and in nude mice, which fail to control L. donovani. These results suggest that, like other Leishmania species, L. donovani infection may trigger a potentially suppressive Th2 cell-associated cytokine response. However, in T-cell-intact mice able to control L. donovani, this response either is insufficient to influence outcome or more likely is overshadowed by the Th1 cell response.

Animals↗
PubMed1993

Role and effect of IL-2 in experimental visceral leishmaniasis.

In experimental visceral leishmaniasis, acquired resistance is T cell-dependent, involves IFN-gamma-activated macrophages, and is expressed in the tissues by granuloma formation. Resistance also correlates with Ag-stimulated IL-2 secretion; therefore, Leishmania donovani-infected BALB/c mice were treated with anti-IL-2 mAb or rIL-2 to determine the host defense effect of IL-2. In control mice, intracellular hepatic infection peaked at 2 wk and then declined coincident with granuloma development. In contrast, liver parasite burdens in anti-IL-2-treated mice continued to increase until after 4 wk, at which time mature granuloma formation was inhibited. Treatment of mice with continuously administered IL-2 reduced liver burdens by > 50% and led to marked accumulation of granuloma mononuclear cells. The IL-2-responsive mechanism was T cell-dependent and required both L3T4+ and Lyt-2+ cells. IL-2 enhanced IFN-gamma mRNA expression in vivo and was required for IFN-gamma secretion in vitro, and anti-IFN-gamma mAb administration abolished the antimicrobial effect of exogenous IL-2. These results: 1) identify the activity of endogenous IL-2 in both antileishmanial resistance and granuloma formation; 2) demonstrate that exogenous IL-2 can enhance the granulomatous tissue reaction; and 3) indicate that IL-2 treatment stimulates intracellular antimicrobial activity largely via the induction of IFN-gamma.

Animals↗
PubMed1993

Cytokines as antimicrobial therapy for the T cell-deficient patient: prospects for treatment of nonviral opportunistic infections.

Patients rendered T cell-deficient by advanced disease due to human immunodeficiency virus, an underlying neoplastic disorder, or immunosuppressive therapy are vulnerable to a select group of opportunistic infections. These infections, which often fail to respond to conventional therapy, provide the clinical setting in which the efficacy of treatment with cytokines can be tested. Particularly pertinent cytokines are those that activate macrophages and monocytes or enhance T-cell function. Experimental observations and emerging data from patients with intact T-cell function suggest that treatment with at least three cytokines, interferon-gamma, interleukin-2, and granulocyte-macrophage colony-stimulating factor (GM-CSF) may be of benefit. Each of these cytokines is already in clinical use, and each has therapeutic potential in a variety of different infectious disease. Patients with infections caused by opportunistic intracellular pathogens appear to be the most appropriate candidates for adjunctive cytokine therapy.

Bacterial Infections↗
PubMed1993

Response to treatment for an intracellular infection in a T cell-deficient host: toxoplasmosis in nude mice.

To examine the experimental basis of treatment failures in T cell-deficient patients with intracellular infections, euthymic and athymic (nude) BALB/c mice were infected with Toxoplasma gondii and treated with sulfadiazine. All euthymic and nude mice survived during 2 weeks of sulfadiazine therapy. Once treatment was discontinued, 100% of euthymic mice survived while all nude mice died. Post-sulfadiazine treatment survival was enhanced in nude mice by reconstitution with either L3T4+ or Lyt-2+ cells and was reduced in euthymic mice by monoclonal antibody treatment directed at depleting either L3T4+ or Lyt-2+ cells or interleukin-2 (IL-2) or interferon-gamma (IFN-gamma). These results suggest that although T cells and their products are not required for an initial response (survival) to treatment in acute experimental toxoplasmosis, survival off drug is strictly T cell-dependent. Optimal posttreatment survival appears to involve both L3T4+ helper and Lyt-2+ cytotoxic cells, probably acting in concert, as well as the endogenous secretion of at least two T cell-derived lymphokines, IL-2 and IFN-gamma.

Animals↗
PubMed1993

Circulating Borrelia burgdorferi in patients with acute Lyme disease: results of blood cultures and serum DNA analysis.

To determine the usefulness of blood culture and polymerase chain reaction (PCR) analysis in detecting circulating Borrelia burgdorferi or its DNA, blood and serum from untreated patients with acute Lyme disease were examined. None of the cultures of blood or serum from the 7 patients tested demonstrated spirochetes. Similarly, all patient serum samples, assayed in two laboratories, were negative for B. burgdorferi DNA using PCR amplification. These results suggest that in patients with acute Lyme disease, spirochetes, spirochete DNA, or both circulate early, only intermittently, or at low levels and that neither culture nor PCR testing of blood or serum, as currently done, appears likely to prove generally useful in the diagnosis of Lyme disease.

Acute Disease↗
PubMed1993

Treatment of experimental visceral leishmaniasis in a T-cell-deficient host: response to amphotericin B and pentamidine.

In experimental visceral leishmaniasis, euthymic but not athymic (nude) BALB/c mice respond to conventional treatment with pentavalent antimony, indicating that the in vivo efficacy of antimony is T cell dependent. This finding correlates with frequent antimony treatment failures for T-cell-deficient patients with visceral leishmaniasis. To determine whether the in vivo efficacies of alternative antileishmanial agents also require T cells, Leishmania donovani-infected euthymic and nude BALB/c mice were treated with pentamidine or amphotericin B. Pentamidine induced leishmanistatic activity in euthymic mice but had little effect in nude mice. In contrast, amphotericin B exerted potent leishmanicidal activities in both euthymic and nude animals. These results suggest that amphotericin B may be of particular use for T-cell-deficient patients with visceral leishmaniasis.

Amphotericin B↗
PubMed1993

Effector role of blood monocytes in experimental visceral leishmaniasis.

In BALB/c mice, liver granulomas provoked by visceral infection with intracellular Leishmania donovani are rapidly populated by influxing blood monocytes. To determine the host defense effector role of these mononuclear phagocytes, we treated three populations of infected animals with 5C6, an anti-type 3 complement receptor monoclonal antibody (MAb), which inhibits monocyte recruitment into inflamed tissues. In naive BALB/c mice, injections of 5C6 impaired the initial acquisition of antileishmanial resistance and arrested the development of mature liver granulomas. In sensitized mice with established immunity, both resistance to rechallenge and accelerated granuloma formation were similarly inhibited by MAb administration. Finally, in naive mice, 5C6 MAb also abolished the antileishmanial activity induced by treatment with the macrophage-activating lymphokine gamma interferon. Together, these results suggest a key effector role for the influxing blood monocyte in both initial and established antileishmanial defense and granuloma assembly and in the infected liver as the mononuclear phagocyte target for the antimicrobial effects of gamma interferon.

Animals↗
PubMed1993

Immunochemotherapy for visceral leishmaniasis: a controlled pilot trial of antimony versus antimony plus interferon-gamma.

Twenty-four Kenyan patients with visceral leishmaniasis were treated for 30 days with either conventional therapy (daily pentavalent antimony, n = 14) or experimental immunochemotherapy (daily antimony plus interferon-gamma [IFN-gamma] every other day, n = 10). All 24 patients responded clinically to treatment, and microscopic splenic aspirate scores rapidly decreased in both groups. As judged by splenic aspirate culture results, IFN-gamma-treated patients responded more quickly (50% versus 22% culture-negative after one week and 75% versus 58% culture-negative after two weeks). While not statistically significant, these differences raise the possibility that combination therapy using IFN-gamma, which was safe and well-tolerated, may accelerate the early parasitologic response in patients with visceral leishmaniasis.

Adolescent↗
PubMed1992

Acquired resistance and granuloma formation in experimental visceral leishmaniasis. Differential T cell and lymphokine roles in initial versus established immunity.

In naive BALB/c mice, acquisition of resistance to Leishmania donovani and formation of antileishmanial tissue granulomas are linked expressions that require both L3T4+ and Lyt 2+ cells as well as both IL-2 and IFN-gamma. To determine the mechanisms of established resistance to L. donovani, rechallenged immune BALB/c mice were treated with T cell- and lymphokine-depleting mAb or cyclosporin A. In the liver, resistance to rechallenge was inhibited by treatment with anti-Lyt 2 but not anti-L3T4 mAb. Resistance was also impaired by anti-IL-2 treatment but not by anti-IFN-gamma mAb. The hepatic granulomatous response to rechallenge, however, was not impaired by either anti-Lyt 2 or anti-IL-2 mAb nor by anti-L3T4 or anti-IFN-gamma treatment. In contrast, cyclosporin A suppressed granuloma formation but not antileishmanial activity. These results indicate a particularly important antileishmanial host defense role for Lyt 2+ cells and IL-2 in sensitized animals, and when compared to prior observations in L. donovani-infected naive mice, suggest that 1) discrete T cell- and lymphokine-dependent mechanisms are involved in initial acquisition of resistance vs established immunity, 2) more than one mechanism can mediate the development of tissue granulomas, and 3) granuloma formation by itself may not be required nor necessarily sufficient to confer antimicrobial activity.

Animals↗
PubMed1992

Malaria--the mime revisited: fifteen more years of experience at a New York City teaching hospital.

PURPOSE AND PATIENTS: A previous review of The New York Hospital experience with malaria during 1968 to 1975 summarized clinical and parasitologic features in 24 travelers and highlighted deficiencies in both chemoprophylaxis and diagnosis. To extend this original study, we describe 86 patients with malaria seen at the same hospital during the subsequent 15 years. RESULTS: Eighty patients were infected with a single Plasmodium species, and 60% had Plasmodium falciparum infection primarily acquired in Africa. Eighty percent were symptomatic while in or within 1 month of departing the malarious region. All patients described a history of fever; however, 25% were afebrile at the initial hospital visit. A normal white blood cell count, thrombocytopenia, and an increased lactate dehydrogenase level were common laboratory results. Seventy-five percent of non-native travelers took either no or inadequate chemoprophylaxis. Malaria was not suspected in 16 of the 20 (80%) patients seen initially by local New York City physicians but was initially suspected and confirmed in 49 of 54 (91%) patients first seen at The New York Hospital. CONCLUSION: In comparison to our 1968 to 1975 experience, these updated results indicate no improvement in either the use of appropriate chemoprophylaxis or the capacity to properly diagnose malaria in the community. Improvement is still clearly needed in both areas.

Adolescent↗