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J L Curtis

Publications and source records attributed to J L Curtis.

At least 37 records · Page 2Linked to original sources
PubMed1997

Lymphocyte recruitment and the kinetics of adhesion receptor expression during the pulmonary immune response to particulate antigen.

The selectins and beta2 integrins participate in the recruitment of neutrophils in acute pulmonary inflammation. However, the cell adhesion receptors that mediate lymphocyte trafficking into the lung have not been defined. This study examined the relationship between cell adhesion molecules on the pulmonary vasculature and on lymphocytes recovered from the lung during a pulmonary immune response to intratracheal (I.T.) sheep red blood cells (SRBCs) in sensitized C57BL/6J mice. Silver-enhanced immunogold staining and reverse transcriptase polymerase chain reaction of lung tissues revealed sustained induction of VCAM-1, E-selectin, and P-selectin on the pulmonary vasculature for up to 7 days after I.T.-SRBC challenge. Neither the MECA 79 nor MECA 367 antigens were induced on the pulmonary vasculature during this period. In the peripheral blood, both CD4 and CD8 T-cell subsets showed an initial increase in P-selectin ligand expression after I.T.-SRBC challenge. The number of P-selectin ligand-positive T cells in the peripheral blood fell as T cells with both P-selectin and, to a lesser extent, E-selectin ligands accumulated in the bronchoalveolar lavage fluid. We conclude that I.T.-SRBC challenge in sensitized mice elicits prolonged synthesis of P-selectin, E-selectin, and VCAM-1 by the lung vasculature as well as selectin ligand synthesis by responding T cells. Furthermore, the entry of selectin-ligand-positive T cells into the circulation and their accumulation in the bronchoalveolar lavage fluid indicates that these receptors may contribute to T cell recruitment. Finally, VCAM-1 on the vasculature may also participate; however, the vascular addressins, required for homing to peripheral and mucosal lymphoid organs, are not essential for T-cell entry into the lung following I.T.-SRBC challenge.

Animals↗
PubMed1996

Deaths among former psychiatric inpatients in an outreach case management program.

OBJECTIVE: The mortality rate of discharged psychiatric inpatients has long been known to be higher than that of persons in the general population. This study assessed the effectiveness of outreach case management in reducing the mortality rate of recently discharged psychiatric inpatients in New York City. METHODS: A sample of 292 patients discharged from an inpatient psychiatry service at an urban general hospital were randomly assigned either to an intervention group (N = 147), which received intensive outreach case management for periods ranging from 15 to 52 months after discharge, or to a control group (N = 145), which received standard aftercare services. Both groups were offered and received regular aftercare and other services during the study period. Both groups were followed for comparable periods of time to determine their rate of mortality. RESULTS: The overall mortality rate for the total group of 292 patients was 7.2 percent, 2.25 times higher than among persons in the general population matched for age, sex, and race. The mortality rates for the intervention group and the control group were 7.5 percent and 6.9 percent, respectively, not a significant difference. CONCLUSIONS: Discharged psychiatric inpatients who received outreach case management did not have a lower mortality rate than similar patients who did not receive this intervention.

Adult↗
PubMed1995

Down-regulation of the afferent phase of T cell-mediated pulmonary inflammation and immunity by a high melanin-producing strain of Cryptococcus neoformans.

The interaction(s) between cryptococcal virulence factors and leukocytes involved in generating protective cell-mediated immunity is not well defined. Intratracheal inoculation of Cryptococcus neoformans strain 52 induced a vigorous T cell-mediated pulmonary inflammatory response that controlled the growth of the organism. In contrast, strain 145 induced a pulmonary inflammatory response that was delayed in onset, slower to develop, and ineffective in controlling the infection. In addition, the expansion of cryptococcus-specific lymphocytes in the pulmonary lymph nodes and titer of specific Abs in the serum of strain 145-infected mice were both diminished markedly. Of the known cryptococcal virulence factors, these two strains differed only in melanin production (52-low and 145-high). Heat-killed strain 145 cryptococci (HKC-145) that had been rendered melanin-negative induced TNF-alpha production by alveolar macrophages in vitro and stimulated vigorous cryptococcus-specific lymphoproliferation. In contrast, high melanin-containing HKC-145 inhibited TNF-alpha production and lymphoproliferation. In vivo, mice infected with melanin low strain 52, but not melanin high strain 145, had elevated levels of TNF-alpha in the bronchoalveolar lavage fluid. Mice co-infected with strains 145 and 52 generated a pulmonary inflammatory response resulting in increased long-term survival. Taken together, these studies demonstrate that melanin does not protect cryptococci from being eliminated in vivo by recruited, activated effector cells; but melanin can inhibit the recognition of the organism by host defenses, thereby down-regulating the afferent phase of T cell-mediated immunity, e.g., TNF-alpha production and lymphoproliferation.

Animals↗
PubMed1995

Adhesion receptor phenotypes of murine lung CD4+ T cells during the pulmonary immune response to sheep erythrocytes.

Understanding the molecular mechanisms of pulmonary lymphocyte recruitment is a crucial step toward selective control of immune lung diseases and infections in immunocompromised hosts. To dissect these mechanisms, we are studying the response induced in primed C57BL/6 mice by intratracheal challenge with the T cell-dependent antigen, sheep red blood cells (SRBC). This study used four-parameter flow cytometry to examine expression by CD4+ murine T cells in peripheral blood and lungs of receptors known to be differentially expressed on primed human lymphocytes (CD2, CD11a, CD44, CD45RB, CD49d, and L-selectin). Compared with peripheral blood, more lung CD4+ T cells recovered by bronchoalveolar lavage (BAL) showed a primed phenotype. Judged by low expression of CD45RB or L-selectin, 76 to 90% of BAL CD4+ T cells were primed at all times. Adhesion receptor phenotype of CD4+ T cells in BAL and lung interstitium agreed closely, although BAL contained a greater percentage of primed cells. The percentage of CD4+ T cells with high expression of CD44+ and CD49d increased late in the response. However, when considering only upregulated adhesion receptors which might mediate recruitment, 22 to 52% of CD4+ T cells in BAL did not have increased adhesion receptor expression. Longer duration between priming and challenge did not increase adhesion receptor upregulation. High adhesion receptor expression was least evident during the periods of maximal lymphocyte influx, suggesting that factors other than increased surface density of organ-nonspecific adhesion receptors contribute to lymphocyte recruitment during pulmonary immune responses.

Animals↗
PubMed1995

The sensitivity of high-resolution CT in detecting idiopathic pulmonary fibrosis proved by open lung biopsy. A prospective study.

OBJECTIVES: To assess the sensitivity of high-resolution chest computed tomography (HRCT) in detecting idiopathic pulmonary fibrosis proved by biopsy specimen. To determine the degree of physiologic and pathologic abnormalities in patients with idiopathic pulmonary fibrosis who have a false-negative HRCT. DESIGN: Prospective 2-year study. SETTING: Tertiary care university hospital. PATIENTS: All patients with dyspnea and suspected interstitial lung disease referred to the University of Michigan for enrollment in the Idiopathic Pulmonary Fibrosis Specialized Center of Research (SCOR) protocol were included; 25 underwent open lung biopsy and formed the final study group. MEASUREMENTS: All patients underwent physiologic (pulmonary function, gas exchange, and exercise testing), radiologic (chest x-ray film and HRCT), and pathologic assessments (bronchoscopic and open lung biopsy). The results of HRCT were prospectively compared with results of standard pulmonary function tests, cardiopulmonary exercise testing, and open lung biopsy. RESULTS: Of 25 patients who had both HRCT and open lung biopsy, 3 patients (12%) had HRCTs that demonstrated no evidence of interstitial lung disease. These three patients had less severe disease based on clinical, radiographic, and physiologic (CRP) scores, gas exchange abnormalities, and pathologic scoring of open lung biopsy specimens, compared with those with an abnormal HRCT. CONCLUSION: We conclude that in the evaluation of patients with dyspnea and abnormal results of pulmonary function studies, a normal HRCT does not exclude early and clinically significant interstitial lung disease. In our patient population, physiologic testing was more sensitive than HRCT in detecting mild abnormalities in patients with idiopathic pulmonary fibrosis proved by biopsy specimen.

Adult↗
PubMed1994

Glutamate regulates intracellular calcium and gene expression in oligodendrocyte progenitors through the activation of DL-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors.

Oligodendrocytes and their progenitors (O-2A) express functional kainate- and DL-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-preferring glutamate receptors. The physiological consequences of activation of these receptors were studied in purified rat cortical O-2A progenitors and in the primary oligodendrocyte cell line CG-4. Changes in the mRNA levels of a set of immediate early genes were studied and were correlated to intracellular Ca2+ concentration, as measured by fura-2 Ca2+ imaging. Both in CG-4 and in cortical O-2A progenitors, basal mRNA levels of NGFI-A were much higher than c-fos, c-jun, or jun-b. Glutamate, kainate, and AMPA greatly increased NGFI-A mRNA and protein by activation of membrane receptors in a Ca(2+)-dependent fashion. Agonists at non-N-methyl-D-aspartate receptors promoted transmembrane Ca2+ influx through voltage-dependent channels as well as kainate and/or AMPA channels. The influx of Ca2+ ions occurring through glutamate-gated channels was sufficient by itself to increase the expression of NGFI-A mRNA. AMPA receptors were found to be directly involved in intracellular Ca2+ and NGFI-A mRNA regulation, because the effects of kainate were greatly enhanced by cyclothiazide, an allosteric modulator that selectively suppresses desensitization of AMPA but not kainate receptors. Our results indicate that glutamate acting at AMPA receptors regulates immediate early gene expression in cells of the oligodendrocyte lineage by increasing intracellular calcium. Consequently, modulation of these receptor channels may have immediate effects at the genomic level and regulate oligodendrocyte development at critical stages.

Animals↗
PubMed1994

Effect of granulocyte-macrophage colony-stimulating factor on rat alveolar macrophage anticryptococcal activity in vitro.

Cryptococcus neoformans, a pathogenic fungus usually acquired by inhalation, causes the most common lethal mycosis in AIDS. The resident lung phagocytes, alveolar macrophages (AM phi), inhibit growth of C. neoformans poorly unless activated by cytokines such as IFN-gamma. In this study, we examined the effect of rat AM phi of the potent hematopoietic and M phi-activating cytokine, granulocyte-macrophage CSF (GM-CSF), alone and in combination with other cytokines. Rat AM phi monolayers were preincubated with 0.1 to 1000 U/ml GM-CSF without or with other recombinant cytokines, and then were incubated with viable C. neoformans (strain H99/C3D). Growth inhibition was assessed by counting cryptococcal CFU at 24 and 48 h of coculture; AM phi proliferation was assessed by measuring both uptake of [3H]TdR and AM phi numbers. AM phi preincubated with GM-CSF for 5 days (but not for shorter periods) inhibited growth of C. neoformans. Anticryptococcal activity required direct contact of AM phi with C. neoformans, but once induced by preincubation, did not require continued exposure to GM-CSF. Induction of anticryptococcal activity by GM-CSF was dose dependent (maximal induction at 250 U/ml), and was due to both increased ingestion and killing. GM-CSF induced AM phi proliferation, but anticryptococcal activity was not due totally to increases in AM phi numbers, indicating AM phi activation by GM-CSF. GM-CSF-induced AM phi proliferation was increased by IL-6, unchanged by IL-8, and abolished by LPS or IFN-gamma. However, IL-6 did not increase GM-CSF-induced anticryptococal activity. The combination of GM-CSF and IFN-gamma showed rapid and sustained anticryptococcal activity, unlike either cytokine alone. Our in vitro data suggest that the combination of GM-CSF and IFN-gamma may have beneficial effects on host defense against C. neoformans in vivo.

Animals↗
PubMed1994

In vivo depletion of murine CD8 positive T cells impairs survival during infection with a highly virulent strain of Cryptococcus neoformans.

Cell-mediated immunity plays an important but incompletely understood role in host defense against Cryptococcus neoformans. Because of their multiple capacities as cytokine-secreting cells, cytotoxic cells, and antigen-specific suppressor cells, CD8 positive T lymphocytes could potentially either enhance or impair host defense against C. neoformans. To determine whether CD8 T cells enhance or inhibit host defence during an infection with a highly virulent strain of C. neoformans, we examined the effect of in vivo CD8 cell depletion on survival and on the number of organisms in mice infected by either the intratracheal or intravenous routes. Adequacy of depletion was confirmed both phenotypically and functionally. Regardless of the route of infection, we found that survival of mice depleted of CD8 T cells was significantly reduced compared to undepleted mice. Surprisingly, however, CD8 depletion did not alter organism burden measured by quantitative CFU assay in mice infected by either route. These data demonstrate that CD8 positive T cells participate in the immune response to a highly virulent strain of C. neoformans. By contrast to minimally virulent isolates that do not cause a life threatening infection, the immune response to a highly virulent isolate does not alter the burden of organisms, but does enhance host defense as it is necessary for the optimal survival of infected mice.

Animals↗
PubMed1994

Experimental murine pulmonary cryptococcosis. Differences in pulmonary inflammation and lymphocyte recruitment induced by two encapsulated strains of Cryptococcus neoformans.

BACKGROUND: Cryptococcus neoformans, the most common cause of lethal mycosis in AIDS, usually causes only subclinical pneumonitis in normal hosts. However, cryptococcosis can induce various pulmonary inflammatory reactions, and pulmonary cellular immunity is postulated to prevent dissemination. We hypothesized that cryptococcal strains possess different capacities to induce recruitment to the lungs of inflammatory cells, especially lymphocytes, which are necessary for cryptococcal clearance. EXPERIMENTAL DESIGN: We examined the pulmonary response of CBA/J mice to intratracheal inoculation with C. neoformans of either of two strains: 52D (ATCC 24067), which rarely kills immunocompetent mice; and 145A (ATCC 62070), which is uniformly fatal. From 2-42 days after inoculation, lungs were either examined grossly and microscopically or were enzymatically digested and inflammatory cells counted and analyzed by flow cytometry. At 42 days, organism burden in lung and brain was quantified by colony-forming unit assay. RESULTS: Pulmonary inflammation differed greatly between the two strains. Strain 52D induced dense perivascular and alveolar inflammation; infection progressed to day 21 and then waned. In contrast, strain 145A induced delayed, meager lymphocytic infiltration and slight alveolitis; organisms grew progressively. Recovery of inflammatory cells increased by day 13 with strain 52D, but not until day 31 with strain 145A. Although all lymphocyte subsets were greater in 52D infection, the disparity was greatest for CD4+ T cells. Nevertheless, lymphocytes from paratracheal nodes of infected mice proliferated in vitro to heat-killed cryptococci, indicating immune recognition of both strains. At day 42, strain 52D lightly infected lungs but not brain, whereas strain 145A heavily infected lungs and brain. CONCLUSIONS; Cryptococcal strains differ in their capacity to induce pulmonary cellular inflammation, especially CD4+ T cell recruitment. Our results suggest that strain-specific difference in the organism's ability to induce (or evade) pulmonary inflammation contributes to the outcome of infection.

Animals↗
PubMed1993

Pulmonary lymphocyte recruitment: depletion of CD8+ T cells does not impair the pulmonary immune response to intratracheal antigen.

CD8+ T cells predominate in the lungs in hypersensitivity and human immunodeficiency virus-related lymphocytic pneumonitis, but their role in the immunopathogenesis of lung disease is unknown. We have shown that in immunized mice depleted of CD4+ T cells, CD8+ T cells are recruited into the lungs in response to intratracheal antigen challenge with sheep red blood cells (SRBC) (J. Clin. Invest. 1991; 88:1244-1254) or to pulmonary infection with Pneumocystis carinii (Am. J. Respir. Cell Mol. Biol. 1991; 5:186-197), suggesting that recruitment of CD8+ T cells does not depend on CD4+ T cell-derived signals. Because CD8+ T cells themselves produce a variety of chemotactic and immunoregulatory cytokines, CD8+ T cells may be important participants in, and modulators of, pulmonary immune responses. To test this hypothesis, we examined the effects of CD8+ T cell depletion on the generation of a pulmonary immune response in vivo. We monitored the recruitment of mononuclear cells into lungs in the absence of CD8-dependent signals and measured the duration of pulmonary inflammation in the absence of suppressor CD8+ T cells. Primed mice were treated with anti-CD8 monoclonal antibody to deplete CD8+ T cells and subsequently were challenged intratracheally with 5 x 10(8) SRBC. At various times after challenge, total and differential cell counts and lymphocyte phenotypes were measured in bronchoalveolar lavage fluid by flow cytometry and lungs were scored histologically. We found that depletion of CD8+ T cells neither decreased recruitment of immune and inflammatory cells nor prolonged the pulmonary immune response.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Depletion of murine CD8+ T cells in vivo decreases pulmonary clearance of a moderately virulent strain of Cryptococcus neoformans.

Host defense mechanisms to the important fungal pathogen Cryptococcus neoformans are complex and incompletely understood. From in vitro studies, we could expect CD8+ T cells to have the potential for both protective and suppressive effects on defense against cryptococci. The current study used the technique of in vivo subset depletion to determine the net effect of CD8+ T cells during actual infection. Mice depleted of CD8+ T cells by monoclonal antibody (YTS 169.4) injections were infected with the moderately virulent cryptococcal strain 613D by the intratracheal route, which mimics natural pulmonary infection. To ensure adequacy of depletion, T cell subsets were enumerated by flow cytometry in blood, spleen, lymph node, and lung. Specific elements of host defense were measured by clearance of cryptococci in vivo and by the response to cryptococcal antigens, both in vivo by delayed-type hypersensitivity (DTH) and in vitro by lymphocyte proliferation. We found that depletion of CD8+ T cells decreased pulmonary clearance of C. neoformans. CD8 depletion abrogated DTH without affecting antigen recognition or lymphocyte proliferation in vitro. These data demonstrate that the net effect of CD8+ T cells to a moderately virulent strain of C. neoformans is to enhance rather than suppresses host defenses. Abrogation of DTH suggests that CD8+ T cells contribute to the protective immunologic response to C. neoformans. It is possible that in hosts deficient in CD4 cells, such as patients with AIDS, the protective effects of CD8+ T cells could be stimulated by selected immunizing epitopes.

Animals↗
PubMed1992

Primary pulmonary hypertension and human immunodeficiency virus infection in a non-hemophiliac man.

We describe clinical and postmortem findings in a 44-year-old man with pulmonary hypertension and infection with the human immunodeficiency virus (HIV-1). Plexogenic angiopathy and veno-occlusive lesions were present, in addition to a mild, patchy pulmonary interstitial lymphoid infiltrate. The clinical data for 14 previously reported cases of HIV-associated primary pulmonary hypertension are summarized. We speculate that these vascular changes may be due to damage from a specific immune response to HIV.

Adult↗
PubMed1992

Effect of case management on rehospitalization and utilization of ambulatory care services.

To explore whether intensive case management would reduce discharged psychiatric inpatients' rates of rehospitalization and increase their use of outpatient ambulatory care services, the authors assigned 435 patients discharged from a public general hospital in New York City to three types of postdischarge services: multidisciplinary intensive outreach case management, less intensive Community Support System (CSS) case management services, or routine aftercare but no case management. Patients eligible for CSS were generally more impaired and had more extensive histories of psychiatric hospitalization. At follow-up 18 to 52 months after entering the study, patients who received intensive outreach case management had twice as many psychiatric hospitalizations as the routine aftercare group and had a pattern of utilization of hospital-based ambulatory care services similar to the more impaired CSS group. Intensive outreach case management did not appear to stimulate sufficient use of ambulatory care services to reduce patients' frequency of psychiatric hospitalization.

Adolescent↗
PubMed1991

Propranolol therapy alters estimation of potential cardiovascular risk derived from submaximal postinfarction exercise testing.

We studied the effect of propranolol administration on risk assessment based on submaximal exercise testing performed early after myocardial infarction. A total of 70 patients with recent infarction underwent modified Bruce treadmill testing with simultaneous measurement of expired gases in the absence of antianginal agents including beta-antagonists. Among these, 31 patients who had at least one of the following abnormalities--ST depression greater than or equal to 1 mm (22 patients), chest pain (four patients), or treadmill time less than 360 seconds (12 patients)--were studied in a randomized double-blind fashion and received either placebo or 240 mg of propranolol/day. A total of 28 patients completed the randomized phase and were able to undergo repeat exercise testing an average of 3.4 +/- 1.8 days later. Randomized groups were equivalent at baseline except for a higher peak oxygen consumption and carbon dioxide production (p less than 0.05) in the propranolol compared with the placebo group; these differences were taken into account in statistical analyses of the study data. Resting heart rate (59 +/- 1.2 versus 82 +/- 4.2 beats/min) and peak heart rate x systolic blood pressure (14,208 +/- 496 versus 20,075 +/- 1,062) were both significantly less (p less than 0.01) after propranolol than after placebo. Eight of nine patients treated with placebo maintained ST depression greater than or equal to 1 mm from the initial to the randomized exercise test, compared with only 4 of 13 receiving propranolol (p less than 0.01). In those with continued ST depression, time to positivity was significantly longer in those receiving propranolol compared with those taking placebo (538 +/- 73 versus 318 +/- 44 seconds, p less than 0.05). In contrast, the peak ratio between carbon dioxide production and oxygen consumption was higher in those receiving propranolol compared with those receiving placebo (0.93 +/- 0.04 versus 0.81 +/- 0.03, p less than 0.05). We conclude that propranolol therapy reduces evidence of ischemia and changes traditional estimates of potential cardiac risk derived from submaximal postinfarction exercise testing.

Cardiovascular Diseases↗
PubMed1991

Inflammatory responses to Pneumocystis carinii in mice selectively depleted of helper T lymphocytes.

Pneumocystis carinii is the most important pulmonary pathogen in patients with the acquired immunodeficiency syndrome, but host defenses against P. carinii are not well characterized. We recently reported an experimental model of P. carinii infection, in which mice selectively depleted of CD4+ lymphocytes develop pulmonary infection after inoculation with P. carinii. In the current study, we compared lung inflammatory responses to P. carinii inoculation in CD4-depleted mice and in normal mice in order to further characterize host defenses against P. carinii. We hypothesized that depletion of CD4+ lymphocytes would prevent recruitment and activation of inflammatory cells in the lungs of these mice, allowing progressive infection with P. carinii. We found that CD4-depleted mice were unable to recruit CD4+ lymphocytes into their lungs and developed progressive infection with P. carinii, but mounted exuberant inflammatory responses to the organisms. These inflammatory responses were characterized by perivascular infiltration with mononuclear cells, increases in cell numbers in bronchoalveolar lavage (particularly CD8+ lymphocytes), and activation of alveolar macrophages (enhanced Ia antigen expression). In contrast, normal mice recruited CD4+ lymphocytes into their lungs and eliminated organisms with only minimal inflammatory responses. We conclude that depletion of CD4+ lymphocytes does not prevent the recruitment and activation of inflammatory cells in the lung. These inflammatory responses occur by mechanisms independent of CD4+ lymphocytes and are insufficient to provide effective host defense against P. carinii.

Animals↗