The clinical assessment of ischaemia modified albumin and troponin I in the early diagnosis of the acute coronary syndrome.

BACKGROUND: An early identification of the patients with the Acute Coronary Syndrome (ACS) is of prime importance, due to the associated very high mortality. Only about 22% of the patients who present at the emergency cardiology care centres with chest pain, have coronary disease. Ischaemia modified albumin has already been licensed by the US Food and Drug Administration for the diagnosis of suspected myocardial ischaemia. AIM: The goal of the present study was to assess the diagnostic value of serum ischaemia modified albumin and to compare it with sensitive cardiac troponin I in patients with the acute coronary syndromes like unstable angina and acute myocardial infarction. METHODS: A diagnostic case control study was conducted on 102 patients who presented to the Emergency Department within 6 hrs of having acute chest pain and on 110 healthy age and sex matched volunteers who formed the control group. The serum Ischaemia Modified Albumin level was estimated by the albumin cobalt binding test by using a digital spectrophotometer, while Troponin I was measured by doing an immunofluroscence assay. A receiver operating characteristic curve was established for ischaemia modified albumin, to determine the cut-off point. The sensitivity and the specificity of ischaemia modified albumin and troponin I for the detection of acute coronary syndromes, were analyzed. The results of ischaemia modified albumin and troponin I alone and in combination, were correlated. RESULTS: The ischaemia modified albumin (p<0.05) and the troponin I (p<0.001) concentrations were significantly higher in acute myocardial infarction and in unstable angina than in the healthy controls. The sensitivity and the specificity of ischaemia modified albumin for the detection of acute coronary syndromes was 88% and 93% as compared to 87% and 75% respectively for troponin I. The combined use of ischaemia modified albumin and troponin I significantly enhanced the sensitivity to 96%. The area which was under the Receiver Operating Characteristic (ROC) curve of ischaemia modified albumin in acute coronary syndromes was 0.90. CONCLUSION: Ischaemia modified albumin is a useful biochemical marker for the early diagnosis of acute coronary syndrome. The combined use of ischaemia modified albumin and cardiac troponin I enhances the sensitivity and specificity. Hence, a combination of ischaemia modified albumin and cardiac troponin I can be used as a more precise diagnostic marker for Acute Coronary Syndrome.

The effect of oral tolerance on the allergic airway response in younger and aged mice.

BACKGROUND: The effect of increased age on the induction of oral tolerance by low-dose antigen feeding and its effect on the response to antigen airway challenge in aged mice have not been well characterized. OBJECTIVE: To determine whether oral tolerance can be induced in aged mice and its impact on the development of allergic airway inflammation. METHODS: Younger (6 weeks old) and aged (18 months old) mice were fed ovalbumin (OVA) prior to sensitization to induce antigen tolerance. Serum antigen-specific immunoglobulins (Igs), bronchoalveolar lavage fluid (BALF), lung histology, enumeration of CD4 + Foxp3+ Treg cells, and airway hyperresponsiveness (AHR) were determined after the final antigen challenge. RESULTS: Feeding antigen to aged mice prior to sensitization induced oral tolerance as determined by a decrease in antigen-specific IgE and IgG(1); however, the effect was greater in younger mice. Induction of oral tolerance was associated with a greater increase in airway Treg cells in the younger mice. Despite these differences, oral tolerance significantly suppressed features of asthma in aged mice, including BALF total cell and eosinophil numbers, cytokine production, and AHR. CONCLUSIONS: Aged mice developed oral tolerance to antigen, which suppressed several features of allergic airway inflammation.

Glycyrrhiza uralensis flavonoids present in anti-asthma formula, ASHMI™, inhibit memory Th2 responses in vitro and in vivo.

Allergic asthma is associated with Th2-mediated inflammation. Several flavonoids were isolated from Glycyrrhiza uralensis, one of the herbs in the anti-asthma herbal medicine intervention. The aim of this investigation was to determine whether Glycyrrhiza uralensis flavonoids have inhibitory effects on memory Th2 responses in vitro and antigen-induced Th2 inflammation in vivo. The effects of three Glycyrrhiza uralensis flavonoids on effector memory Th2 cells, D10.G4.1 (D10 cells), were determined by measuring Th2 cytokine production. Isoliquiritigenin, 7, 4'-dihydroxyflavone (7, 4'-DHF) and liquiritigenin significantly suppressed IL-4 and IL-5 production in a dose-dependent manner, 7, 4'-DHF being most potent. It was also evaluated for effects on D10 cell proliferation, GATA-3 expression and IL-4 mRNA expression, which were suppressed, with no loss of cell viability. Chronic treatment with 7, 4'-DHF in a murine model of allergic asthma not only significantly reduced eosinophilic pulmonary inflammation, serum IgE levels, IL-4 and IL-13 levels, but also increased IFN-γ production in lung cell cultures in response to antigen stimulation.

Attenuation of serum ferritin and iron burden by intake of antioxidants in beta thalassemia major.

It has been anticipated that iron and ferritin burden in patients with beta thalassemia major is associated with enhanced free radical formation and blemished antioxidant defense system. The goal of study was to scrutinize impact of serum iron, total iron binding capacity (TIBC), ferritin and erythrocyte catalase in patients with beta thalassemia major. 140 beta thalassemia major patients were studied before and after supplementation of antioxidants for one month, and status was compared with 140 age and sex matched healthy controls. A significant elevation was found in the levels of serum iron and ferritin (P < 0.001) with concomitant decrease in erythrocyte catalase (P < 0.001) in patients when compared with controls. After one month supplementation of antioxidants, catalase was elevated significantly (P < 0.001) and marginal rise in serum TIBC concentration increased marginally while iron and ferritin were decreased marginally (P > 0.05) when compared with controls and baselines values. Beta thalassemia major children receive multiple blood transfusions, and are at risk of secondary iron overload induced oxidative stress. These effects may be help to minimize with supplementation of antioxidants.

Evaluation of oxidative stress and anti-oxidant status in essential hypertension.

The present study was planned to access the role of oxidative stress and anti-oxidant status in essential hypertension. Malondialdehyde is one of the by-products of lipid peroxidase and so extent of lipid peroxidation was measured by estimating malondialdehyde levels, nitrite concentration was used as an index of nitric oxide synthesis and anti-oxidant status was measured in terms of total antioxidant capacity. One hundred and eighty cases with essential hypertension and 60 volunteers as healthy controls were selected for the study. The subjects under study were grouped as pregeriatric (35-50 years) and geriatric (51-65 years). These cases were further subdivided into group I (mild), group II (moderate) and group III (severe), depending upon the levels of blood pressure. The study results showed statistically significant increased levels of serum malondialdehyde in all the groups of essential hypertensive patients when compared to that of healthy controls (p < 0.001), whereas levels of serum nitric oxide and total anti-oxidant capacity were significantly decreased in all groups of essential hypertensive patients when compared to those of controls (p < 0.001). These clear findings of the present study focuses the attention towards an alteration in the status of oxidants and anti-oxidant parameters indicating an impact of free radical action in the pathogenesis of essential hypertension.

Clinical safety of Food Allergy Herbal Formula-2 (FAHF-2) and inhibitory effect on basophils from patients with food allergy: Extended phase I study.

BACKGROUND: Food allergy is a common and increasing health concern in westernized countries. No effective treatment is available, and accidental ingestion can be life-threatening. Food Allergy Herbal Formula-2 (FAHF-2) blocks peanut-induced anaphylaxis in a murine model of peanut-induced anaphylaxis. It was found to be safe and well tolerated in an acute phase I study of patients with food allergy. OBJECTIVE: We sought to assess the safety of FAHF-2 in an extended phase I clinical trial and determine the potential effects on peripheral blood basophils from patients with food allergy. METHODS: Patients in an open-label study received 3.3 g (6 tablets) of FAHF-2 three times a day for 6 months. Vital signs, physical examination results, laboratory data, pulmonary function test results, and electrocardiographic data were acquired at baseline and at 2-month intervals. During the course of the study, basophil activation and basophil and eosinophil numbers were evaluated by using CCR3/CD63 staining and flow cytometry. RESULTS: Of 18 patients enrolled, 14 completed the study. No significant drug-associated differences in laboratory parameters, pulmonary function study results, or electrocardiographic findings before and after treatment were found. There was a significant reduction (P < .010) in basophil CD63 expression in response to ex vivo stimulation at month 6. There was also a trend toward a reduction in eosinophil and basophil numbers after treatment. CONCLUSION: FAHF-2 was safe and well tolerated and had an inhibitory effects on basophil numbers in an extended phase I clinical study. A controlled phase II study is warranted.

Detection of immunological biomarkers correlated with asthma control and quality of life measurements in sera from chronic asthmatic patients.

BACKGROUND: Clinical outcomes of patients with asthma are highly variable. Immunological biomarkers associated with asthma control have not been elucidated. OBJECTIVE: To identify the association between clinical control of asthma and serum immunological profiles of asthmatics and compare these profiles with those of healthy controls by using a multiplex assay. METHODS: Sera were obtained from 28 nonsmokers 18 to 55 years of age with moderate and severe persistent asthma. Patients were classified as having well-controlled (WC, n = 14) or poorly controlled (PC, n = 14) asthma based on their responses to the Asthma Control Questionnaire and Asthma Quality of Life Questionnaire. Sera from nonasthmatic control individuals (NAC, n = 14) were used for comparison. Levels of 50 analytes, including cytokines, chemokines, angiogenic, and growth factors, were determined, using a multiplex assay. RESULTS: Twelve of the 29 cytokines levels were significantly higher in patients with asthma than in NACs, but only interferon gamma levels were significantly lower in patients with asthma than in the NAC group. Among these, interleukin (IL)-3 and IL-18 levels were significantly higher in the PC group than the WC group. Five of the 12 tested chemokine levels were significantly higher in patients with asthma than in NACs. Five of six growth factor levels were significantly higher in patients with asthma than in NACs, and 3 were higher in PC than WC. Interleukin-18, fibroblast growth factor, hepatocyte growth factor, and stem cell growth factor-beta were positively correlated with poor asthma control and negatively with quality of life scores. CONCLUSIONS: Increased serum levels of fibroblast growth factor, hepatocyte growth factor, and stem cell growth factor-beta might be useful biomarkers of asthma control status and targets of future asthma therapy.

A Comparative Study of Clinical Utility of Spot Urine Samples with 24-h Urine Albumin Excretion for Screening of Microalbuminuria in Type 2 Diabetic Patients.

UNLABELLED: Twenty-four hour urinary albumin excretion (UAE) is considered as gold standard method for albuminuria measurement, but collection of 24-h urine is inconvenient. The aim of present study was to evaluate whether albumin: creatinine ratio (ACR) and urinary albumin concentration (UAC) in different spot urine samples correlate or not with 24-h UAE for screening of microalbuminuria in type 2 diabetic patients. We collected first morning void (FMV), random urine sample (RUS) and 24-h urine, separately on consecutive days from 104 type 2 diabetic patients. ACR and UAC in each spot urine sample compared with 24-h UAE with regard to Pearson correlation coefficient. Pearson's correlation of albumin: creatinine ratio (ACR) with 24-h UAE was (r = 0.802 and 0.623) in first morning void (FMV) and random urine sample (RUS), respectively. Pearson's correlation coefficient of urinary albumin concentration (UAC) compared with 24-h UAE was (r = 0.943 and 0.920), in FMV and RUS, respectively, P < 0.01. Results revealed that values in first morning void (FMV) were better correlated with 24-h urinary albumin excretion (UAE), than the values in random urine sample (RUS). We conclude that the first morning void (FMV) may be able to replace 24-h urine collection, preferably urinary albumin concentration (UAC) in the initial screening of microalbuminuria in diabetic patients. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s12291-011-0136-0) contains supplementary material, which is available to authorized users.

Relationship of Pneumocystis jiroveci humoral immunity to prevention of colonization and chronic obstructive pulmonary disease in a primate model of HIV infection.

Pulmonary colonization by the opportunistic pathogen Pneumocystis jiroveci is common in HIV(+) subjects and has been associated with development of chronic obstructive pulmonary disease (COPD). Host and environmental factors associated with colonization susceptibility are undefined. Using a simian-human immunodeficiency virus (SHIV) model of HIV infection, the immunologic parameters associated with natural Pneumocystis jiroveci transmission were evaluated. SHIV-infected macaques were exposed to P. jiroveci by cohousing with immunosuppressed, P. jiroveci-colonized macaques in two independent experiments. Serial plasma and bronchoalveolar lavage (BAL) fluid samples were examined for changes in antibody titers to recombinant Pneumocystis-kexin protein (KEX1) and evidence of Pneumocystis colonization by nested PCR of BAL fluid. In experiment 1, 10 of 14 monkeys became Pneumocystis colonized (Pc(+)) by 8 weeks post-SHIV infection, while 4 animals remained Pneumocystis colonization negative (Pc(-)) throughout the study. In experiment 2, 11 of 17 animals became Pneumocystis colonized by 16 weeks post-SHIV infection, while 6 monkeys remained Pc(-). Baseline plasma KEX1-IgG titers were significantly higher in monkeys that remained Pc(-), compared to Pc(+) monkeys, in experiments 1 (P = 0.013) and 2 (P = 0.022). Pc(-) monkeys had greater percentages of Pneumocystis-specific memory B cells after SHIV infection compared to Pc(+) monkeys (P = 0.037). After SHIV infection, Pc(+) monkeys developed progressive obstructive pulmonary disease, whereas Pc(-) monkeys maintained normal lung function throughout the study. These results demonstrate a correlation between the KEX1 humoral response and the prevention of Pneumocystis colonization and obstructive lung disease in the SHIV model. In addition, these results indicate that an effective Pneumocystis-specific memory B-cell response is maintained despite progressive loss of CD4(+) T cells during SHIV infection.

Safety, tolerability, and immunologic effects of a food allergy herbal formula in food allergic individuals: a randomized, double-blinded, placebo-controlled, dose escalation, phase 1 study.

BACKGROUND: Food allergy is a common and serious health problem. A new herbal product, called food allergy herbal formula 2 (FAHF-2), has been demonstrated to have a high safety profile and potent long-term efficacy in a murine model of peanut-induced anaphylaxis. OBJECTIVE: To evaluate the safety and tolerability of FAHF-2 in patients with food allergy. METHODS: In this randomized, double-blinded, placebo-controlled, dose escalation, phase 1 trial, patients received 1 of 3 doses of FAHF-2 or placebo: 2.2 g (4 tablets), 3.3 g (6 tablets), or 6.6 g (12 tablets) 3 times a day for 7 days. Four active and 2 placebo patients were treated at each dose level. Vital signs, physical examination results, laboratory data, pulmonary function test results, and electrocardiogram data were monitored. Immunomodulatory studies were also performed. RESULTS: Nineteen food allergic participants were included in the study. Two patients (1 in the FAHF-2 group and 1 in the placebo group) reported mild gastrointestinal symptoms. One patient withdrew from the study because of an allergic reaction that was unlikely related to the study medication. No significant differences were found in vital signs, physical examination results, laboratory data, pulmonary function test results, and electrocardiogram data obtained before and after treatment visits. Significantly decreased interleukin (IL) 5 levels were found in the active treatment group after 7 days. In vitro studies of peripheral blood mononuclear cells cultured with FAHF-2 also demonstrated a significant decrease in IL-5 and an increase in culture supernatant interferon gamma and IL-10 levels. CONCLUSIONS: FAHF-2 appeared to be safe and well tolerated in patients with food allergy.

Persistent pneumocystis colonization leads to the development of chronic obstructive pulmonary disease in a nonhuman primate model of AIDS.

Human immunodeficiency virus (HIV)-infected patients are at increased risk for development of pulmonary complications, including chronic obstructive pulmonary disease (COPD). Inflammation associated with subclinical infection has been postulated to promote COPD. Persistence of Pneumocystis is associated with HIV infection and COPD, although a causal relationship has not been established. We used a simian/human immunodeficiency virus model of HIV infection to study pulmonary effects of Pneumocystis colonization. Simian/human immunodeficiency virus-infected/Pneumocystis-colonized monkeys developed progressive obstructive pulmonary disease characterized by increased emphysematous tissue and bronchial-associated lymphoid tissue. Increased levels of T helper type 2 cytokines and proinflammatory mediators in bronchoalveolar lavage fluid coincided with Pneumocystis colonization and a decline in pulmonary function. These results support the concept that an infectious agent contributes to the development of HIV-associated lung disease and suggest that Pneumocystis colonization may be a risk factor for the development of HIV-associated COPD. Furthermore, this model allows examination of early host responses important to disease progression, thus identifying potential therapeutic targets for COPD.

Decrease in airway mucous gene expression caused by treatment with anti-tumor necrosis factor alpha in a murine model of allergic asthma.

BACKGROUND: Mucous hypersecretion increases asthma morbidity and mortality. Tumor necrosis factor a (TNF-a) levels are elevated in bronchoalveolar fluid, sputum, and monocyte membranes in some patients with asthma. Anti-TNF-a decreased asthma exacerbations and improved forced expiratory volume in 1 second in these patients. Whether anti-TNF-a reduces mucous cell metaplasia or hyperplasia has not been evaluated. OBJECTIVE: To investigate the role of anti-TNF-alpha in mucous hypersecretion. METHODS: BALB/c mice sensitized intraperitoneally and challenged intratracheally with ovalbumin were treated with 250 microg of anti-TNF-alpha before ovalbumin sensitization and challenge or before only ovalbumin challenge. Control groups were sham treated. The tumor necrosis factor receptor (TNFR) mice (TNFR-/- and TNFR+/+) were identically sensitized and challenged. Seventy-two hours after the final challenge, the airway pressure time index (APTI), which measures airway hyperresponsiveness, was recorded. Mucous cell metaplasia was accessed by quantitative polymerase chain reaction for MUC-5AC (the epithelial cell mucous-inducing gene) and the percentage of periodic acid-Schiff (PAS) staining of bronchial epithelial cells. A human airway cell line (constitutively expressing MUC-5AC) was pretreated with a NF-kappaB inhibitor before TNF-alpha culture. RESULTS: The mean (SE) fold change of MUC-5AC expression (compared with naive controls), the percentage of PAS-positive bronchiole epithelial cells, and the APTI decreased in BALB/c mice treated with anti-TNF-alpha before sensitization and challenge (4.9 [1.14], P = .007; 28.9% [6.8%], P < .001; and 545.8 [104.5] cm H2O/s, P < .001, respectively) and before challenge alone (9.3 [1.8], P = .03; 43.6% [10.7%], P = .009; and 896.8 [81.23] cm H2O/s, P = .06, respectively) compared with sham-treated mice (20.9 [3.9], 82.4% [1.8%], and 1,055 [30.6] cm H20/s, respectively). MUC-5AC expression decreased in ovalbumin sensitized or challenged TNFR-/- (2.41 [0.4]) compared with ovalbumin sensitized or challenged TNFR+/+ mice (18.4 [2.5], P < .001). TNF-alpha-induced MUC-5AC expression in human airway culture significantly decreased with pretreatment of a NF-kappaB inhibitor. CONCLUSIONS: Anti-TNF-alpha treatment reduces airway mucous cell metaplasia in a mouse model of asthma, which may in part underlie its beneficial effect as asthma therapy.

Safety and tolerability of an antiasthma herbal Formula (ASHMI) in adult subjects with asthma: a randomized, double-blinded, placebo-controlled, dose-escalation phase I study.

BACKGROUND: Complementary and alternative medicines are increasingly used for the treatment of asthma in Western countries. A novel three-herb antiasthma herbal medicine intervention (ASHMI; Sino-Lion Pharmaceutical Company; Shan Dong China) was demonstrated to be effective and safe in a murine model of asthma and in a preliminary clinical study in China. OBJECTIVE: The objective of this study was to evaluate the safety and tolerability of ASHMI in adult subjects with allergic asthma. DESIGN: Randomized, double-blind, placebo-controlled, dose escalation, phase I trial aimed at developing a botanical drug under the United States Food and Drug Administration Investigational New Drug title. INTERVENTIONS: Subjects received one of three doses of ASHMI or placebo: 600 mg (2 capsules); 1200 mg (4 capsules); or 1800 mg (6 capsules) twice daily for 1 week. Four (4) ASHMI and 2 placebo subjects were treated at each dose level. Subjects continued to use their conventional asthma medications for the duration of the study. OUTCOME MEASURES: Vital signs, physical examination, laboratory data, and electrocardiogram data were monitored throughout the study to assess occurrence of adverse events (AEs). Immunomodulatory studies were performed to evaluate the effect of ASHMI on cytokine, chemokine, and growth factor levels. RESULTS: Twenty (20) nonsmoking, allergic subjects with asthma were included in the study. Eight (8) subjects (4 ASHMI and 4 placebo) reported mild gastrointestinal symptoms. No grade 3 AEs were observed during the study period. Vital signs, electrocardiogram findings, and laboratory results obtained at pre- and post-treatment visits remained within normal range. No abnormal immunologic alterations were detected. CONCLUSION: In this phase I study, ASHMI appeared to be safe and well tolerated by subjects with asthma. These findings allowed initiation of a larger phase II study to assess the efficacy of ASHMI.

Elevated immune response in the brain of autistic patients.

UNLABELLED: This study determined immune activities in the brain of ASD patients and matched normal subjects by examining cytokines in the brain tissue. Our results showed that proinflammatory cytokines (TNF-alpha, IL-6 and GM-CSF), Th1 cytokine (IFN-gamma) and chemokine (IL-8) were significantly increased in the brains of ASD patients compared with the controls. However the Th2 cytokines (IL-4, IL-5 and IL-10) showed no significant difference. The Th1/Th2 ratio was also significantly increased in ASD patients. CONCLUSION: ASD patients displayed an increased innate and adaptive immune response through the Th1 pathway, suggesting that localized brain inflammation and autoimmune disorder may be involved in the pathogenesis of ASD.

Pneumocystis colonization in immunocompetent and simian immunodeficiency virus-infected cynomolgus macaques.

Pneumocystis (Pc) colonization is common among human immunodeficiency virus (HIV)-infected subjects, although the clinical consequences of Pc carriage are not fully understood. We examined the frequency of asymptomatic carriage in healthy and simian immunodeficiency virus (SIV)-infected cynomolgus macaques by use of polymerase chain reaction (PCR) and assessment of changes in the serologic response to a recombinant fragment of the Pc protein kexin (KEX1). Anti-KEX1 antibodies were detected in 95% of healthy monkeys. To create a model of natural transmission of Pc, SIV-infected monkeys were cohoused with macaques coinfected with SIV and Pc. Pc colonization occurred when the CD4(+) T cell count decreased to <500 cells/microL, despite anti-Pc prophylaxis with trimethoprim-sulfamethoxazole. Increases in anti-KEX1 antibody titers preceded detection of Pc DNA in bronchoalveolar lavage (BAL) fluid samples by use of PCR. These results demonstrate the usefulness of recombinant KEX1 in serologic studies of Pc colonization and will improve the understanding of Pc transmission and clinical consequences of Pc colonization in HIV-infected patients.

Evaluation of reference intervals of serum lipid profile from healthy population in Western Maharashtra.

Fasting samples of 914 subjects from healthy population were analyzed for total cholesterol, triglyceride and three major fractions of lipoproteins i.e. high-density lipoprotein cholesterol, low lipoprotein cholesterol and very low-density lipoprotein cholesterol. The values obtained were (in mg/dl) 165.7±30.2,88.36±31.2, 44.86±10.68, 101.66±29.8 and 18.11±7.35 respectively. When these subjects were grouped according to the age and sex, no appropriate differences were observed between most of the groups. Triglycerides were found to be low and HDL cholesterol was high in female when compared with male of similar age. Beyond age 40 years cholesterol level and low density lipoprotein cholesterol was found to be gradually increased in case of women. Minor difference was observed with dietary pattern. Present study suggests that clinical evaluation of patient should be made on the basis of these reference values for Western Maharashtra population.

Effect of oral antioxidant supplementation on lipid peroxidation during radiotherapy in head and neck malignancies.

The objectives of the present study were to ascertain the variations in the serum levels of malondialdehyde and total antioxidant status, in head and neck malignancies with different stages, with and without oral antioxidant supplementation, before and after radiotherapy, and to validate the protective effects of an antioxidant supplementation during radiotherapy. The pretreatment values of serum malondialdehyde were significantly raised, while that of serum total antioxidant status were significantly declined in all the stages of head and neck malignancies, when compared with the healthy controls values (P<0.001). A significant correlation was observed related to the studied parameters and different stages of the disease. The study suggests that an oral antioxidant supplementation during radiotherapy is an effective mode in reducing oxidative stress. Antioxidant supplementation during radiotherapy may serve as an adjuvant therapy in malignancies offering a protection to normal cells that may further reduce the risk of developing secondary cancers.

Pneumocystis colonization, airway inflammation, and pulmonary function decline in acquired immunodeficiency syndrome.

As a result of improved diagnosis, treatment, and supportive care for HIV-infected patients, AIDS in developed countries has now become a chronic infection with prolonged survival time, but longterm complications are increasing contributors to morbidity and mortality. HIV-infected patients are at increased risk for the development of pulmonary complications, including chronic obstructive pulmonary disease (COPD); however, the mechanisms associated with this increased susceptibility have not been defined. Infectious agents may contribute to the development of COPD by upregulating inflammatory mediators in the lung that act in concert with cigarette smoke to promote lung pathology. Studies in human subjects and non-human primate models of AIDS suggest that the inflammatory response to asymptomatic carriage or colonization by the opportunistic pathogen, Pneumocystis sp. (Pc), is similar to that of COPD, which is characterized by influx of CD8+ T cells, neutrophils, and macrophages into the lungs. We have shown a high frequency of Pc colonization among asymptomatic HIV-infected subjects and in non-HIV infected subjects with COPD. To investigate the role of Pc in the progression of obstructive lung disease in HIV infections, we developed a non-human primate model of Pc colonizatoin and infection in simian immunodeficiency virus (SIV)-infected macaques. These animals develop a prolonged colonization state characterized by a persistent influx of CD8+ T cells and neutrophils, and local increases in IL-8, IFN-gamma, and TNF-alpha. SIV-infected Pc-colonized monkeys show progressive decline in pulmonary function compared to SIV-infected monkeys. We hypothesize that in the context of AIDS-immune dysfunction, Pc colonization induces inflammatory responses leading to changes in pulmonary function and architecture similar to that seen in emphysema. Information gained from these studies will lead to the development of interventions to prevent lung injury associated with Pc colonization and the development of HIV-associated COPD.

Experimental Pneumocystis carinii pneumonia in simian immunodeficiency virus-infected rhesus macaques.

To establish experimental Pneumocystis carinii infection in simian immunodeficiency virus (SIV)-infected macaques as a model of acquired immunodeficiency syndrome (AIDS)-associated P. carinii pneumonia (PCP), SIV-infected macaques were inoculated intrabronchially with macaque-derived P. carinii, and P. carinii-specific polymerase chain reaction (PCR) and flow cytometric analysis of bronchoalveolar lavage fluid were done biweekly for up to 44 weeks after inoculation. All inoculated animals had a P. carinii-specific PCR product after infection. CD8(+) T cells in lung lavage samples from SIV- and P. carinii-coinfected animals increased to >90% of total CD3(+) cells, a pattern associated with naturally acquired P. carinii infection. Progression of disease also was correlated with increased neutrophil infiltration to the lungs. The animals had a protracted period of asymptomatic colonization with P. carinii before progression to PCP. The development of a model of PCP in SIV-infected rhesus macaques provides the means to study AIDS-associated PCP.