Coronary calcium, subsequent events, and selection bias.
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Calcinosis↗
Biomedical subjects
T M Doherty
Publications and source records attributed to T M Doherty.
IL-12 promotes drug-induced clearance of Mycobacterium avium infection in mice.
The intracellular pathogen Mycobacterium avium is a major cause of opportunistic infection in AIDS patients and is difficult to manage using conventional chemotherapeutic approaches. In the current study, we describe a strategy for the treatment of M. avium in T cell-deficient hosts based on the simultaneous administration of antibiotics and the immunomodulatory cytokine IL-12. In contrast to SCID mice, which were partially resistant, animals lacking a functional IL-12 p40 gene were found to be highly susceptible to M. avium infection, suggesting that the cytokine can control bacterial growth even in immunodeficient mice. Indeed, rIL-12 that was injected into infected SCID mice in high doses caused small but significant reductions in splenic pathogen loads. Moreover, a lower dose of IL-12, when combined with the antimycobacterial drugs clarithromycin or rifabutin, induced a decrease in bacterial numbers that was significantly greater than that resulting from the administration of the cytokine or drug alone. A similar synergistic effect of IL-12 and antibiotics was seen when immunocompetent mice were treated with the same regimen. The activity of IL-12 in these experiments was shown to be dependent upon the induction of endogenous IFN-gamma. Nevertheless, IFN-gamma itself, even when given at a higher dose than IL-12, failed to significantly enhance antibiotic clearance of bacteria. Together these findings suggest that IL-12 may be a particularly potent adjunct for chemotherapy of M. avium infection in immunocompromised individuals and may result in more effective control of the pathogen without the need for increased drug dosage.
Adjuvants, Immunologic↗
How does warfarin affect the activated coagulation time?
BACKGROUND: The activated coagulation time (ACT) is a rapid measurement of a patient's level of heparin anticoagulation during cardiac catheterization. Patients receiving warfarin therapy occasionally are seen at the catheterization laboratory for emergent procedures. The effects of warfarin on ACT activity have not been previously described. We compared the ACT and the international normalized ratios (INR) in 77 patients receiving warfarin and 57 patients who were not receiving any anticoagulation (controls). RESULTS: Both the mean ACT (131+/-17.0 seconds) and INR (2.5+/-0.90 seconds) of the anticoagulated patients differed from the controls (ACT=115+/-14.5 seconds, INR=1.0+/-0.10 seconds; P< 0.05). The ACT increased linearly with INR in the warfarin group (r=0.70, P< .001). There was no relation between ACT and INR in the control group. CONCLUSION: Patients receiving warfarin therapy will have a linear increase in ACT develop similar to patients receiving heparin therapy.
Adult↗
TACHY: an expert system for the management of supraventricular tachycardia in the elderly.
PURPOSE: Many physicians find the management of supraventricular tachyarrhythmia (SVT) in the elderly complex and challenging. With the use of artificial intelligence theory, we developed an interactive computer expert system, TACHY, to recommend therapies and warn physicians of potential therapeutic side effects. METHODS: We developed a knowledge base that stores guidelines for the management of SVT in the elderly. After the diagnosis of current SVT was input into the computer, TACHY generated a list of therapeutic options as hypotheses. TACHY then prompted the user to provide current patient-specific clinical information, and the optimal therapeutic option was then selected. Potential therapeutic side effects were also displayed. TACHY was tested in a retrospective and a prospective study. The retrospective study, comprising 96 patients with 126 episodes of SVT, was performed to determine the concordance of therapy between TACHY and cardiologists. A prospective study in 18 patients with 26 episodes of SVT was also performed to validate TACHY's recommendations in restoring sinus rhythm. RESULTS: In the retrospective study the concordance between TACHY and the cardiologist's first therapeutic option was 95.9% (121 of 126 episodes). In the prospective study sinus rhythm was restored in 18 (69%) of 26 episodes of SVT by the first therapeutic option recommended by TACHY. In the remaining eight episodes use of the second or third suggestion of TACHY was successful in controlling the ventricular response to SVT. No adverse reaction to the therapeutic options suggested by TACHY occurred. CONCLUSION: TACHY, a knowledge-based computer expert system that simulates human decision making, produced promising results in the management of SVT in the elderly.
Aged↗
Paclitaxel (Taxol)-induced killing of Leishmania major in murine macrophages.
The antitumor drug paclitaxel (Taxol) has been demonstrated to be a lipopolysaccharide mimetic in murine macrophages. In this study, the capacity of paclitaxel to activate macrophages to become microbicidal for Leishmania major was examined. Paclitaxel and gamma interferon synergized to kill intracellular L. major in Lpsn, but not Lpsd, macrophages by a nitric oxide (NO.)-dependent mechanism.
Animals↗
Cytokines as determinants of disease and disease interactions.
The immune response to pathogens results in both host resistance and immunopathology. Cytokines and in particular those lymphokines produced by Th1 and Th2 cells play a key role in determining the balance between these two immunologic outcomes. Recent data suggest that interleukin-10, a product of both Th2 cells and macrophages, protects the host against excessive immunopathology. The cytokine environment generated by different pathogens may also influence the course and outcome of infections with unrelated organisms. This relationship may be particularly important in the case of HIV-1 where prior Th1 or Th2 biases established by helminth or intracellular infections may influence either initial viral susceptibility or drive progression to AIDS through immune activation.
Acquired Immunodeficiency Syndrome↗
Interferon (IFN) consensus sequence-binding protein, a transcription factor of the IFN regulatory factor family, regulates immune responses in vivo through control of interleukin 12 expression.
Mice with a null mutation of the gene encoding interferon consensus sequence-binding protein (ICSBP) develop a chronic myelogenous leukemia-like syndrome and mount impaired responses to certain viral and bacterial infections. To gain a mechanistic understanding of the contributions of ICSBP to humoral and cellular immunity, we characterized the responses of control and ICSBP-/- mice to infection with influenza A (flu) and Leishmania major (L. major). Mice of both genotypes survived infections with flu, but differed markedly in the isotype distribution of antiflu antibodies. In sera of normal mice, immunoglobulin (Ig)G2a antibodies were dominant over IgG1 antibodies, a pattern indicative of a T helper cell type 1 (Th1)-driven response. In sera of ICSBP-/- mice, however, IgG1 antibodies dominated over IgG2a antibodies, a pattern indicative of a Th2-driven response. The dominance of IgG1 and IgE over IgG2a was detected in the sera of uninfected mice as well. A seeming Th2 bias of ICSBP-deficient mice was also uncovered in their inability to control infection with L. major, where resistance is known to be dependent on IL-12 and IFN-gamma as components of a Th1 response. Infected ICSBP-deficient mice developed fulminant, disseminated leishmaniasis as a result of failure to mount a Th1-mediated curative response, although T cells remained capable of secreting IFN-gamma and macrophages of producing nitric oxide. Compromised Th1 differentiation in ICSBP-/- mice could not be attributed to hyporesponsiveness of CD4(+) T cells to interleukin (IL)-12; however, the ability of uninfected and infected ICSBP-deficient mice to produce IL-12 was markedly impaired. This indicates that ICSBP is a deciding factor in Th responses governing humoral and cellular immunity through its role in regulating IL-12 expression.
Animals↗
Ethnic origin and serum levels of 1alpha,25-dihydroxyvitamin D3 are independent predictors of coronary calcium mass measured by electron-beam computed tomography.
BACKGROUND: Blacks have been found to have lower amounts of coronary calcium as well as higher levels of the osteoregulatory steroid 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] than whites. We sought to determine if racial differences in coronary calcium mass could be explained by differences in serum levels of 1,25(OH)2D3. METHODS AND RESULTS: We evaluated standard coronary risk factors, quantified coronary calcium mass with electron-beam computed tomography (EBCT), and measured serum 1,25(OH)2D3 with radioimmunoassay in 283 high-risk subjects (51 [180%] black, 232 [82%] white). Black subjects had lower masses of coronary calcium than whites (14 versus 47 mg; P=.003). Serum 1,25(OH)2D3 levels were slightly higher in blacks (41 versus 38 pg/mL; P=.05). Log 1,25(OH)2D3 levels were inversely proportional to log-transformed calcium mass (r=-.19; P=.001) in both races. Multivariate linear regression demonstrated that both black race (P=.02) and 1,25(OH)2D3 levels (P=.007) contributed inversely and independently to coronary calcium mass. However, an interaction term of racex1,25(OH)2D3 did not significantly contribute to coronary calcium mass, indicating that other undetermined factors in addition to 1,25(OH)2D3 are responsible for ethnic differences in coronary calcium mass. CONCLUSIONS: Both black race and serum levels of 1,25(OH)2D3 are independent negative determinants of coronary calcium mass. Nevertheless, diminished amounts of coronary calcium in blacks are not accounted for by higher 1,25(OH)2D3 levels.
Aged↗
Defects in cell-mediated immunity affect chronic, but not innate, resistance of mice to Mycobacterium avium infection.
To investigate the role of cell-mediated immunity in the control of Mycobacterium avium infection, we studied the effects of targeted gene disruptions in components of the T lymphocyte-dependent, macrophage-mediated response on resistance of mice to this pathogen. Normal mice developed a chronic, asymptomatic infection, with rapid induction of mRNAs for IFN-gamma, IL-12, and TNF-alpha in spleen, liver, and lung. Bacterial loads in gene knockout, scid, and wild-type mice were indistinguishable for the first 4 wk of infection. However, by 8 wk postinfection, scid mice as well as animals with a targeted disruption of the IFN-gamma gene showed enhanced bacterial growth compared with wild-type controls. In contrast, knockout mice lacking the genes for the TNF-alpha p55/p75 receptors or inducible nitric oxide synthase not only developed comparable bacterial loads to wild-type animals, they also failed to display the splenomegaly and profound suppression of mitogen-induced lymphocyte proliferative responses evident in infected wild-type controls. Thus, M. avium is clearly distinct from other intracellular pathogens (e.g., Leishmania monocytogenes, Toxoplasma gondii, and Mycobacterium tuberculosis) whose initial replication in the host is tightly controlled by Th1-dependent effector mechanisms. Instead, the major effect of host cell-mediated immunity is to limit bacterial growth during the chronic phase of infection. Surprisingly, inducible nitric oxide appears to be more important for the immunopathology than for the host resistance induced by this bacterial pathogen.
Animals↗
Prognostic significance of coronary calcific deposits in asymptomatic high-risk subjects.
PURPOSE: To determine the predictive value of coronary calcifications for coronary heart disease events in high-risk, asymptomatic adults: PATIENTS AND METHODS: A prospective cohort study of 1,461 high-risk, asymptomatic subjects were followed for 55 months with a 98% success rate. Coronary risk factor assessment and cardiac fluoroscopy with digital subtraction enhancement were performed to determine the number of calcified coronary arteries. RESULTS: Fifty-eight percent of this cohort (852 subjects) had fluoroscopically detectable coronary calcification: 437 (30%) had calcium in one, 253 (17%) in two, and 162 (11%) in all three coronary vessels. There were 90 (6%) deaths, 35 (39%) attributable to coronary heart disease, and 43 (3%) nonfatal myocardial infarctions. Subjects with calcification in more than one major coronary artery were 2.2 times more likely to suffer coronary death or nonfatal infarction (P = 0.001) than were subjects with one or no calcified arteries. Multivariable logistic regression analysis showed that only the number of calcified arteries, age, total cholesterol, history of diabetes, and left ventricular hypertrophy by electrocardiogram were associated independently with the incidence of coronary death or infarction in these subjects. CONCLUSIONS: Coronary calcification predicts coronary heart disease death or infarction in high-risk asymptomatic adults as well as do standard risk factors.
Adult↗
Modulation of murine AIDS-related pathology by concurrent antibody treatment and coinfection with Leishmania major.
Infection of C57BL/6 mice with a mixture of murine leukemia viruses (MuLVs) designated LP-BM5 MuLV leads to a disease characterized by progressive immunodeficiency and lymphoproliferation, known as murine AIDS (MAIDS). The development of MAIDS is associated with increased B-cell lymphoblast proliferation, but there is reason to believe that T-cell function and, particularly, T-cell-derived cytokines may also play a role. We have previously shown that concurrent infection with Leishmania major (which induces a strongly polarized Th1 response in C57BL/6 mice) and LP-BM5 MuLV modulates the disease induced by both infections. Here we show by treatment of mice with anticytokine antibodies that this modulation is largely exerted through the balance of Th1 and Th2 cytokines. Infected mice treated with antibodies to interleukin-4 and interleukin-10 exhibited a delayed development of MAIDS-related pathology and maintained T-cell responsiveness longer than mice treated with control antibody. Gamma interferon induced by coinfection with L. major synergized with anti-IL-4 treatment to inhibit the development of MAIDS pathology. Conversely, treatment with anti-gamma interferon led to a significant increase in splenomegaly and lymphadenopathy and slightly exacerbated loss of T-cell function. These data suggest that the production of Th2-associated cytokines may promote MAIDS pathology, while Th1-associated cytokines may help control the disease.
Animals↗
Interleukin (IL)-4-independent immunoglobulin class switch to immunoglobulin (Ig)E in the mouse.
Immunoglobulin (Ig) class switching in B cells is regulated by stimuli transduced by cytokines and cell-cell contact. Among these stimuli, interleukin (IL)-4 has been considered an absolute prerequisite for class switching to IgE in the mouse. Here we report that IL-4-deficient (IL-4-/-) and wildtype mice had comparably elevated serum IgE levels during the course of a murine retrovirus-induced immunodeficiency syndrome, MAIDS. IgE switching in IL-4-/- mice was also induced by injection of anti-IgD antibody. Treatment with anti-IgD induced germline epsilon (g epsilon) transcripts with comparable efficiency in IL-4-/- mice and controls, but the levels of productive epsilon transcripts (p epsilon) were lower by a factor of 200 and serum IgE levels were lower by a factor of 300 in IL-4-/- mice as compared with controls. Induction of g epsilon after anti-IgD treatment of IL-4-/- mice was unaffected by simultaneous treatment with monoclonal antibodies to IL-4 and IL-4 receptor alpha chain. Infection of IL-4-/- mice with Nippostrongylus brasiliensis, a potent stimulus for IgE production, resulted in induction of g epsilon transcripts; however, p epsilon transcripts were barely detectable and serum IgE was not detected. These findings establish a novel IL-4-independent pathway for IgE switching in the mouse that is strongly activated in retroviral infection but weakly in nematode infection. This pathway appears to be dependent on distinct factors that separately control induction of g epsilon transcription and switch recombination to p epsilon.
Animals↗
Induction and regulation of IL-15 expression in murine macrophages.
IL-15 is a recently described cytokine which resembles IL-2 in its biologic activities, stimulating T cell and NK cell proliferation and activation as well as enhancing B cell expansion and Ab production. Unlike IL-2, IL-15 is not produced by lymphocytes, but instead (at least among cells of the immune system) appears to be synthesized primarily by monocyte/macrophages. We have examined the induction of IL-15 in murine macrophages (by semiquantitative reverse transcriptase-PCR and bioassay) in response to a variety of different macrophage-activating stimuli and compared the regulation of IL-15 production to that of IL-12 and TNF-alpha. Optimal induction of IL-15, in each of the macrophages populations tested, was found to require both priming (IFN-gamma) and triggering (LPS, mycobacteria, or Toxoplasma gondii) stimuli. When compared with IL-12 mRNA synthesis by the same macrophages, IL-15.mRNA production was more resistant to inhibition by the down-regulatory cytokines IL-14, IL-13, and TGF-beta. Moreover, IL-10, which is inhibitory for most other monokines, increased levels of IL-15 mRNA found after stimulation. These data establish IL-15 as a product of the macrophage/monocyte lineage, which is up-regulated on activation. IL-15 could thus play an important role in the initiation of immune responses by microbial agents.
Animals↗
Subclavian vein anatomic subtypes defined by digital cinefluroscopic venography prior to permanent pacemaker lead insertion.
Digital cinefluoroscopic venography of the subclavian vein was performed in 26 consecutive patients. The optimal stored image of the anticipated venipuncture site was magnified, road mapped, and used to compare with fluoroscopic-guided venipuncture. Two anatomic subtypes for both subclavian veins were observed. For the left subclavian vein, a gradual curve was seen most often (57%), while the remainder (43%) exhibited an "s"-shaped curve. For the right subclavian, a gradual curve was observed most frequently (60%) while an acute 90 degrees angle was noted in the remainder (40%). The "s"-shaped curve in the left subclavian vein necessitated redirection of the needle site both laterally and cranially. In three or 12% of patients venography showed either subclavian thrombosis or a persistent left superior vena cava and lead insertion was moved to the opposite side. Successful venipuncture and subsequent cannulation of the subclavian vein was achieved with the first or second passage of the needle in 22 or 85% of the 26 patients. Digital cinefluoroscopic venography appears to be both safe and rapid and may facilitate insertion of permanent pacemaker leads into the subclavian vein.
Catheterization, Central Venous↗
Leishmania major: effect of infectious dose on T cell subset development in BALB/c mice.
Leishmania major, the causative agent of cutaneous leishmaniasis in humans, causes either a local cutaneous lesion or a fatal, disseminated infection in different strains of mice. It has been well established that the BALB/c strain of mice is extremely susceptible to L. major infection, due to the preferential development of Th2 responses. It has also been shown, however, that these mice have the potential to develop protective Th1 responses under appropriate conditions. In this paper we confirm earlier reports that BALB/c mice are capable of developing immunity when challenged with low doses of L. major and show that this is dependent on the induction of a Th1 response which can be manipulated with anti-cytokine antibodies in the same way as more conventional experimental infections. Moreover, our data indicate that the development of immunity or susceptibility to L. major in the BALB/c mouse may reflect factors specific to infection such as persistance of the pathogen, infection of APC, or relative cytokine levels rather than simple antigen load, a finding which may be of general significance in infectious disease.
Animals↗
Detection of coronary calcification with electron-beam computed tomography: evaluation of interexamination reproducibility and comparison of three image-acquisition protocols.
The purpose of this investigation was to determine the variability of electron-beam computed tomography (EBCT) measurement of coronary calcification by using two commonly employed image-acquisition protocols and to compare this variability with that of a new image-acquisition protocol. We performed three EBCT scans within 15 minutes on each of 324 consecutive high-risk, asymptomatic subjects participating in an ongoing epidemiologic research investigation. Subjects were divided into three groups: group 1 (n = 175) received two scans with a standard 20-slice, 3 mm slice thickness image-acquisition protocol and a third scan with the new 20-slice, 6 mm slice thickness protocol; group 2 (n = 77) received two scans with a new 6 mm slice thickness image-acquisition protocol and a third scan with a standard 20-slice, 3 mm slice thickness protocol; group 3 (n = 72) received two scans with a 30-slice, 3 mm slice thickness image-acquisition protocol and a third scan with a 20-slice, 6 mm slice thickness protocol. Calcium score, calcium mass estimate, and calcium volume estimate were determined for each scan. We compared retest variability of calcium measurements for each of the three image-acquisition protocols. The variability of the new 6 mm slice thickness protocol was significantly lower than that of either the 20-slice 3 mm slice thickness protocol (p = 0.009) or the 30-slice 3 mm slice thickness protocol (p = 0.02) for measurement of calcium score, mass, or volume. Retest reproducibility for all three image-acquisition protocols was low; however, the 20-slice 6 mm slice thickness protocol gave reproducibility superior to either of the 3 mm slice thickness protocols. Variability of absolute indices increased, and variability of relative indices decreased as the value of these indices increased. EBCT is not sufficiently reproducible to allow serial quantitation of coronary calcium in individual patients over relatively short periods (< 2 years).
Aged↗
Racial differences in coronary calcium prevalence among high-risk adults.
A total of 1,461 asymptomatic high-risk adult subjects were studied with digital subtraction fluoroscopy and conventional cinefluoroscopy to detect coronary calcium. Ethnicity and risk factor data were recorded. No subject had a history or electrocardiographic evidence of prior myocardial infarction. The prevalence of coronary calcium by digital subtraction fluoroscopy was high (58%). Substantial ethnic differences in prevalence were noted: 36% of African American subjects, 60% of Caucasian subjects, and 60% of Asian American subjects had definite radiographic evidence of coronary calcium. The difference in prevalence between African American and other subjects was significant (p < 0.0001) by chi-square test for all 3 races. These differences persisted in the unsubtracted cinefluoroscopic images (p < 0.0001) and after controlling for age, gender, and other risk factors (p = 0.003). After 20 +/- 11 months of follow-up, African Americans had more coronary artery disease events (13%) than Caucasians (6%) or Asian Americans (5%) (p = 0.04). Thus, African Americans have a significantly lower prevalence of coronary calcium than do Caucasians or Asian Americans. Based on the follow-up results, these differences in prevalence are not explained by differences in coronary artery disease risk.
Aged↗
T-cell regulation of macrophage function.
Macrophage function has long been known to be controlled by activated T cells. As the cytokines that control macrophage activation are defined, it is becoming apparent that macrophage 'activation' is more subtle than previously appreciated. Moreover, recent work has shown the dependence of T-cell development on macrophages, from the costimulation of T cells by macrophage surface molecules such as the B7 family, to the modulation by monokines of T-cell phenotype and growth, including IL-1, IL-10, IL-12 and IL-15. Combinations of cytokines and costimulators have revealed some of the processes by which an apparently dichotomous T-cell response can regulate the subtle diversity of the immune response.
Cell Communication↗