Showing papers by "National Jewish Health published in 2002"

Significant variability in response to inhaled corticosteroids for persistent asthma

Abstract: Background: A clinical model is needed to compare inhaled corticosteroids (ICSs) with respect to efficacy. Objective: The purpose of this investigation was to compare the relative beneficial and systemic effects in a dose-response relationship for 2 ICSs. Methods: A 24-week, parallel, open-label, multicenter trial examined the benefit-risk ratio of 2 ICSs in persistent asthma. Benefit was assessed by improvements in FEV 1 and PC 20 ; risk was assessed by overnight plasma cortisol suppression. Thirty subjects were randomized to either beclomethasone dipropionate (BDP) 168, 672, and 1344 μg/day (n = 15) or fluticasone propionate (FP) 88, 352, and 704 μg/day (n = 15), both administered by means of a metered dose inhaler (MDI) with chlorofluorocarbon propellant via a spacer, in 3 consecutive 6-week intervals; this was followed by 3 weeks of FP dry powder inhaler (DPI) 2000 μg/day. Results: Maximum FEV 1 response occurred with the low dose for FP-MDI and the medium dose for BDP-MDI and was not further increased by treatment with FP-DPI. Near-maximum methacholine PC 20 improvement occurred with the low dose for FP-MDI and the medium dose for BDP-MDI. Both BDP-MDI and FP-MDI caused dose-dependent cortisol suppression. Responsiveness to ICS treatment was found to vary markedly among subjects. Good (>15%) FEV 1 response, in contrast to poor ( 1 /forced vital capacity ratio (0.63 vs 0.73) before treatment. Excellent (>3 doubling dilutions) improvement in PC 20 , in contrast to poor ( Conclusions: Near-maximal FEV 1 and PC 20 effects occurred with low-medium dose for both ICSs in the subjects studied. High-dose ICS therapy did not significantly increase the efficacy measures that were evaluated, but it did increase the systemic effect measure, overnight cortisol secretion. Significant intersubject variability in response occurred with both ICSs. It is possible that higher doses of ICSs are necessary to manage more severe patients or to achieve goals of therapy not evaluated in this study, such as prevention of asthma exacerbations. (J Allergy Clin Immunol 2002;109:410-8.)

Therapeutic Drug Monitoring in the Treatment of Tuberculosis

Abstract: Therapeutic drug monitoring (TDM) is a standard clinical technique used for many disease states, including many infectious diseases. As for these other conditions, the use of TDM in the setting of tuberculosis (TB) allows the clinician to make informed decisions regarding the timely adjustment of drug therapy. Such adjustments may not be required for otherwise healthy individuals who are responding to the standard, four-drug TB regimens. However, some patients are slow to respond to treatment, have drug-resistant TB, are at risk of drug-drug interactions or have concurrent disease states that significantly complicate the clinical situation. Such patients may benefit from TDM and early interventions may preclude the development of further drug resistance. It is not possible to collect multiple blood samples in the clinical setting for logistical and financial reasons. Therefore, one typically is limited to one or two time points. When only one sample can be obtained, the 2-hour post-dose concentrations of isoniazid, rifampin, pyrazinamide and ethambutol are usually most informative. Unfortunately, low 2-hour values do not distinguish between delayed absorption (late peak, close to normal range) and malabsorption (low concentrations at all time points). A second sample, often collected at 6-hour post-dose, can differentiate between these two scenarios. The second time point can also provide some information about clearance and half-life, assuming that drug absorption was nearly completed by 2 hours. TDM requires that samples are promptly centrifuged, and that the serum is promptly harvested and frozen. Isoniazid and ethionamide, in particular, are not stable in human serum at room temperature. Rifampin is stable for more than 6 hours under these conditions. During TB treatment, isoniazid causes the greatest early reduction in organisms and is considered to be one of the two most important TB drugs, along with rifampin. Although isoniazid is highly active against TB, low isoniazid concentrations were associated with poorer clinical and bacteriological outcomes in US Public Health Services (USPHS) TB Trial 22. Several earlier trials showed a clear dose-response for rifampin and pyrazinamide, so low concentrations for those two drugs also may correlate with poorer treatment outcomes. At least in USPHS TB Trial 22, the rifampin pharmacokinetic parameters were not predictive of the outcome variables. In contrast, low concentrations of unbound rifapentine may have been responsible, in part, for the worse-than-anticipated performance of this drug in clinical trials. The 'second-line' TB drugs, including p-aminosalicylic acid, cycloserine and ethionamide, are relatively weak TB drugs. Under the best conditions, treatment with these drugs takes over 2 years, as opposed to 6 to 9 months with isoniazid- and rifampin-containing regimens. Therefore, TB centres such as National Jewish Medical and Research Center in Denver, CO, USA, measure serum concentrations of the 'second-line' TB drugs early in the course of treatment. That way, poor drug absorption can be dealt with in a timely manner. This helps to minimise the time that patients are sputum smear- and culture-positive with multidrug-resistant TB, and may prevent the need for even longer treatment durations. Patients with HIV are at particular risk for drug-drug interactions. Because the published guidelines typically reflect interactions only between two drugs, these guidelines are of limited value when the patient is treated with three or more interacting drugs. Under such complicated circumstances, TDM often is the best available tool for sorting out these interactions and placing the patient the necessary doses that they require. TDM is only one part of the care of patients with TB. In isolation, it is of limited value. However, combined with clinical and bacteriological data, it can be a decisive tool, allowing the clinician to successfully treat even the most complicated TB patients.

Cost of atopic dermatitis and eczema in the United States

Abstract: Background: Atopic dermatitis/eczema (AD/E) is a common disease. Few studies have attempted to quantify the cost to third-party payers. Objective: Our purpose was to identify the annual cost of medical services and prescription drugs for the treatment of AD/E to private insurance and Medicaid payers in the United States. Methods: We used a retrospective study design employing claims data from 1997 and 1998 from a private insurer and a state Medicaid program to analyze costs incurred. Beneficiaries were considered to have AD/E if they had at least one claim in 1997 with a primary or secondary listing of 1 of 3 diagnosis codes: 691.8, other atopic dermatitis and related conditions; 692.9, contact dermatitis and other eczema when no cause is specified; or 373.3, noninfectious dermatoses of eyelid. Patients who did not meet the diagnosis criteria served as a control group in each payer for comparisons of expenditures with the AD/E group. Results: Disease prevalence was 2.4% (private insurer) to 2.6% (Medicaid) of all eligible beneficiaries, and 3.5% to 4.1% of patients submitted at least one health care claim during the study period. Medicaid-insured patients used outpatient hospital visits and hospitalizations at a greater rate than did privately insured patients; neither used emergency departments extensively. The third-party payer cost of illness for AD/E ranged from $0.9 billion to $3.8 billion when projected across the total number of persons younger than 65 years insured by private insurers and Medicaid in the United States. More than one fourth of all health care costs for patients with AD/E may be attributed to AD/E and co-morbid conditions. Conclusions: Annual costs of AD/E are similar to those of other diseases such as emphysema, psoriasis, and epilepsy. Patients incur significant costs associated with AD/E and co-morbid conditions. (J Am Acad Dermatol 2002;46:361-70.)

Cre/loxP recombination system and gene targeting.

Abstract: Embryonic stem (ES) cell technology has clearly established itself as a powerful technique for the examination of gene function in vivo. The vast majority of gene-targeting experiments to date have been designed simply to inactivate the function of the gene of interest by the targeted insertion of a selectable marker into the ES genome. Homologous recombinant ES cells are used without further modification for the generation of mice that bear a permanently modified allele in all cells from the onset of development. In contrast to this “conventional” gene-targeting strategy, in recent years, the use of the Cre/loxP recombination system in conjunction with gene targeting has greatly expanded the versatility and avenues with which biologic questions can be addressed in the mouse. In addition to the generation of subtle mutations, this system allows for a number of other genotypic options in ES cells or mice by strategically incorporating Cre recombinase recognition (loxP) sites into the genome and the subsequent expression of recombinase in vitro or in vivo. In particular, when Cre is expressed in mice harboring a loxP-containing target gene, the desired gene modification can be restricted to certain cell types or developmental stages of the mouse (conditional gene targeting) depending on the tissue specificity and timing of recombinase expression. There is no definitive rule to decide whether, for a particular experiment, conventional or conditional gene targeting is more appropriate since this depends on the specific biologic question and the peculiarities of the gene studied.

Early B-Cell Factor, E2A, and Pax-5 Cooperate To Activate the Early B Cell-Specific mb-1 Promoter

Abstract: Previous studies have suggested that the early-B-cell-specific mb-1(Igalpha) promoter is regulated by EBF and Pax-5. Here, we used in vivo footprinting assays to detect occupation of binding sites in endogenous mb-1 promoters at various stages of B-cell differentiation. In addition to EBF and Pax-5 binding sites, we detected occupancy of a consensus binding site for E2A proteins (E box) in pre-B cells. EBF and E box sites are crucial for promoter function in transfected pre-B cells, and EBF and E2A proteins synergistically activated the promoter in transfected HeLa cells. Other data suggest that EBF and E box sites are less important for promoter function at later stages of differentiation, whereas binding sites for Pax-5 (and its Ets ternary complex partners) are required for promoter function in all mb-1-expressing cells. Using DNA microarrays, we found that expression of endogenous mb-1 transcripts correlates most closely with EBF expression and negatively with Id1, an inhibitor of E2A protein function, further linking regulation of the mb-1 gene with EBF and E2A. Together, our studies demonstrate the complexity of factors regulating tissue-specific transcription and support the concept that EBF, E2A, and Pax-5 cooperate to activate target genes in early B-cell development.

Selective suppression of neutrophil accumulation in ongoing pulmonary inflammation by systemic inhibition of p38 mitogen-activated protein kinase.

Abstract: The p38 mitogen-activated protein kinase (MAPK) signaling pathway regulates a wide range of inflammatory responses in many different cells. Inhibition of p38 MAPK before exposing a cell to stress stimuli has profound anti-inflammatory effects, but little is known about the effects of p38 MAPK inhibition on ongoing inflammatory responses. LPS-induced activation of p38 MAPK in human neutrophils was inhibited by poststimulation exposure to a p38 MAPK inhibitor (M39). Release of TNF-alpha, macrophage-inflammatory protein (MIP)-2 (MIP-1beta), and IL-8 by LPS-stimulated neutrophils was also reduced by poststimulation p38 MAPK inhibition. In contrast, release of monocyte chemoattractant protein-1 was found to be p38 MAPK independent. Ongoing chemotaxis toward IL-8 was eliminated by p38 MAPK inhibition, although the rate of nondirectional movement was not reduced. A murine model of acute LPS-induced lung inflammation was used to study the effect of p38 MAPK inhibition in ongoing pulmonary inflammation. Initial pulmonary cell responses occur within 4 h of stimulation in this model, so M39 was administered 4 h or 12 h after exposure of the animals to aerosolized LPS to avoid inhibition of cytokine release. Quantities of TNF-alpha, MIP-2, KC, or monocyte chemoattractant protein-1 recovered from bronchial alveolar lavage or serum were not changed. Recruitment of neutrophils, but not other leukocytes, to the airspaces was significantly reduced. Together, these data demonstrate the selective reduction of LPS-induced neutrophil recruitment to the airspaces, independent of suppression of other inflammatory responses. These findings support the feasibility of p38 MAPK inhibition as a selective intervention to reduce neutrophilic inflammation.

Clinical and radiologic manifestations of hypersensitivity pneumonitis.

Abstract: Hypersensitivity pneumonitis (HP) is an inflammatory interstitial lung disease caused by recurring exposure to a variety of occupational and environmental antigens. It features widely variable clinical, radiologic, and histopathologic findings. Because the clinical findings of HP mimic multiple other diseases, a high degree of clinical suspicion and a thorough occupational and environmental history are essential for accurate diagnosis. There is no single pathognomonic feature for HP; rather, diagnosis relies on a constellation of clinical, radiologic, and pathologic findings. The radiologic manifestations, particularly the high-resolution computed tomography (HRCT) pattern, provide important clues and frequently point clinicians towards the correct diagnosis. The HRCT findings in HP may include ground-glass opacification, centrilobular nodules, air trapping (mosaic pattern), fibrosis, emphysema, or more frequently a combination of these. The combination of a mosaic pattern with ground-glass opacification and centrilobular nodules is particularly suggestive of the diagnosis. The best long-term prognosis is achieved with early diagnosis and removal from exposure.

MHC class I-dependent Vγ4+ pulmonary T cells regulate αβ T cell-independent airway responsiveness

Abstract: Mice exposed to aerosolized ovalbumin (OVA) develop increased airway responsiveness when deficient in gammadelta T cells. This finding suggests that gammadelta T cells function as negative regulators. The regulatory influence of gammadelta T cells is evident after OVA-sensitization and -challenge, and after OVA-challenge alone, but not in untreated mice. With aerosolized Abs to target pulmonary T cells, we now demonstrate that negative regulation of airway responsiveness is mediated by a small subpopulation of pulmonary gammadelta T cells. These cells express Vgamma4 and depend in their function on the presence of IFN-gamma and MHC class I. Moreover, their effect can be demonstrated in the absence of alphabeta T cells. This novel type of negative regulation seems to precede the development of the adaptive, antigen-specific allergic response.

Immunomodulatory Effects of Melatonin in Asthma

Abstract: Patients with nocturnal asthma demonstrate circadian variations in airway inflammation. We hypothesized that melatonin, a circadian rhythm regulator, modulates circadian inflammatory variations in asthma. The effect of melatonin stimulation on peripheral blood mononuclear cell cytokine production was evaluated at 4:00 P.M. and 4:00 A.M. in normal control subjects, patients with nocturnal asthma, and patients with non-nocturnal asthma. Melatonin was proinflammatory, causing significantly increased production of interleukin-1, interleukin-6, and tumor necrosis factor-alpha at 4:00 P.M. and 4:00 A.M. in all subject groups (range, 12.8 +/- 3.3 to 131.72 +/- 16.4%, p 0.05, both cases). At 4:00 P.M., the cytokine response to melatonin of patients with nocturnal asthma was greater than that of control subjects or patients with non-nocturnal asthma and did not change significantly at 4:00 A.M. At 4:00 P.M., the cytokine response of patients with non-nocturnal asthma was less than that of patients with nocturnal asthma and rose significantly at 4:00 A.M. (p = 0.0001, all comparisons). Melatonin is proinflammatory in both patients with asthma and healthy subjects. Patients with nocturnal asthma demonstrate the largest daytime cytokine response and cannot be further stimulated at 4:00 A.M., suggesting chronic overstimulation in vivo. These results suggest differential immunomodulatory effects of melatonin based on asthma clinical phenotype and may indicate an adverse effect of exogenous melatonin in asthma.

The role of the macrophage in apoptosis: hunter, gatherer, and regulator.

Abstract: Clearance of cellular corpses is a critical feature of apoptosis in vivo during development, tissue homeostasis, and resolution of inflammation. As the professional phagocytes of the body, macrophages play a key role in this process. By recognizing emerging signals using several different receptors, macrophages engulf apoptotic cells swiftly and efficiently. In addition, the binding of apoptotic cells profoundly down-regulates the ability of the macrophage to produce inflammatory mediators by inducing the release of antiinflammatory mediators. Finally, macrophages may actually induce cell death in specific cells during embryogenesis.Abnormalities of apoptotic cell clearance may contribute to the pathogenesis of chronic inflammatory diseases, including those of autoimmune etiology. It is also possible that certain malignant tumor cells co-opt the mechanisms for apoptotic cell clearance to avoid immune surveillance by subverting macrophage and dendritic cell responses.

Regulation of Airway Hyperresponsiveness by Calcitonin Gene-related Peptide in Allergen Sensitized and Challenged Mice

Abstract: Sensory neuropeptides are localized to airway nerves and endocrine cells in both human and animal species and may participate in the development of airway inflammation and hyperresponsiveness (AHR). We used a mouse model to identify the changes that occur in calcitonin gene-related peptide (CGRP) expression in the airways during development of allergic inflammation and to investigate the potential role of this neuropeptide in modulating AHR. In sensitized mice, allergen challenge induced eosinophilic airway inflammation and AHR and resulted in considerable depletion of CGRP in neuroepithelial bodies and submucosal nerve plexuses without altering the overall density of airway nerve fibers. This depletion was subsequent to the development of airway inflammation and was prevented by anti-very late antigen-4 and anti-interleukin-5 treatments, which blocked airway eosinophilia and abolished AHR. Administration of CGRP to sensitized and challenged mice resulted in the normalization of airway responsiveness to inhaled methacholine, an effect that was neutralized by the receptor antagonist CGRP(8-37). These data demonstrate that replacement of CGRP following its depletion in allergic mice can reverse the changes in airway responsiveness and suggest that CGRP may have potential for the treatment of allergic AHR.

The failure of interleukin-10-deficient mice to develop airway hyperresponsiveness is overcome by respiratory syncytial virus infection in allergen-sensitized/challenged mice

Abstract: Interleukin-10–deficient mice develop a robust pulmonary inflammatory response but no airway hyperresponsiveness (AHR) to inhaled methacholine (MCh) following allergen sensitization and challenge. In the present study, we investigated the effect of respiratory syncytial virus (RSV) infection on AHR and pulmonary inflammation in allergic IL-10 − / − mice. Unlike littermate control mice, RSV-infected or ovalbumin (OVA)-sensitized/challenged IL-10 − / − mice failed to develop significant AHR. In contrast, sensitized/challenged IL-10 − / − mice infected with RSV did develop AHR accompanied by increased eosinophil numbers, both in bronchoalveolar lavage (BAL) and pulmonary tissue, and mucin production in airway epithelium. The cytokine profile in OVA-sensitized/challenged IL-10 − / − mice was skewed toward a Th1 response but after RSV infection, this response was more of a Th2 type, with increased IL-5 levels in the BAL. Studies with an RSV mutant that lacks the G and SH genes showed equal enhancement of the A...

Bradykinin antagonist dimer, CU201, inhibits the growth of human lung cancer cell lines by a “biased agonist” mechanism

Abstract: All small cell (SCLCs) and many non-small cell lung cancers (NSCLCs) have neuroendocrine features including production of neuropeptides and cell surface receptors creating autocrine and paracrine growth loops. Neuropeptides bind to a family of 7-transmembrane receptors and activate heterotrimeric G proteins consisting of Gαq and Gα12,13. Substance P derivatives (SPDs) induced apoptosis and inhibited growth of lung cancer cells by discoordinately inhibiting Gαq and stimulating Gα12,13. However, these SPDs had low potency and short half-lives. In this report we show that a bradykinin antagonist dimer, CU201, inhibited the growth of SCLC and NSCLC cell lines with or without multidrug-resistant proteins and was 10-fold more potent with a longer plasma half-life than SPDs. Bradykinin agonists in either monomeric or dimeric form and monomeric bradykinin antagonist have no effect on lung cancer cell growth. The dimeric linking moiety of the two molecules was created, requiring a sufficient number of carbon chains to provide critical spacing between the two antagonists. CU201 inhibited intracellular Ca2+ release in response to bradykinin, indicating blockage of the Gαq signal, and stimulated c-Jun kinases, indicating stimulation of the Gα12,13 pathway. CU201-induced apoptosis was preceded by unique changes in apparent nuclear DNA binding and by c-Jun kinase and caspase-3 activation. At the concentration at which CU201 inhibited the growth of the cancer cells, it had no effect on the growth of normal lung cells in vitro. CU201 and similar compounds offer hope of becoming a new form of targeted therapy for tumors with neuroendocrine properties.

Exposure misclassification and threshold concentrations in time series analyses of air pollution health effects.

Abstract: Linear, no-threshold relationships are typically reported for time series studies of air pollution and mortality. Since regulatory standards and economic valuations typically assume some threshold level, we evaluated the fundamental question of the impact of exposure misclassification on the persistence of underlying personal-level thresholds when personal data are aggregated to the population level in the assessment of exposure-response relationships. As an example, we measured personal exposures to two particle metrics, PM 2 . 5 and sulfate (SO 2 - 4 ), for a sample of lung disease patients and compared these with exposures estimated from ambient measurements. Previous work has shown that ambient:personal correlations for PM 2 . 5 are much lower than for SO 2 - 4 , suggesting that ambient PM 2 . 5 measurements misclassify exposures to PM 2 . 5 . We then developed a method by which the measured:estimated exposure relationships for these patients were used to simulate personal exposures for a larger population and then to estimate individual-level mortality risks under different threshold assumptions. These individual risks were combined to obtain the population risk of death, thereby exhibiting the prominence (and the value) of the threshold in the relationship between risk and estimated exposure. Our results indicated that for poorly classified exposures (PM 2 . 5 in this example) population-level thresholds were apparent at lower ambient concentrations than specified common personal thresholds, while for well-classified exposures (e.g., SO 2 - 4 ), the apparent thresholds were similar to these underlying personal thresholds. These results demonstrate that surrogate metrics that are not highly correlated with personal exposures obscure the presence of thresholds in epidemiological studies of larger populations, while exposure indicators that are highly correlated with personal exposures can accurately reflect underlying personal thresholds.

Cell surface expression of the HIV-1 envelope glycoproteins is directed from intracellular CTLA-4-containing regulated secretory granules

Abstract: The envelope glycoprotein (Env) of HIV-1 is incorporated into virions that bud from the cell surface of infected T cells. With immunofluorescence microscopy and subcellular membrane fractionation techniques, the intracellular fate of Env in the secretory pathway of HIV-1-infected T cells was evaluated. Rather than trafficking constitutively from the Golgi to the cell surface, Env is directed to intracellular CTLA-4-containing granules, whose recruitment to the cell surface is regulated. The use of the regulated pathway for intracellular Env storage before virion assembly holds implications for the staging of Env exposure at the cell surface of infected cells and of coordinating HIV virion assembly.

Influence of lipopolysaccharide exposure on airway function and allergic responses in developing mice.

Abstract: Exposure to endotoxin has been associated with an exacerbation of asthmatic responses in humans and animal models. However, recent evidence suggests that microbial exposure in early life may protect from the development of asthma and atopy. In this study, we sought to evaluate the effects of lipopolysaccaride (LPS) on airway function in developing mice. In addition, we evaluated the influence of LPS on subsequent allergen sensitization and challenge. Under light anesthesia, 2–3-week-old Balb/c mice received a single intranasal instillation of LPS or sterile physiologic saline. Measurements of airway function were obtained in unrestrained animals, using whole-body plethysmography. Airway responsiveness was expressed in terms of % enhanced pause (Penh) increase from baseline to aerosolized methacholine (Mch). In additional studies, we assessed the functional and cellular responses to ovalbumin sensitization and challenge following prior exposure to LPS. We found that exposure to LPS induced transient airway hyperresponsiveness to Mch. These functional changes were associated with the recruitment of neutrophils and lymphocytes into the bronchoalveolar lavage (BAL) fluid. Airway responsiveness after allergen sensitization and challenge was decreased by prior exposure to LPS. The analysis of BAL cells and cytokines (interferon-γ and interleukin-4) did not reveal alterations in the overall Th1/Th2 balance. Our findings suggest that LPS leads to airway hyperresponsiveness in developing mice, and may protect against the development of allergen-driven airway dysfunction. Pediatr Pulmonol. 2002; 34:267–277. © 2002 Wiley-Liss, Inc.

Material asthma status alters relation of infant feeding to asthma childhood

Abstract: The relation of infant feeding to childhood asthma is controversial. This study tested the hypothesis that maternal asthma alters the relation of breastfeeding to childhood asthma. Questionnaires were completed at age 6, 9 or 11 years by parents of 1043 children enrolled at birth. Active MD asthma was defined as a physician diagnosis of asthma plus asthma symptoms reported on one of the questionnaires. Duration of exclusive breastfeeding, categorized as never, <4 months, or≥_4 months, was based on prospective physician reports or questionnaires completed at 18 months. The relationship between breastfeeding and asthma differed by maternal asthma status. For children with maternal asthma, the percent developing active MD asthma increased significantly with longer duration of exclusive breastfeeding. Odds of developing asthma among these children were significantly elevated (OR: 5.7,CI; 2.8–11.5), after adjusting for confounders. This association of longer exclusive breastfeeding with increased risk of reported asthma among children with asthmatic mothers may be biologically based, or may reflect reporting biases.

Hematopoietic Development of ES Cells in Culture

Abstract: Under appropriate culture conditions, ES cells will spontaneously differentiate and generate colonies known as embryoid bodies (EBs) that contain precursors of multiple lineages, including those of the hematopoietic system (1-7). Previous studies have demonstrated that the molecular events leading to hematopoietic commitment, as well as the kinetics of lineage development within the EBs, parallel that found in the normal mouse embryo (5). More recent studies (8-11) have supported these earlier findings and have provided evidence that hematopoietic development within EBs can be divided into the following distinct stages: hemangioblast, primitive and early definitive, and multilineage definitive. These stages most closely correspond to the preblood island, the early-mid yolk sac, and the late yolk sac-early fetal-liver hematopoietic programs within the mouse embryo.

Ofloxacin population pharmacokinetics in patients with tuberculosis

Abstract: CADRE : Deux hopitaux de tuberculose aux Etats-Unis. OBJECTIF : Determiner les parametres de pharmacocinetique de population (PK) de l'ofloxacine apres doses orales multiples. SCHEMA : Ont participe 73 patients atteints de tuberculose (TB). Les sujets ont recu des doses multiples d'ofloxacine comme element de leur traitement. Ils ont recu egalement des medications concomitantes basees sur les donnees de sensibilite in vitro. Les echantillons de serum ont ete preleves pendant une duree de 10 heures et examines grâce a une technique validee de chromatographie liquide a haute performance (HPLC). Les donnees concentration-temps ont ete analysees en utilisant la methode de population. RESULTATS: Les concentrations d'ofloxacine augmentent de facon lineaire avec l'augmentation des doses orales. Des retards d'absorption ont ete observes au moins une fois chez 29% des patients. L'elimination de l'ofloxacine decroit en cas de deficience de la fonction renale et d'augmentation de l'âge. Des doses quotidiennes plus elevees ont ete bien tolerees, et s'averent porter au maximum le ratio concentration de pointe/ concentration inhibitrice minimale (Cmax/CMI). CONCLUSION : Les parametres PK de l'ofloxacine sont comparables a ceux publies anterieurement pour d'autres populations de patients. Des doses quotidiennes plus elevees peuvent presenter des avantages pharmacodynamiques pour le traitement de la TB.

Some properties of T cells in animals.

Abstract: T cells in animals have several unexpected properties. The work described here concerns two of these properties. The first property to be discussed concerns the fact that T cells divide in the apparent absence of antigen when transferred to T cell deficient mice. The second investigates the finding that memory T cells contain very large amounts of mRNA for certain chemokines. These two phenomena will be discussed in separate sections below.

Hin-2 nucleic acid molecules, proteins, antibodies, homologues, receptors, and uses thereof

Abstract: Disclosed are HIN-2 proteins and homologues, nucleic acid molecules encoding HIN-2 proteins and homologues, antibodies that selectively bind to HIN-2 proteins and homologues; compositions comprising HIN-2 proteins and homologues, nucleic acid molecules, or antibodies; and methods of making and using HIN-2 proteins and homologues, nucleic acid molecules, and antibodies. Also disclosed are receptors and ligands that selectively bind to HIN-2, as well as fragments and homologues of such receptors, agonists and antagonists of such receptors, and methods of using such receptors to regulate the biological activity mediated by HIN-2.

Method and composition for increasing CD4+ T lymphocyte immune responsiveness

Abstract: A method and composition to restore and/or increase immune responsiveness in CD4 + T lymphocytes that display a loss of immune function (i.e., immune unresponsiveness) after CD4 is ligated by human immunodeficiency virus (HIV) gp120 are disclosed. Such a method and composition are useful for restoring immune surveillance and host defense capabilities to an HIV-infected patient, for causing HIV-infected T lymphocytes to become targets of the immune system, and for increasing the survival and development of CD4 + T lymphocytes in HIV-infected patients so the immune system can be reconstituted. Also disclosed are a method to identify putative regulatory compounds useful in a composition of the invention and a method to identify suitable candidate patients for treatment by a method of the invention.

Efficient Total Synthesis of 5-Oxo-6(E),8(Z),11(Z),14(Z)-eicosatetraenoic Acid (5-Oxo-ETE), a Potent Proinflammatory Autacoid.

Abstract: The title eicosanoid was prepared in good overall yield via a convergent aldol strategy that obviates the need for HPLC separation of olefinic isomers.