Prevalence and risk factors of restrictive spirometry in a cohort of Peruvian adults.

INTRODUCTION: Few studies have described the prevalence of and lung function decline among those with a restrictive spirometric pattern (RSP) in low- and middle-income countries. METHODS: We analyzed prospective data from 3055 adults recruited across four diverse settings in Peru over a 3-year period. Multivariable logistic regression was used to study the association between the presence of restriction and associated risk factors. Multivariable linear mixed models were used to determine lung function decline. RESULTS: Among 3055 participants, the average age was 55.4 years (SD 12.4); 49% were male. Overall prevalence of RSP was 4.7%, ranging from 2.8% (Lima) to 6.9% (Tumbes). The odds of having RSP were higher among those who lived in a rural environment (OR 2.19, 95%CI 1.43-3.37), had a diagnosis of diabetes (OR 1.94, 95%CI 1.10-3.40) and among women (OR 2.09, 95%CI 1.41-3.09). When adjusting for baseline lung function, adults with RSP had accelerated decline in forced expiratory volume in 1 s (FEV1) compared with non-obstructed, non-restricted individuals. DISCUSSION: RSP is prevalent particularly among women and in individuals living in rural settings of Peru. When adjusted for baseline lung function, participants with RSP had accelerated rates of FEV1 decline. Our findings are consistent with the notion that RSP is an insidious inflammatory condition with deleterious effects of lung function decline.

Genetic analysis of peptidoglycan biosynthesis in mycobacteria: characterization of a ddlA mutant of Mycobacterium smegmatis.

A temperature-sensitive mutant of Mycobacterium smegmatis was characterized that contains a mutation in ddlA, the gene encoding D-alanine:D-alanine ligase. Enzymatic assays using recombinant proteins and D-cycloserine susceptibility indicate that the A365V mutation in the SMEG35 DdlA protein causes a reduction in enzymatic activity in vitro and in vivo.

Developmental changes in molecular forms of immunoreactive adrenocorticotropin in the anterior pituitary gland of humans.

In extracts of anterior pituitary tissue obtained at autopsy of fetal, infant, and adult humans, five molecular forms of immunoreactive ACTH (ACTHi) were detected that had apparent molecular weights of approximately 4044, 30-34, 24-28, 16-18, and 4.5 kilodaltons (K). The relative proportion of each molecular form of ACTHi was similar in tissues that were extracted at the time of autopsy and in tissues that were stored frozen (-20 degrees C) for up to 2 years prior to extraction. We found that 40-44K ACTHi comprised a significantly greater proportion of total ACTHi in fetuses (12.3+/-3.5%) than in adults (3.8+/-0.8%); intermediate amounts of this form of ACTHi (8.0+/-4.1%) were found in tissues obtained from infants. On the other hand, the proportion of 4.5 K ACTHi in fetal pituitaries (67 %) was less than that in those of adults (84 %). The ratio of 40-44/30-34K ACTHi was significantly greater (P<0.001) in fetuses (1.46+/-0.12) and infants (1.31+/-0.07) than in adults (0.52+/-0.07). The ontogenetic differences in molecular forms of pituitary ACTHi are thought to reflect alterations in the processing of proopiomelanocortin as a function of human development.

Integrins take partners: cross-talk between integrins and other membrane receptors.

This review discusses an emerging theme in the understanding of how an integrin contributes to the life of a cell. Previously, integrins have been thought to 'go it alone', but it is now appreciated that their duties extend beyond that of being 'sticky' receptors. By interacting in cis with other receptors on the cell membrane, integrins and their partner receptors inteact to form distinct membrane complexes that recruit signalling molecules to each receptor's mutual benefit. Here, Joanna Porter and Nancy Hogg discuss a few of the best characterized of these specialist integrin partnerships.

Sticky and smelly issues: lessons on tumour cell and leucocyte trafficking, gene and immunotherapy of cancer.

The Second Meeting of the British Society for Immunology Tumour Immunology Affinity Group (TIAG) took place at King's College (London, UK) on 17-18 June 1997 and brought together over 100 tumour immunologists from the UK and abroad. In contrast to previous meetings the focus of the meeting was on the role of adhesion in immunosurveillance and tumour dissemination. In addition, recent achievements in the areas of chemokines, cytotoxic T-lymphocyte (CTL) and natural killer (NK) cells, co-stimulation, gene and adoptive immunotherapy were also addressed. The purpose of this report is to outline current trends in tumour immunology.

Adenosine acts by A1 receptors to stimulate release of prolactin from anterior-pituitaries in vitro.

Adenosine has been identified in the anterior pituitary gland and is secreted from cultured folliculostellate (FS) cells. To determine whether adenosine controls the secretion of anterior pituitary hormones in vitro, adenosine was incubated with anterior pituitaries. It stimulated prolactin (PRL) release at the lowest concentration used (10(-10) M); the stimulation peaked at 10(-8) M with a threefold increase in release and declined to minimal stimulation at 10(-4) and 10(-3) M. Follicle-stimulating hormone release was maximally inhibited at 10(-8) M, whereas luteinizing hormone release was not significantly inhibited. Two selective A1 adenosine receptor antagonists (10(-7) or 10(-5) M) had no effect on basal PRL release, but either antagonist completely blocked the response to the most effective concentration of adenosine (10(-8) M). In contrast, a highly specific A2 receptor antagonist (10(-7) or 10(-5) M) had no effect on basal PRL release or the stimulation of PRL release induced by adenosine (10(-8) M). We conclude that adenosine acts to stimulate PRL release in vitro by activating A1 receptors. Since the A1 receptors decrease intracellular-free calcium, this would decrease the activation of nitric oxide synthase in the FS cells, resulting in decreased release of nitric oxide (NO). NO inhibits PRL release by activating guanylate cyclase that synthesizes cGMP from GTP; cGMP concentrations increase in the lactotrophs leading to inhibition of PRL release. In the case of adenosine, NO release from the FS cells decreases, resulting in decreased concentrations of NO in the lactotrophs, consequent decreased cGMP formation, and resultant increased PRL release.

Integrin cross talk: activation of lymphocyte function-associated antigen-1 on human T cells alters alpha4beta1- and alpha5beta1-mediated function.

A regulated order of adhesion events directs leukocytes from the vascular compartment into injured tissues in response to inflammatory stimuli. We show that on human T cells, the interaction of the beta2 integrin leucocyte function-associated antigen-1 (LFA-1) with its ligand intercellular adhesion molecule-1 (ICAM-1) will decrease adhesion mediated by alpha4beta1 and, to a lesser extent, alpha5beta1. Similar inhibition is also seen when T cells are exposed to mAb 24, which stabilizes LFA-1 in an active state after triggering integrin function through divalent cation Mg2+, PdBu, or T cell receptor/ CD3 complex (TCR/CD3) cross-linking. Such cross talk decreases alpha4beta1 integrin-mediated binding of T cells to fibronectin and vascular cell adhesion molecule-1 (VCAM-1). In contrast, ligand occupancy or prolonged activation of beta1 integrin has no effect on LFA-1 adhesion to ICAM-1. We also show that T cell migration across fibronectin, unlike adhesion, is mediated solely by alpha5beta1, and is increased when the alpha4beta1-mediated component of fibronectin adhesion is decreased either by cross talk or the use of alpha4-blocking mAb. The ability of mAb 24 Fab' fragments to induce cross talk without cross-linking LFA-1 suggests signal transduction through the active integrin. These data provide the first direct evidence for cross talk between LFA-1 and beta1 integrins on T cells. Together, these findings imply that activation of LFA-1 on the extravasating T cell will decrease the binding to VCAM-1 while enhancing the subsequent migration on fibronectin. This sequence of events provides a further level of complexity to the coordination of T cell integrins, whose sequential but overlapping roles are essential for transmigration.

The motor neuron degeneration (mnd) gene acts intrinsically in motor neurons and peripheral fibroblasts.

In motor neuron degeneration (mnd/mnd) mice, multiple cell types develop cytopathology and motor neurons degenerate prematurely. Here, to investigate whether the expression of mnd within affected cells is responsible, we analyzed the evolution of cellular pathology in aggregation chimeras containing cells of both mnd/mnd and +/+ genotypes. In addition, skin fibroblasts were maintained in vitro in the absence of other cell types and examined for their disease manifestation. In the chimeras, neuronal genotype was identified by expression of an unrelated transgene. Consistent with an intrinsic action of mnd, the genotype and phenotype of motor neurons correlated perfectly. In addition, abnormal lipopigment accumulation, signifying the disease phenotype, evolved in the cultured fibroblasts. We conclude that neurons and fibroblasts develop pathological abnormalities in response to intrinsic expression of the mnd mutation. Further, as cellular pathology is not attenuated in the chimeric environment, it is unlikely that mnd and its human counterparts, neuronal caroid lipofuscinoses, will be responsive to a treatment strategy involving transplantation of normal cells.

A study of the cellular mechanism by which lead affects catecholamine secretion.

Our purpose was to determine the role of protein kinases in the mediation of the stimulatory effects of lead on catecholamine secretion. Pheochromocytoma cells were incubated for 90 minutes with W-7 (calmodulin antagonist), calphostin C (protein kinase C inhibitor), Sp-cAMPS (cAMP agonist), Rp-cAMPS (cAMP antagonist), forskolin (activator of adenylyl cyclase), or lead nitrate. Catecholamines were measured by liquid chromatography. Lead had a stimulatory effect on catecholamine secretion, whereas W-7 was inhibitory. In the presence of both lead and W-7, the response was markedly decreased compared to that seen with lead alone. Calphostin C suppressed the secretion of catecholamines; however, in the presence of lead and calphostin C, the secretion was similar to that seen with lead alone. Compared to control, Sp-cAMPS was stimulatory. Co-incubation of Sp-cAMPS and lead had a slight synergistic effect. Rp-cAMPS decreased catecholamine secretion, but co-incubation of Rp-cAMPS and lead resulted in a slight reduction compared to lead alone. Forskolin markedly increased the secretion of catecholamines, and co-incubation of lead and forskolin resulted in a synergistic increase. In the absence of calcium, lead had no effect. We conclude that lead stimulates catecholamine secretion by acting through the calcium/calmodulin-dependent protein kinase II system and not through the protein kinase C or protein kinase A system, and requires the presence of calcium for its action.

Plasma proinflammatory cytokine concentrations, Acute Physiology and Chronic Health Evaluation (APACHE) III scores and survival in patients in an intensive care unit.

OBJECTIVE: To more clearly define the relationships between plasma proinflammatory cytokine concentrations, physiologic disturbance, and survival in severely ill patients. DESIGN: Prospective, longitudinal, cohort analytic study. SETTING: Teaching hospital intensive care unit (ICU). PATIENTS: Two hundred fifty-one consecutive nonselected patients admitted to the ICU. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Daily Acute Physiology and Chronic Health Evaluation (APACHE) III scores were calculated from clinical and laboratory data. In concurrent blood samples, plasma concentrations were measured of four proinflammatory cytokines (tumor necrosis factor-[TNF] alpha, interleukin [IL]-1 beta, IL-6, and IL-8), all of which are believed to be of central importance in host proinflammatory and immune responses. Plasma TNF concentrations were increased in 42 patients, plasma IL-1 beta in 15 patients, IL-6 in 194 patients, and IL-8 in 52 patients at presentation. Although admission plasma IL-1 beta, IL-6, and IL-8 concentrations were higher in patients who died in the ICU compared with survivors (n = 33; p < .02, p < .01, p < .02, respectively), only admission plasma IL-8 concentrations were higher in patients with a fatal outcome if all in-hospital deaths were considered (n = 53; p = .05). APACHE III score was the best predictor of mortality (odds ratio 11.41; p = .003). Detection, but not the absolute level, of TNF bioactivity in plasma was a weak independent predictor of death (odds ratio 3.17; p = .02). There was no relationship between bacteremia or presence of the systemic inflammatory response syndrome and plasma cytokine concentrations. Nineteen patients were in the ICU for > or = 10 days, and of these 19 patients, 16 patients had prolonged increases of plasma cytokines. Two patients with persistently increased plasma TNF concentrations died. Otherwise, persistently increased plasma cytokine concentrations had a variable relation to daily APACHE scores and to mortality. CONCLUSIONS: Plasma cytokine concentrations fluctuate in serious illness and have a poor correlation with derangement of whole body physiology in seriously ill patients. Only the presence of bioactive TNF in plasma was an independent predictor of mortality. Daily measurement of plasma proinflammatory cytokine concentrations is unlikely to have clinical application in the ICU setting, except possibly in specific subgroups of patients.

Recombinant human erythropoietin reduces the need for erythrocyte and platelet transfusions in pediatric patients with sarcoma: a randomized, double-blind, placebo-controlled trial.

OBJECTIVE: To evaluate the effect of recombinant human erythropoietin (EPO) and iron supplementation on transfusion requirements in pediatric patients with sarcoma who were receiving chemotherapy, we performed a double-blind, placebo-controlled, randomized trial. METHODS: Twenty-four pediatric patients with malignant solid tumors were randomly assigned to receive either placebo (saline solution) or EPO for a 16-week study period. The starting dose was 150 IU/kg per dose three times a week and was escalated by 50 IU/kg per dose increments monthly until packed red blood cell (PRBC) transfusion independence was achieved or a dosage of 300 IU/kg per dose was reached. Iron supplementation was prescribed at a dose of 6 mg of elemental iron per kilogram daily. The primary study end point was the comparison of PRBC transfusion requirements in the two groups. RESULTS: Of 24 patients, 20 were evaluable for response. The median PRBC transfusion requirement during the 16-week period was 23 ml/kg in EPO-treated patients versus 80 ml/kg in placebo patients (p = 0.02). The median number of single-donor platelet units transfused was zero in the EPO-treated patients compared with four in the placebo group (p = 0.005). No statistical difference in the intensity of bone marrow suppression was seen, as measured by the median number of complete blood cell counts with an absolute neutrophil count of < 1000 cells/microliter. CONCLUSIONS: Treatment with EPO and iron significantly reduces PRBC transfusions in pediatric patients receiving concomitant chemotherapy for malignant sarcomas. A decrease in the number of platelet transfusions was also seen and deserves further study.

Purification and identification of pituitary cytotropic factor.

It has been shown that the pituitary contains a cytotropic factor (CTF) that stimulates the secretion of catecholamines by dopaminergic neurons of the hypothalamus. In the present study, CTF was purified from rat pituitaries and found by means of mass spectrometric analysis to be adenosine. This finding was corroborated by the observations that CTF behaves identically to adenosine when subjected to liquid chromatography, is inactivated and converted to inosine by adenosine deaminase, and is qualitatively and quantitatively indistinguishable from adenosine in its biological activity. It is concluded that pituitary adenosine is a trophic factor for hypothalamic dopaminergic neurons.

Tuberculous bronchoesophageal fistulae in patients infected with the human immunodeficiency virus: three case reports and review.

To our knowledge, < 30 patients with tuberculous bronchoesophageal fistulae have been described in the English-language literature. However, the overall incidence of infection due to Mycobacterium tuberculosis has been increasing during the epidemic of human immunodeficiency virus (HIV) infection. We describe three HIV-infected patients who presented with tuberculous esophagomediastinal fistulae during their initial illness. Fistulous connections appeared to be secondary to mycobacterial mediastinal adenopathy. All fistulae healed with antituberculous therapy and nasogastric feeding, and surgical intervention was not necessary. The combination of mediastinal lymphadenopathy, cough, and retching or vomiting should alert clinicians treating HIV-infected patients to the possibility of tuberculous bronchoesophageal fistulae.